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History of Exercise Physiology brings together leading authorities in the profession to present this first-of-its-kind resource that is certain to become an essential reference for exercise physiology researchers and practitioners. The contributing authors were selected based on their significant contributions to the field, including many examples in which they were part of seminal research. The result of this vast undertaking is the most comprehensive resource on exercise physiology research ever compiled.
Exercise physiology research is ongoing, and its knowledge base is stronger than ever. But today’s scholars owe much of their success to their predecessors. The contributors to this book believe it is essential for exercise physiologists to understand the past when approaching the future, and they have compiled this reference to aid in that process. The text includes the following features:
• A broad scope of the primary ideas and work done in exercise physiology from antiquity to the present
• A review of early contributions to exercise physiology made by Scandinavian scientists, the Harvard Fatigue Laboratory, German laboratories, and the Copenhagen Muscle Research Centre
• The incorporation of molecular biology into exercise biology and physiology research that paved the way for exercise physiology
• An explanation of the relationship between genomics, genetics, and exercise biology
• An integrative view of the autonomic nervous system in exercise
• An examination of central and peripheral influences on the cardiovascular system
• An in-depth investigation and analysis of how exercise influences the body’s primary systems
• A table in most chapters highlighting the significant research milestones
Well illustrated with figures and photos, History of Exercise Physiology helps readers understand the research findings and meet the most prominent professionals in the field. From studying great thinkers of antiquity and cutting-edge work done by pioneers at research institutions, to exploring the inner workings of all the body’s systems, researchers will gain a precise understanding of what happens when human bodies move—and who influenced and furthered that understanding.
Part I: Antiquity, Early Laboratories, and Entering the 21st Century
Chapter 1.
Antiquity to the Early Years of the 20th Century
Charles M. Tipton
Chapter 2.
Influence of Scandinavian Scientists in Exercise Physiology
P.-O. Åstrand
Chapter 3.
Contributions From the Harvard Fatigue Laboratory
Charles M. Tipton and G. Edgar Folk, Jr.
Chapter 4.
Contributions From German Laboratories
Wildor Hollmann
Chapter 5.
PhD Specialization and Incorporating Molecular Biology Into Exercise Biology and Physiology Research
P. Darrell Neufer and Charles M. Tipton
Chapter 6.
Contributions From Copenhagen Muscle Research Centre
Peter B. Raven, Michael Kjaer, and Ylva Hellsten
Chapter 7.
Genomics, Genetics, and Exercise Biology
Claude Bouchard and Robert M. Malina
Part II: A Century of Discoveries (1910-2010)
Chapter 8.
The Sensorimotor Nervous System
Phillip F. Gardiner and V. Reggie Edgerton
Chapter 9.
The Autonomic Nervous System in Exercise: An Integrative View
Katarina T. Borer
Chapter 10.
The Respiratory System
Brian J. Whipp and Susan A. Ward
Chapter 11.
The Oxygen Transport System: Maximal Oxygen Uptake
Peter G. Snell, Benjamin D. Levine, and Jere H. Mitchell
Chapter 12.
The Cardiovascular System: Central Influences
Charles M. Tipton
Chapter 13.
The Cardiovascular System: Peripheral Circulation
Grant H. Simmons, Bruno Roseguini, Jaume Padilla, and M. Harold Laughlin
Chapter 14.
The Muscular System: Muscle Plasticity
Kenneth M. Baldwin, and Fadia Haddad
Chapter 15.
The Endocrine System: Actions of Select Hormones
Peter A. Farrell, and Henrik Galbo
Chapter 16.
The Gastrointestinal System
G. Patrick Lambert
Chapter 17.
Metabolic Systems: Substrate Utilization
Andrew R. Coggan
Chapter 18.
Metabolic Systems: The Formation and Utilization of Lactate
George A. Brooks
Chapter 19.
The Temperature Regulatory System
Suzanne Schneider and Pope Moseley
Chapter 20.
The Renal System
Jacques R. Poortmans and Edward J. Zambraski
Chapter 21.
The Immune System
Roy J. Shephard
Chapter 22.
The Skeletal System
Sarah L. Manske, Grant C. Goulet, and Ronald F. Zernicke
Charles M. Tipton, PhD, is an active emeritus professor of physiology at the University of Arizona. He received a PhD in physiology from the University of Illinois in 1962. He retired after 35 years of directing exercise physiology laboratories that investigated physiological mechanisms associated with the effects of acute and chronic exercise. He is recognized as a leading authority of exercise physiology.
Professor Tipton taught physiology and exercise physiology courses to undergraduate, graduate, medical, and professional students at the University of Iowa and the University of Arizona and mentored 21 PhD students at these locations. He has written, coauthored, or edited six books, 33 chapters and proceedings, and approximately 18 articles. In addition, he served as editor in chief of Medicine and Science in Sports and Exercise and was an associate editor of the Journal of Applied Physiology for nearly a decade. He has been both member and chair of select National Institutes of Health (NIH) study sections and of several American College of Sports Medicine (ACSM) research committees. A past president of ACSM, Professor Tipton has been appointed to many microgravity advisory committees that include the NASA Review Panel on Space Medicine and Countermeasures, the External Advisory Committee for the National Space Biomedical Research Institute (NSBRI), and the Congress-directed National Research Council Steering Committee on Recapturing a Future for Space Exploration. For his research and professional endeavors, he received Honor Awards from the ACSM and from the Environmental and Exercise Physiology Section of the American Physiological Society. Fellow Tipton also received the Clark W. Hetherington Award from the National Kinesiology Academy.
“This book is the first to focus on the history of exercise physiology. The content is rich and well supported by the most pertinent findings from the field, both historical and current.”
--Doody’s Book Review (5-star review)
“It packs in tables, charts, bibliographic references, and plenty of detail and it’s filled with important insights for any who want to better understand the technical relationship between exercise and the body’s functioning, making it a pick for sports and health collections alike.”
--The Midwest Book Review
Early German roots of exercise physiology
In 1719, Friedrich Hoffmann (1660-1742), a physician from Halle, obtained his doctoral degree with experimental investigations about the effects of physical exercise on the human cardiovascular system and on digestion.
Exercise Physiology Research in Germany 1700 to 1910
In 1719, Friedrich Hoffmann (1660-1742), a physician from Halle, obtained his doctoral degree with experimental investigations about the effects of physical exercise on the human cardiovascular system and on digestion. In 1796, the physician Christoph Wilhelm Hufeland (1762-1836) published a textbook about the significance of different types of physical exercise for human health and life expectancy (66).
In the 19th century, the physiologist Emil Dubois-Reymond (1818-1896) studied the role of gymnastics in the human body (21, 22). The physician and chemist Max von Pettenkofer (1818-1901) detected the existence of creatine in the skeletal muscle and described a strengthening of the circulatory system in connection with physical training (111).
The first ergometer in the present-day sense of the word was developed by the German physician Speck in 1883. When using this cranked ergometer, the test person was in the standing position (figure 4.1). The crank friction could be modified by pulling up a screw. Speck determined the resistance with weights hung on the crank. The number of revolutions could be determined by noting the number of turns of twine wound up around the crank axle. The exhaled air was collected in a double spirometer and the postexperimental air composition was determined, thus enabling conclusions to be drawn about the individual performance reaction (2, 125).
In 1887 the Viennese physician Friedrich Gaertner (1847-1917) presented a mechanically braked ergometer, based on Speck's equipment that could measure the work performed in kilogram-meter. This device, called the ergostat, later went into standard production (112).
The first heyday of exercise physiology began with the veterinarian Nathan Zuntz (1847-1920) in Berlin (figure 4.2), who developed the first motor-driven treadmill in 1889 (figure 4.3). His work is described in chapter 1 (142).
Of substantial significance in the application of aspects of exercise physiology in medicine were Adolf Theophil Ferdinand Hueppe (1852-1938) and Ferdinand August Schmidt (1852-1929). In 1899 Hueppe wrote a fundamental work titled A Textbook of Hygiene that covered the whole of the exercise physiology discipline of those days. This was followed by the work titled Hygiene of Physical Exercises, published in 1911. In 1893 Schmidt published the book Physical Exercise According to the Exercise Value, which deals with an overview of suitable physical exercises for different ages (122, 123).
From 1904 to 1906 Kuelbs examined the influence of physical training on the internal organs, particularly the heart. He took two dogs from the same litter and trained one of them 5 times/wk for about 2 h on a treadmill, which he had taken over from Zuntz; the other dog had a normal, everyday life. After 1 yr both animals were killed and all internal organs were measured and examined. Although both dogs had more or less the same body weight, the heart of the dog trained on the treadmill was approximately 33% larger than that of the untrained dog. Similar differences were also manifest in the weights of the liver, kidneys, adrenal glands, spleen, and lungs (77).
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Over the subsequent decades Arthur Mallwitz (1880-1968) became the most important promoter for German, and later international, sports medicine. He obtained his doctor's degree at Halle University (Saale) in 1908 with what is presumed to be the first ever dissertation in sports medicine. In his dissertation, titled Maximum Performances With Special Consideration of Sports Done at the Olympic Games, Mallwitz considered, above all, the investigations of Hueppe and Schmidt as well as those of Zuntz and his school. In 1910 a comprehensive book about exercise physiology in connection with numerous kinds of sports was edited by Weissbein (141).
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The first ergometer was developed by Speck in 1883. Gaertner produced it in series.
Hollmann W, Strueder HK, Predel HG, Tagarakis CVM. Spiroergometrie. Stuttgart, Schattauer, 2006.
Exercise Physiology Research in Germany 1911 to 1933
German Empire Committee for Scientific Research in Sport and Physical Exercise
The First Congress for Scientific Research in Sport and Physical Exercise took place in Oberhof, Germany, from September 20 to 23, 1912. The congress was conducted by the professor for internal medicine of the University Clinic Berlin Charité, Friedrich Kraus (1858-1936), and was chaired by Schmidt and Hueppe. Approximately 70 doctors participated (93). On September 21, 1912, the German Empire Committee for Scientific Research in Sport and Physical Exercise - the first national medical sport association worldwide - was founded under the chairmanship ofKraus, who was elected president.
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Nathan Zuntz (1847-1920).
Reprinted, by permission, from W. Hollmann and K. Tittel, 2008, History of German sports medicine (Gera: Druckhaus Gera), 15.
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The world's first motorized treadmill, developed by Zuntz and Lehmann in 1889 in Berlin. This apparatus was shown in the international hygiene exhibition in Dresden in 1911.
Hollmann W, Strueder HK, Predel HG, Tagarakis CVM. Spiroergometry. Stuttgart, Schattauer, 2006.
Period From 1913 to 1924
In 1913, Arthur Mallwitz was appointed the first full-time sport physician worldwide by the Prussian State Gymnastics Institute. Mallwitz then took up his office under the official designation of sport physician (94).
At the same time the physician and chemist Otto Meyerhof (1884-1951) recognized the regulating relationship between respiration rate and the suppression of glycolysis in muscles. He demonstrated that the consumption of one molecule of oxygen prevents the formation of two molecules of lactate. Meyerhof's findings supported the assumption that the enzymes fanning lactate also function aerobically but that the lactate formed is resynthesized to carbohydrate at the expense of the energy provided by respiration (98).
Hugo Wilhelm Knipping (1895-1984), physician and internist at Hamburg University, developed a gas metabolism apparatus for examination of humans at rest in 1924 and constructed a dynamo cranked ergometer in 1928. In 1929 he combined an enlarged gas metabolism apparatus for exercise examinations with the crank ergometer and designated the method as spiroergometry (73, 74). It was the genesis of precise and simple clinical exercise diagnostics. Engineering, however, was not able to construct the equipment to satisfy all technical requirements until 1949 (75, 76).
German Medical Association for the Promotion of Physical Exercise (1924-1933)
Because of the political confusion and economic difficulties after the finish of World War I in 1918, approximately 6 yr elapsed before research in sports medicine and thus exercise physiology was renewed in 1924. The founding of the German Physician Association for the Promotion of Physical Exercise in 1924 was the impetus for this.
In 1925 Max Rubner (1854-1932), director of the Robert Koch Institute in Berlin and an internationally recognized metabolism researcher, ascertained that the skeletal musculature in adults amounts to 43% of the total body mass and that the total musculoskeletal system inclusive of bones, heart, and lungs amounts to 61%. The greatest proportion of the musculature was allotted to the legs (56%) and the upper extremities (28%). The head and torso muscles contributed to 16% of the total body mass (120).
Approximately 3,200 kcal could meet the daily energy requirements for physical exercise for a 70 kg person whereas 2,600 calories was sufficient for simple office work. The metabolism of a farm worker during harvesting would require 4,300 kcal. The peak values of the daily calorie consumption for lumberjacks would amount to approximately 6,000 kcal for a 70 kg person. Long-distance racing cyclists, however, could reach a peak daily metabolic rate of 11,000 kcal. Rubner believed that the limiting factor for the uptake of calories in the human body was the intestinal system. A repeat of such great exertion over several days would inevitably lead to loss of body weight (119).
As early as 1925, Herbert Herxheimer (1894-1985) and others precisely described the psychic and physical effects of overtraining, including a decrease in maximal oxygen uptake, reduced appetite, tendency to sweat, shivering, jerky reflexes, and pronounced respiratory arrhythmia with a clear preponderance of the parasympathetic part. Obstipation and painful stomach spasms also could be observed. Herxheimer published all his sports medicine knowledge in his famous book in 1933.
Herxheimer also described the connection between heart size and distance running. He found an increase in the transverse diameters of the heart in the following ascending order: boxing, swimming, middle-distance running, long-distance running, marathon running, and long-distance skiing. Particularly large hearts would work with a large stroke volume. This would result in the corresponding bradycardia at rest. The blood pressure of endurance athletes would be low (39).
Ludwig Aschoff (1866-1942) in Freiburg ascertained that there is one physiological work hypertrophy of the heart muscle as an adaptation to increased muscular activity. The enlargement remains within moderate limits. Sport does not cause a pathological hypertrophy. If a conspicuous general hypertrophy of the heart exists, it is a matter of pathological circumstances (e.g., cardiac valve ailments, hypertony or glomerular-tubular cirrhosis of the kidney). It is impossible for sport to cause a fatality in an individual with a healthy heart. A muscular cardiac insufficiency is to be treated by taking it easy. Puberty is a dangerous period regarding possible functional damage of the heart through sport.
Another significant exercise physiologist of the 1920s was Richard Herbst (1893-1949) in KÃöenigsberg East Prussia. He conducted numerous experimental investigations on the behavior of maximum oxygen absorption in humans of different ages and in different training conditions. He published his findings in 1928, 4 yr after the first description of maximum oxygen uptake by Hill. According to Herbst (1928), endurance-trained subjects had a higher oxygen intake than did untrained subjects. Also, after reaching the maximum oxygen uptake value, ventilation could be increased still further. Herbst used the Douglas bag with the subsequent respiratory gas analysis method for runners and cyclists. Further, he examined running distances between 100 m and marathon using the Douglas bag and gas analysis. The values obtained at that time (e.g., marathon with an energy consumption of 3,050 kcal, 10 m sprint with an energy consumption of 50 kcal) agree with measurements made nowadays. Sustained running loads of more than 3 min were determined from the magnitude of the maximal oxygen uptake. Thus, these parameters were a measure of performance. The lung ventilation volume would still increase further after reaching the maximum oxygen absorption. Cardiac output is represented as the most important factor limiting physical performance (37).
Read more from History of Exercise Physiology by Charles M. Tipton, PhD.
Harvard Fatigue Laboratory influential in promoting exercise physiology research
Despite its brief history (1927-1947), no physiology laboratory in America is more revered than the Harvard Fatigue Laboratory.
Despite its brief history (1927-1947), no physiology laboratory in America is more revered than the Harvard Fatigue Laboratory. Described as "the first laboratory for the comprehensive study of man" (5), it was perhaps more influential and effective in promoting scientific and collaborative research in exercise physiology (76). This chapter discusses the laboratory's contributions to the study of the acute and chronic effects of exercise and to the effects of altitude and temperature on the exercise response. This chapter includes information from the laboratory's extensive published record as well as from the perspective of the last surviving member of its faculty and staff (figure 3.1) (41).
G. Edgar Folk (1914-) of the University of Iowa in the United States who became a staff member of the Harvard Fatigue Laboratory in 1943. Folk remained at the Harvard Fatigue Laboratory until its closure in 1947. He subsequently spent six yr at Bowdoin College in Maine conducting research and teaching biology to undergraduate students. In 1953, he accepted an appointment in the department of physiology at the University of Iowa. Professor Folk continues to attend APS meetings, write manuscripts, and enjoy life as an elder statesman for physiology.
Harvard University (1920-1927)
In 1920, physiology at Harvard University was represented by four departments: physiology, comparative physiology, applied physiology, and physical chemistry. These departments were collectively known as the laboratories of physiology(53). Three years later, the department of industrial hygiene was transferred from the medical school to the recently established school of public health, facilitated by the efforts of Roger Lee (53). Subsequently, the department of industrial hygiene was renamed the department of applied physiology. At this time, Walter B. Cannon (1871-1945) was chairman of the department of physiology, David Edsall was dean of both the medical school and the school of public health, Lawrence Joseph Henderson (1888-1984) was director of the department of physical chemistry (figure 3.2), Wallace B. Donham was dean of the business school, and A. Laurence Lowell was president of the university (53). Also at this time, Dr. Arlie V. Bock was establishing a laboratory in Massachusetts General Hospital after being a physician in World War I, a Moseley Traveling Fellow in Sir Joseph Barcroft's laboratory for two years learning exercise protocols and blood-equilibration techniques, and after being a participant in Barcroft's high-altitude expedition in Peru (23) (figure 3.2).
David Bruce Dill (1891-1986) received his PhD in chemistry in 1925 from Stanford University and accepted a 2 yr National Research Council fellowship to work in the laboratory of L.J. Henderson to study the physical chemistry of proteins. However, after his arrival at Harvard, he was assigned to a Massachusetts General Hospital laboratory, where the senior staff physician was Dr. John H. Talbott. There he was reassigned to study with Dr. Bock the physiochemical properties of blood (46). When the fellowship was terminated, Dill was appointed as assistant professor of biochemistry in the school of public health, a position he retained until 1936. In addition, from 1927 to 1947, he held a professorship in the department of industrial hygiene at Harvard University (72). Although during his tenure at Harvard Henderson remained as director of the laboratory, it was Dill's leadership, organizational ability, and scientific insights that made the laboratory famous throughout the world. Between 1947 and 1961, Dill served as director of research for the U.S. Army Chemical Research and Development Laboratory. During this interval, he became president of the American Physiological Society (1950-1951) and later (1960-1961) was elected president of the American College of Sports Medicine (45, 74).
Henderson and the Establishment of the Harvard Fatigue Laboratory
Henderson, a recipient of an MD from Harvard in 1902, was professor of biological chemistry from 1919 until 1934 and the Abbot and James Lawrence professor of chemistry from 1934 until his death in 1942 (18) (figure 3.2). Besides chemistry and biology, Henderson had broad interests in sociology, psychology, anthropology, and the philosophy of Vilfredo Pareto, an Italian engineer and socialist (18, 46). He and Elton Mayo (a professor of industrial hygiene who, like Henderson, believed that workers should be studied in the workplace) developed the concept of establishing a laboratory to conduct research on industrial hazards (46). Such a laboratory would study the "group psychology, the social problems, and physiology of fatigue of normal man . . . not only as individual factors in determining physical and mental health, but more especially to determine their interrelatedness and the effect upon work" (46, p. 20).
With leadership from Henderson, the support of advisory and planning committees that included most of the previously mentioned deans and professors, the endorsement of President Lowell, and funding from the Laura Spelman Rockefeller Memorial and the Rockefeller Foundation, the Harvard Fatigue Laboratory was established in 1927 with Lawrence Joseph Henderson as its official director (46). According to Chapman, the term fatigue was selected because all parties believed it was important. However, because they could not agree on a definition, it did not force research activities into a specific departmental shape(19, p. 19). Its home was in the basement of Harvard Business School.
As noted, Dill was designated (although never officially appointed) to organize and direct the research program of the laboratory and quickly assumed the duties and responsibilities of Henderson. Hence, his curriculum vitae in the Mandeville Special Collections Library at the University of California in the United States lists him as the informal director of the laboratory between 1927 and 1946 (72). The Horvaths identified the senior members of the laboratory from 1927 to before World War II as Henderson, Dill, Bock, and Talbott (figure 3.2) (46).
Contributions to Undergraduate and Graduate Student Education
Although the education of undergraduate and graduate students was not a purpose for establishing the laboratory, the laboratory did provide opportunities for undergraduate and graduate students to be introduced to research and become involved with projects that all pertained to physiology and sometimes to exercise physiology. Although the laboratory offered no courses or degrees, it offered opportunities for students to conduct senior theses under the supervision of select faculty members. Twelve undergraduates were involved in activities of the laboratory. Henry Taylor became a renowned exercise physiologist at the University of Minnesota in the United States (figure 3.4). Richard Riley was recognized as an outstanding respiratory physiologist at Johns Hopkins University, and John Pappenheimer and Clifford Barger received acclaim as physiologists on the faculty of Harvard University (46). Sid Robinson and Steven Horvath (figures 3.5 and 3.6) conducted research for their PhD dissertations in the laboratory but received their degrees in biological sciences. Dill served as chairman of Robinson's committee but was unable to do so for Horvath because Horvath had married Dill's daughter (73). G. Edgar Folk Jr. received an MA from Harvard University in 1937 and served as a research associate in the laboratory from 1943 to 1947 (figure 3.1). In 1947, he received a PhD in the biological sciences with John Welch as his advisor (74). Additionally, Pappenheimer, Robinson, and Horvath served along with 13 other staff members as tutors for students in biochemistry (46).
Read more from History of Exercise Physiology by Charles M. Tipton, PhD.
Advances in studies of genes associated with exercise behavior traits
Several research designs and technologies have been used over the past two decades in the effort to identify genomic regions, genes, and sequence variants associated with exercise behavior and exercise biology traits.
Genomics Studies
Several research designs and technologies have been used over the past two decades in the effort to identify genomic regions, genes, and sequence variants associated with exercise behavior and exercise biology traits. This section reviews advances made over time and key laboratories and investigators involved in these studies. Candidate genes, genome-wide linkage scans, genome-wide association (GWA) studies, and contributions from combinations of transcriptomics and genomics are reviewed. Efforts to identify genetic differences between elite athletes and sedentary controls are also briefly summarized.
Candidate Genes
A candidate gene is a gene that has a theoretical relationship with the behavioral, physiological, or metabolic system regulating the trait of interest. Candidate genes for exercise biology traits have been defined on the basis of advances in exercise physiology studies and animal models and on purely theoretical grounds. Transgenic (overexpression of a gene or genes), knockdown (reduced expression level), and knockout (ablation of a gene or genes) mice have generated a number of candidate genes that were subsequently investigated for potential involvement in human variation. The expression level of a gene has also been used as a candidate phenotype against which DNA variants can be tested for associations. The complete transcriptome, which is the full set of ribonucleic acid (RNA) transcripts in a given cell or tissue, has been used to define new panels of candidate genes for further genomics studies (e.g., 72, 224).
Candidate genes were very prominent in the early phase of exercise genomics. Many of the earlier studies were quite simple in design and were launched primarily because of the availability of whole blood stored in freezers. They were generally case-control or cross-sectional cohort studies with unrelated subjects. In the case of continuous traits (e.g., V\od\O2max), the association with a candidate gene or marker is tested by comparing mean trait values across genotypes or between carriers and noncarriers of a specific allele. In the case-control design, testing for a relation between a trait and a candidate gene marker is based on the comparison of allele and genotype frequencies between two informative groups of subjects, one with the phenotype of interest (e.g., elite power and strength athletes - the "cases") and the other without the phenotype of interest (the "controls").
Special Case of Athletes Versus Controls
Luigi Gedda from the Gregor Mendel Institute of Medical Genetics and Twin Research at the University of Rome was perhaps the pioneer in the effort to understand the importance of genetic differences between athletes and nonathletes (67, 68) (figure 7.7). The initial efforts were based on surveys of Italian twins, specifically on 351 pairs of twins who were engaged in competitive sport. The results of the surveys indicated familial aggregation among athletes and the potential importance of zygosity in concordance of sport selection; participation in markedly different sports occurred in 85% of DZ twins in contrast to only 6% of MZ twins (68). The familial aggregation of athletes was also noted by others, such as Grebe (75, 76) of Germany, Linc and Fleischmann (117) of Czechoslovakia, and Jokl (92, 93), who at the time was in the United States. The work of Gedda and his longtime collaborator, Paolo Parisi, was the most systematic in this regard and focused on genealogical and twin methods. The research of Parisi continues today with the Italian Registry of Twin Athletes (154, 155). A higher prevalence of MZ twins among swimmers has been one of their findings (154). In a large sample of adult British female twins, athlete status (nonathlete vs. local-, county-, or national-level athlete) had a heritability of 0.66 (50).
Luigi Gedda (1902-2000), MD, Mendel Institute of Medical Genetics and Twin Research in Rome, right, and Paolo Parisi (1940 - ), PhD, professor of biology and rector, Italian University Sport and Movement, University of Rome "Foro Italico," left. Gedda was the first to confirm, through classic pedigree studies in the mid-1950s, the common knowledge that elite athletes often cluster in families and to then attempt to quantify the role of genetic factors using the twin concordance model. He studied a large sample of MZ and DZ twin pairs and found considerably higher concordance rates in the former than in the latter with respect to various aspects of sport participation, such as kind of sport practiced and performance level. In later decades, Gedda's longtime associate Paolo Parisi conducted epidemiological and cell genetics research, also through the aid of a special registry of Italian twin athletes, in order to explore the genetic basis of athletic performance. Of particular interest to him is the relation of physical activity to health, aging, and chronic disease. One major line of research of his institute focuses on the role of exercise-induced oxidative stress in genetic regulation processes.
The first documented attempt to identify differences in genetic markers for performance-related phenotypes dates to the late 1960s. A group of geneticists, taking advantage of the 1968 Olympic Games in Mexico, investigated common blood genetic markers in an attempt to discriminate between Olympic athletes and controls (45).
Interestingly, phenylthiocarbamide nontasters were underrepresented among the athletes. The effort to document genetic differences between elite athletes and sedentary controls was continued on the occasion of the 1976 Olympic Games in Montreal (37, 41). A slightly higher frequency of the A1 allele of the ABO blood group was observed in endurance athletes participating in the 1976 Summer Olympic Games than in reference populations (37). However, the other plasma and red blood cell markers (ABO, MNSs, Rhesus, Duffy, Kell, P, LDH, MDH, phosphoglucomutase, adenosine deaminase, adenylate kinase, esterase D, haptoglobin, transferrin, hemoglobin, glucose-6-phosphate dehydrogenase, and acid phosphatase) did not differ between athletes and controls (37, 41, 45). These early attempts were all based on polymorphisms in red blood cell antigens and enzymes. Later, skeletal muscle gene product variants were screened (17, 128) and selected enzyme markers were investigated for their putative effects on a variety of skeletal muscle and cardiorespiratory endurance indicators. Genetic variants of skeletal muscle creatine kinase (CKM) and adenylate kinase 1 (AK1) were screened for using isoelectric focusing in 295 subjects (16). A variant form of both enzymes was identified with an allele frequency of 1% (CKM) and 3.5% (AK1). There was no difference in V\od\O2max between the carriers of the variant alleles and matched controls homozygous for the nonvariant allele (16). None of these studies yielded reliably significant genomic predictors of performance or fitness.
Genomic differences between athletes and untrained controls began to be investigated in a more systematic fashion with the launch of the GENATHLETE study in the laboratory of Claude Bouchard at Laval University in 1993. The main collaborators on GENATHLETE included Louis Perusse, Marcel Boulay, and the late Jean-Aime Simoneau (all from Laval University), Rainer Rauramaa (Kuopio, Finland), and particularly Bernd Wolfahrt (from Germany). The study focused on DNA sequence differences between a panel that has now attained more than 300 elite endurance athletes with a V\od\O2max no lower than 75 ml·kg-1·min-1 and more than 300 sedentary controls with a V\od\O2max no higher than 50 ml·kg-1·min-1. The participants are all white males from Canada, Germany, Finland, and the United States. Single nucleotide polymorphisms (SNPs) in several genes have been investigated to date, but none have provided strong evidence for differences in allele and genotype frequencies between athletes and controls (16, 178, 184, 185, 245-247). However, a common variant and haplotype in the hypoxia inducible factor 1, alpha subunit (HIF1A) gene were found to be more prevalent in athletes compared with controls in a 2010 report based on the GENATHLETE cohort (54), an observation that was defined in an accompanying editorial as an important milestone (194).
Another effort to delineate the differences between athletes and nonathletes is under way in Spain under the leadership of Jonatan Ruiz and Alejandro Lucia. They have used samples of Spanish Caucasian endurance athletes (about 100), power athletes (about 50), and nonathlete controls. A number of differences at candidate genes between athletes and controls, as well as between endurance and power athletes, have been reported (34, 71, 190). Taking advantage of the concept of a total genotype score developed by Williams and Folland (238), Ruiz and colleagues in 2009 attempted to predict world-class endurance athlete status based on the frequency of variant alleles at 7 candidate genes genotyped in 43 Spanish endurance athletes and 123 controls (191).
Yannis Pitsiladis from the faculty of biomedical and life sciences at the University of Glasgow has taken advantage of striking performance differences at the elite level in athletes of various ethnic backgrounds to investigate the potential role of variation in nuclear and mitochondrial DNA (figure 7.8). For instance, distance runners from Kenya and Ethiopia and sprinters from Jamaica won 25% of all track and field medals at the 2008 Olympic Games in Beijing (166). The effort to impute ethnic differences in sport performance to genetic differences is clearly challenging, particularly because only about 10% of human genetic variation can be found between the major ethnic groups. Pitsiladis' laboratory has explored differences in sequence variants in mitochondrial DNA and in Y chromosome markers between Ethiopian athletes, Ethiopian controls, Kenyan athletes, and Kenyan controls. Mitochondrial DNA haplogroups found in Kenya were different from those found in Ethiopia (197). Differences in haplogroup distributions were observed between athletes and controls in Kenya but not in Ethiopia. The full significance of this observation needs to be established. Analyses of Y chromosome haplogroups in endurance athletes from Ethiopia revealed differences between them and samples from the more general Ethiopian population (145). Population stratification was ruled out as the explanation for such differences. One important conclusion reached by Pitsiladis and colleagues is that the clusters of Kenyan and Ethiopian elite runners are distinct from each other from a genetic point of view (166).
Yannis P. Pitsiladis (1967 - ), MMedSci, PhD, FACSM, integrative and systems biology research theme, faculty of biomedical and life sciences, University of Glasgow, Scotland. Pitsiladis is a reader in exercise physiology at the Institute of Biomedical and Life Sciences at the University of Glasgow and founding member (and previous director) of the International Centre for East African Running Science, set up to investigate the physiological, genetic, psychosocial, and economic determinants of the phenomenal success of East African distance runners in international athletics. Recent projects include the study of West African sprinters (including elite sprinters from Jamaica and the United States) and the study of world-class swimmers (e.g., why there are very few black swimmers). He is a visiting professor in medical physiology at Moi University (Eldoret, Kenya), Addis Ababa University (Addis Ababa, Ethiopia), and University of Technology (Kingston, Jamaica). Pitsiladis has a particular research interest in mitochondrial DNA and Y chromosome markers and their potential role in ethnic differences in performance.
Photo courtesy of Yannis P. Pitsiladis.
Two genes have received considerable attention in the exercise genomics literature: angiotensin I-converting enzyme (ACE) and actinin alpha 3 (ACTN3). Both have been strong favorites of exercise scientists over the past decade or so.
ACE Gene
Hugh Montgomery (1962 - ), MB, BS, BSc, FRCP, MD, FRGS, director of University College London Institute for Human Health and Performance; consultant intensivist at Whittington Hospital; and professor of intensive care medicine at University College London. Montgomery obtained his BSc degree in neuropharmacology and in circulatory and respiratory physiology in 1984 before graduating with a medical degree in 1987. He has since trained and accredited in general internal medicine, cardiology, and intensive care medicine. He is now professor of intensive care medicine at University College London, where he also directs the Institute for Human Health and Performance. In the early 1990s, he began using gene - environment interaction as a means to explore human physiology. Working with army recruits, he first identified a role for the angiotensin I-converting enzyme (ACE) I/D polymorphism in the regulation of human cardiac growth. This work was extended to broader measures of performance, including high-altitude mountaineering aptitude. Mechanistically, a role in the regulation of metabolic efficiency was suggested, leading to phase IV studies of ACE inhibition in the treatment of cancer cachexia. Studies of downstream gene variants (e.g., those of the bradykinin B2 receptor gene) have offered further mechanistic insight. Montgomery has a special interest in high-altitude performance: He was science lead for the Caudwell Xtreme Everest Expedition in 2007 and has identified genes under selection pressure in high-altitude populations.
The potential role of ACE sequence differences in human physical performance was first investigated in the 1990s by Hugh Montgomery from the University College London (figure 7.9). He and his coworkers reported in 1997 that 10 wk of physical training in British army recruits induced greater increases in left ventricular mass and septal and posterior wall thickness in the ACE D/D homozygotes than in the I allele carriers (141). A few years later, the same group of investigators confirmed the finding by reporting that the training-induced increase in left ventricular mass in another cohort of army recruits was 2.7 times greater in the D/D genotype compared with the I/I homozygotes (147). The I allele was associated with higher muscular endurance gains after 10 wk of physical training in British army recruits (142).
The story began in 1990 when it was reported that a 287 bp I/D polymorphism in intron 16 of the ACE gene was associated with plasma ACE activity (183). ACE activity was highest in D/D homozygotes and lowest in I/I homozygotes. More than 50 reports have subsequently dealt with the potential role of the ACE I/D genotype in some aspects of fitness or performance. Overall, the results are heterogeneous and often contradictory. For instance, in postmenopausal women, I/I homozygotes had a higher V\od\O2max than D/D homozygotes (79), whereas the opposite was observed in Chinese males (251). In the HERITAGE Family Study, no associations were found between the ACE I/D polymorphism and maximal and submaximal exercise V\od\O2 and power output phenotypes in healthy, sedentary blacks and whites (41).
This literature was recently reviewed by Montgomery and colleagues (206). In the aggregate, it appears that the ACE I/D polymorphism may contribute to human variation in skeletal and cardiac muscle growth and functional properties as well as in adaptation to hypoxia. However, its contribution to variation in human physical performance remains a matter of debate.
ACTN3 Gene
Kathryn North and colleagues from the Children's Hospital at Westmead in Australia discovered a common variant in the gene for actinin-3, a structural actin binding protein found in skeletal muscle fast-twitch fibers (figure 7.10). The polymorphism (R577X) replaces an arginine residue by a premature stop codon at position 577 and results in ACTN3 deficiency. About 16% of the world population is homozygous for the XX null genotype; the frequency of the null allele is highest in Caucasians and Asians and lowest in Africans (8). The first report on ACTN3 genotype and performance was from North's laboratory in 2003. It indicated that the frequency of the stop codon mutation was lower in sprinters than in controls and endurance athletes (248). Several studies have concluded that the stop codon variant (X577X) was lower in sprint and strength athletes than in nonathletes (55, 57, 153, 189, 192, 248), but other reports have been negative (149, 198, 249). Interestingly, a number of studies based on direct measures of muscle strength and power have also been published and the results are contradictory; that is, the X allele is negatively associated with these muscle phenotypes in some studies whereas the converse is found in others (39, 51, 66, 132, 133, 146, 150, 228). North has reviewed the biology of the ACTN3 polymorphism in recent publications (8, 120). In the aggregate, the data suggest that there is probably a role of the X allele in skeletal muscle function and muscle performance, but the data remain inconclusive at present. More studies with appropriate power and designs, as well as more extensive functional studies, are warranted.
Kathryn North (1960 - ), MD, FRACP, Director, Murdoch Childrens Research Institute, and David Danks Professor of Child Health Research at University of Melbourne, Australia. In the process of studying genes implicated in muscle disease, North and colleagues at the Children's Hospital at Westmead discovered a common variant in the actinin alpha 3 (ACTN3) gene. ACTN3 encodes a structural protein found in fast-twitch skeletal muscle fibers. The ACTN3 gene variant results in complete deficiency of actinin-3 in almost 20% of the general population. North showed that ACTN3 deficiency is rare in sprint athletes, suggesting that this protein plays a crucial role in the function of fast-twitch muscle fibers. North and her team developed a strain of mice engineered to be completely deficient in ACTN3 and showed that the muscle of these knockout mice displays an increase in oxidative metabolism. This metabolic shift could explain why ACTN3 deficiency is detrimental to sprint activities that require fast or glycolytic metabolism. Her analysis of deoxyribonucleic acid (DNA) samples from individuals from around the world suggests that the ACTN3 deficiency provided some benefit to the ancestors of modern Europeans and Asians after their migration out of Africa, resulting in its increase in frequency due to natural selection. The benefit provided by ACTN3 deficiency may have allowed them to adapt to the more hostile environments of Eurasia. North's group plans to use mouse and human studies to determine the effect of ACTN3 deficiency on muscle aging, response to exercise, and the progression of inherited muscle diseases such as the muscular dystrophies.
Other Candidate Genes
A series of studies has dealt with the contributions of other candidate genes to human variation in muscular strength and power. These genes were identified because of their biological relevance to muscle contractile and sarcomeric proteins, myogenesis and muscle regeneration, muscle mass atrophy and sarcopenia, hormonal regulation of muscle mass, energy transfer to sustain muscle contraction, and other properties. The evidence from candidate gene studies of muscle strength and power was recently reviewed by Thomis (220).
An example of such genes is the myostatin (MSTN) gene. Mutations in MSTN leading to inactive or defective gene product have been shown to double or even triple skeletal muscle mass in mice, cows, and sheep. Functional MSTN mutations are very rare in humans. However, a boy appeared extraordinarily muscular at birth and at 4.5 yr of age was described as muscular and very strong (196). It turned out that he was a homozygote for a G/A mutation located five nucleotides downstream of exon 1, which abolishes a normal splice donor site and activates a cryptic splice site further downstream in intron 1, resulting in a truncated, inactive myostatin peptide. A number of polymorphisms in MSTN have been investigated for their associations with muscle hypertrophy or muscle strength and power (40, 60, 107, 199, 231), but the overall findings have been inconsistent.
Another class of candidate genes of great interest for muscular strength and power is that of the insulin-like growth factors and related binding proteins. These molecules play important roles in muscle growth and repair and in muscle response to exercise. Polymorphisms in insulin-like growth factors 1 (IGF1) and 2 (IGF2) have been rather consistently associated with muscle strength and its response to training, as well as other relevant endophenotypes (52, 81, 108, 193, 195).
The laboratories of James Hagberg and Stephen Roth in the department of kinesiology at the University of Maryland in the United States have pioneered a number of candidate gene research avenues since the late 1990s (figure 7.11). Their efforts focused on sequence variants in ACE; nitric oxide synthase 3 (NOS3); angiotensinogen (AGT); ACTN3; angiotensin II receptor, type 1 (AGTR1); tumor necrosis factor (TNF); nuclear factor of kappa light polypeptide gene enhancer in B-cells 1 (NFKB1); activin A receptor, type IIB (ACVR2B); adenosine monophosphate deaminase 1 (AMPD1); vascular endothelial growth factor A (VEGFA); vitamin D receptor (VDR); and MSTN, among others (see 59, 78, 79, 81, 134, 156, 167). Hagberg has a strong interest in exercise blood pressure and other hemodynamic phenotypes and through most of his career has consistently focused on the role of exercise in health-related outcomes and therapeutic applications, with an emphasis on the importance of genetic differences at key genes. Roth, whose primary interest is in muscle size and strength, has contributed a primer on exercise genetics (187) and has a longstanding interest in the role of genetic variation in talent selection for athletic performance. Both have trained a good number of graduate students in exercise genetics and have been longtime contributors to the fitness and performance gene map series that was published in Medicine and Science in Sports and Exercise until 2009.
Stephen M. Roth (1973 - ), PhD, FACSM, associate professor, and James M. Hagberg (1950 - ), PhD, FACSM, professor, department of kinesiology, school of public health, University of Maryland. Hagberg completed his graduate studies at the University of Wisconsin. He has been on the faculty of a number of universities and at the University of Maryland for nearly 20 yr, where he is a distinguished scholar-teacher. He has been funded by the National Institute of Aging for genetics-based investigations and has published numerous papers identifying genetic markers that associate with the degree to which endurance-exercise training improves cardiovascular disease risk factors in older men and women. Stephen M. Roth completed graduate studies in exercise physiology at the University of Maryland in 2000 and postdoctoral training in human genetics at the University of Pittsburgh. In 2003 he was recruited back to the University of Maryland as director of the Functional Genomics Laboratory. He has been funded by the National Institutes of Health to perform a variety of genetics investigations. In addition to several research publications, Roth is author of a textbook titled Genetics Primer for Exercise Science and Health. The department of kinesiology at the University of Maryland was one of the first to develop a research focus in the area of exercise genomics. As a group, they have published more than 60 peer-reviewed publications in the areas of exercise genomics.
When the last version of the fitness and performance gene map was published based on the publications available by the end of 2007, there were 214 autosomal, 7 X chromosome, and 18 mitochondrial gene and other loci entries (31). Most of the entries were related to specific candidate genes and were supported by more than 350 peer-reviewed papers. With the exception of the ACE and ACTN3 common variants, few of the genes had been replicated in multiple studies. Moreover, after almost 25 yr of candidate gene studies in exercise biology, this line of research continues to be plagued by small sample sizes and lack of appropriate statistical power (31, 177). Studies with small sample sizes occasionally report positive findings, especially if they include several traits and perform multiple statistical tests for association. Fortunately, these positive findings are seldom replicated and usually fall into oblivion.
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Early German roots of exercise physiology
In 1719, Friedrich Hoffmann (1660-1742), a physician from Halle, obtained his doctoral degree with experimental investigations about the effects of physical exercise on the human cardiovascular system and on digestion.
Exercise Physiology Research in Germany 1700 to 1910
In 1719, Friedrich Hoffmann (1660-1742), a physician from Halle, obtained his doctoral degree with experimental investigations about the effects of physical exercise on the human cardiovascular system and on digestion. In 1796, the physician Christoph Wilhelm Hufeland (1762-1836) published a textbook about the significance of different types of physical exercise for human health and life expectancy (66).
In the 19th century, the physiologist Emil Dubois-Reymond (1818-1896) studied the role of gymnastics in the human body (21, 22). The physician and chemist Max von Pettenkofer (1818-1901) detected the existence of creatine in the skeletal muscle and described a strengthening of the circulatory system in connection with physical training (111).
The first ergometer in the present-day sense of the word was developed by the German physician Speck in 1883. When using this cranked ergometer, the test person was in the standing position (figure 4.1). The crank friction could be modified by pulling up a screw. Speck determined the resistance with weights hung on the crank. The number of revolutions could be determined by noting the number of turns of twine wound up around the crank axle. The exhaled air was collected in a double spirometer and the postexperimental air composition was determined, thus enabling conclusions to be drawn about the individual performance reaction (2, 125).
In 1887 the Viennese physician Friedrich Gaertner (1847-1917) presented a mechanically braked ergometer, based on Speck's equipment that could measure the work performed in kilogram-meter. This device, called the ergostat, later went into standard production (112).
The first heyday of exercise physiology began with the veterinarian Nathan Zuntz (1847-1920) in Berlin (figure 4.2), who developed the first motor-driven treadmill in 1889 (figure 4.3). His work is described in chapter 1 (142).
Of substantial significance in the application of aspects of exercise physiology in medicine were Adolf Theophil Ferdinand Hueppe (1852-1938) and Ferdinand August Schmidt (1852-1929). In 1899 Hueppe wrote a fundamental work titled A Textbook of Hygiene that covered the whole of the exercise physiology discipline of those days. This was followed by the work titled Hygiene of Physical Exercises, published in 1911. In 1893 Schmidt published the book Physical Exercise According to the Exercise Value, which deals with an overview of suitable physical exercises for different ages (122, 123).
From 1904 to 1906 Kuelbs examined the influence of physical training on the internal organs, particularly the heart. He took two dogs from the same litter and trained one of them 5 times/wk for about 2 h on a treadmill, which he had taken over from Zuntz; the other dog had a normal, everyday life. After 1 yr both animals were killed and all internal organs were measured and examined. Although both dogs had more or less the same body weight, the heart of the dog trained on the treadmill was approximately 33% larger than that of the untrained dog. Similar differences were also manifest in the weights of the liver, kidneys, adrenal glands, spleen, and lungs (77).
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Over the subsequent decades Arthur Mallwitz (1880-1968) became the most important promoter for German, and later international, sports medicine. He obtained his doctor's degree at Halle University (Saale) in 1908 with what is presumed to be the first ever dissertation in sports medicine. In his dissertation, titled Maximum Performances With Special Consideration of Sports Done at the Olympic Games, Mallwitz considered, above all, the investigations of Hueppe and Schmidt as well as those of Zuntz and his school. In 1910 a comprehensive book about exercise physiology in connection with numerous kinds of sports was edited by Weissbein (141).
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The first ergometer was developed by Speck in 1883. Gaertner produced it in series.
Hollmann W, Strueder HK, Predel HG, Tagarakis CVM. Spiroergometrie. Stuttgart, Schattauer, 2006.
Exercise Physiology Research in Germany 1911 to 1933
German Empire Committee for Scientific Research in Sport and Physical Exercise
The First Congress for Scientific Research in Sport and Physical Exercise took place in Oberhof, Germany, from September 20 to 23, 1912. The congress was conducted by the professor for internal medicine of the University Clinic Berlin Charité, Friedrich Kraus (1858-1936), and was chaired by Schmidt and Hueppe. Approximately 70 doctors participated (93). On September 21, 1912, the German Empire Committee for Scientific Research in Sport and Physical Exercise - the first national medical sport association worldwide - was founded under the chairmanship ofKraus, who was elected president.
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Nathan Zuntz (1847-1920).
Reprinted, by permission, from W. Hollmann and K. Tittel, 2008, History of German sports medicine (Gera: Druckhaus Gera), 15.
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The world's first motorized treadmill, developed by Zuntz and Lehmann in 1889 in Berlin. This apparatus was shown in the international hygiene exhibition in Dresden in 1911.
Hollmann W, Strueder HK, Predel HG, Tagarakis CVM. Spiroergometry. Stuttgart, Schattauer, 2006.
Period From 1913 to 1924
In 1913, Arthur Mallwitz was appointed the first full-time sport physician worldwide by the Prussian State Gymnastics Institute. Mallwitz then took up his office under the official designation of sport physician (94).
At the same time the physician and chemist Otto Meyerhof (1884-1951) recognized the regulating relationship between respiration rate and the suppression of glycolysis in muscles. He demonstrated that the consumption of one molecule of oxygen prevents the formation of two molecules of lactate. Meyerhof's findings supported the assumption that the enzymes fanning lactate also function aerobically but that the lactate formed is resynthesized to carbohydrate at the expense of the energy provided by respiration (98).
Hugo Wilhelm Knipping (1895-1984), physician and internist at Hamburg University, developed a gas metabolism apparatus for examination of humans at rest in 1924 and constructed a dynamo cranked ergometer in 1928. In 1929 he combined an enlarged gas metabolism apparatus for exercise examinations with the crank ergometer and designated the method as spiroergometry (73, 74). It was the genesis of precise and simple clinical exercise diagnostics. Engineering, however, was not able to construct the equipment to satisfy all technical requirements until 1949 (75, 76).
German Medical Association for the Promotion of Physical Exercise (1924-1933)
Because of the political confusion and economic difficulties after the finish of World War I in 1918, approximately 6 yr elapsed before research in sports medicine and thus exercise physiology was renewed in 1924. The founding of the German Physician Association for the Promotion of Physical Exercise in 1924 was the impetus for this.
In 1925 Max Rubner (1854-1932), director of the Robert Koch Institute in Berlin and an internationally recognized metabolism researcher, ascertained that the skeletal musculature in adults amounts to 43% of the total body mass and that the total musculoskeletal system inclusive of bones, heart, and lungs amounts to 61%. The greatest proportion of the musculature was allotted to the legs (56%) and the upper extremities (28%). The head and torso muscles contributed to 16% of the total body mass (120).
Approximately 3,200 kcal could meet the daily energy requirements for physical exercise for a 70 kg person whereas 2,600 calories was sufficient for simple office work. The metabolism of a farm worker during harvesting would require 4,300 kcal. The peak values of the daily calorie consumption for lumberjacks would amount to approximately 6,000 kcal for a 70 kg person. Long-distance racing cyclists, however, could reach a peak daily metabolic rate of 11,000 kcal. Rubner believed that the limiting factor for the uptake of calories in the human body was the intestinal system. A repeat of such great exertion over several days would inevitably lead to loss of body weight (119).
As early as 1925, Herbert Herxheimer (1894-1985) and others precisely described the psychic and physical effects of overtraining, including a decrease in maximal oxygen uptake, reduced appetite, tendency to sweat, shivering, jerky reflexes, and pronounced respiratory arrhythmia with a clear preponderance of the parasympathetic part. Obstipation and painful stomach spasms also could be observed. Herxheimer published all his sports medicine knowledge in his famous book in 1933.
Herxheimer also described the connection between heart size and distance running. He found an increase in the transverse diameters of the heart in the following ascending order: boxing, swimming, middle-distance running, long-distance running, marathon running, and long-distance skiing. Particularly large hearts would work with a large stroke volume. This would result in the corresponding bradycardia at rest. The blood pressure of endurance athletes would be low (39).
Ludwig Aschoff (1866-1942) in Freiburg ascertained that there is one physiological work hypertrophy of the heart muscle as an adaptation to increased muscular activity. The enlargement remains within moderate limits. Sport does not cause a pathological hypertrophy. If a conspicuous general hypertrophy of the heart exists, it is a matter of pathological circumstances (e.g., cardiac valve ailments, hypertony or glomerular-tubular cirrhosis of the kidney). It is impossible for sport to cause a fatality in an individual with a healthy heart. A muscular cardiac insufficiency is to be treated by taking it easy. Puberty is a dangerous period regarding possible functional damage of the heart through sport.
Another significant exercise physiologist of the 1920s was Richard Herbst (1893-1949) in KÃöenigsberg East Prussia. He conducted numerous experimental investigations on the behavior of maximum oxygen absorption in humans of different ages and in different training conditions. He published his findings in 1928, 4 yr after the first description of maximum oxygen uptake by Hill. According to Herbst (1928), endurance-trained subjects had a higher oxygen intake than did untrained subjects. Also, after reaching the maximum oxygen uptake value, ventilation could be increased still further. Herbst used the Douglas bag with the subsequent respiratory gas analysis method for runners and cyclists. Further, he examined running distances between 100 m and marathon using the Douglas bag and gas analysis. The values obtained at that time (e.g., marathon with an energy consumption of 3,050 kcal, 10 m sprint with an energy consumption of 50 kcal) agree with measurements made nowadays. Sustained running loads of more than 3 min were determined from the magnitude of the maximal oxygen uptake. Thus, these parameters were a measure of performance. The lung ventilation volume would still increase further after reaching the maximum oxygen absorption. Cardiac output is represented as the most important factor limiting physical performance (37).
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Harvard Fatigue Laboratory influential in promoting exercise physiology research
Despite its brief history (1927-1947), no physiology laboratory in America is more revered than the Harvard Fatigue Laboratory.
Despite its brief history (1927-1947), no physiology laboratory in America is more revered than the Harvard Fatigue Laboratory. Described as "the first laboratory for the comprehensive study of man" (5), it was perhaps more influential and effective in promoting scientific and collaborative research in exercise physiology (76). This chapter discusses the laboratory's contributions to the study of the acute and chronic effects of exercise and to the effects of altitude and temperature on the exercise response. This chapter includes information from the laboratory's extensive published record as well as from the perspective of the last surviving member of its faculty and staff (figure 3.1) (41).
G. Edgar Folk (1914-) of the University of Iowa in the United States who became a staff member of the Harvard Fatigue Laboratory in 1943. Folk remained at the Harvard Fatigue Laboratory until its closure in 1947. He subsequently spent six yr at Bowdoin College in Maine conducting research and teaching biology to undergraduate students. In 1953, he accepted an appointment in the department of physiology at the University of Iowa. Professor Folk continues to attend APS meetings, write manuscripts, and enjoy life as an elder statesman for physiology.
Harvard University (1920-1927)
In 1920, physiology at Harvard University was represented by four departments: physiology, comparative physiology, applied physiology, and physical chemistry. These departments were collectively known as the laboratories of physiology(53). Three years later, the department of industrial hygiene was transferred from the medical school to the recently established school of public health, facilitated by the efforts of Roger Lee (53). Subsequently, the department of industrial hygiene was renamed the department of applied physiology. At this time, Walter B. Cannon (1871-1945) was chairman of the department of physiology, David Edsall was dean of both the medical school and the school of public health, Lawrence Joseph Henderson (1888-1984) was director of the department of physical chemistry (figure 3.2), Wallace B. Donham was dean of the business school, and A. Laurence Lowell was president of the university (53). Also at this time, Dr. Arlie V. Bock was establishing a laboratory in Massachusetts General Hospital after being a physician in World War I, a Moseley Traveling Fellow in Sir Joseph Barcroft's laboratory for two years learning exercise protocols and blood-equilibration techniques, and after being a participant in Barcroft's high-altitude expedition in Peru (23) (figure 3.2).
David Bruce Dill (1891-1986) received his PhD in chemistry in 1925 from Stanford University and accepted a 2 yr National Research Council fellowship to work in the laboratory of L.J. Henderson to study the physical chemistry of proteins. However, after his arrival at Harvard, he was assigned to a Massachusetts General Hospital laboratory, where the senior staff physician was Dr. John H. Talbott. There he was reassigned to study with Dr. Bock the physiochemical properties of blood (46). When the fellowship was terminated, Dill was appointed as assistant professor of biochemistry in the school of public health, a position he retained until 1936. In addition, from 1927 to 1947, he held a professorship in the department of industrial hygiene at Harvard University (72). Although during his tenure at Harvard Henderson remained as director of the laboratory, it was Dill's leadership, organizational ability, and scientific insights that made the laboratory famous throughout the world. Between 1947 and 1961, Dill served as director of research for the U.S. Army Chemical Research and Development Laboratory. During this interval, he became president of the American Physiological Society (1950-1951) and later (1960-1961) was elected president of the American College of Sports Medicine (45, 74).
Henderson and the Establishment of the Harvard Fatigue Laboratory
Henderson, a recipient of an MD from Harvard in 1902, was professor of biological chemistry from 1919 until 1934 and the Abbot and James Lawrence professor of chemistry from 1934 until his death in 1942 (18) (figure 3.2). Besides chemistry and biology, Henderson had broad interests in sociology, psychology, anthropology, and the philosophy of Vilfredo Pareto, an Italian engineer and socialist (18, 46). He and Elton Mayo (a professor of industrial hygiene who, like Henderson, believed that workers should be studied in the workplace) developed the concept of establishing a laboratory to conduct research on industrial hazards (46). Such a laboratory would study the "group psychology, the social problems, and physiology of fatigue of normal man . . . not only as individual factors in determining physical and mental health, but more especially to determine their interrelatedness and the effect upon work" (46, p. 20).
With leadership from Henderson, the support of advisory and planning committees that included most of the previously mentioned deans and professors, the endorsement of President Lowell, and funding from the Laura Spelman Rockefeller Memorial and the Rockefeller Foundation, the Harvard Fatigue Laboratory was established in 1927 with Lawrence Joseph Henderson as its official director (46). According to Chapman, the term fatigue was selected because all parties believed it was important. However, because they could not agree on a definition, it did not force research activities into a specific departmental shape(19, p. 19). Its home was in the basement of Harvard Business School.
As noted, Dill was designated (although never officially appointed) to organize and direct the research program of the laboratory and quickly assumed the duties and responsibilities of Henderson. Hence, his curriculum vitae in the Mandeville Special Collections Library at the University of California in the United States lists him as the informal director of the laboratory between 1927 and 1946 (72). The Horvaths identified the senior members of the laboratory from 1927 to before World War II as Henderson, Dill, Bock, and Talbott (figure 3.2) (46).
Contributions to Undergraduate and Graduate Student Education
Although the education of undergraduate and graduate students was not a purpose for establishing the laboratory, the laboratory did provide opportunities for undergraduate and graduate students to be introduced to research and become involved with projects that all pertained to physiology and sometimes to exercise physiology. Although the laboratory offered no courses or degrees, it offered opportunities for students to conduct senior theses under the supervision of select faculty members. Twelve undergraduates were involved in activities of the laboratory. Henry Taylor became a renowned exercise physiologist at the University of Minnesota in the United States (figure 3.4). Richard Riley was recognized as an outstanding respiratory physiologist at Johns Hopkins University, and John Pappenheimer and Clifford Barger received acclaim as physiologists on the faculty of Harvard University (46). Sid Robinson and Steven Horvath (figures 3.5 and 3.6) conducted research for their PhD dissertations in the laboratory but received their degrees in biological sciences. Dill served as chairman of Robinson's committee but was unable to do so for Horvath because Horvath had married Dill's daughter (73). G. Edgar Folk Jr. received an MA from Harvard University in 1937 and served as a research associate in the laboratory from 1943 to 1947 (figure 3.1). In 1947, he received a PhD in the biological sciences with John Welch as his advisor (74). Additionally, Pappenheimer, Robinson, and Horvath served along with 13 other staff members as tutors for students in biochemistry (46).
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Advances in studies of genes associated with exercise behavior traits
Several research designs and technologies have been used over the past two decades in the effort to identify genomic regions, genes, and sequence variants associated with exercise behavior and exercise biology traits.
Genomics Studies
Several research designs and technologies have been used over the past two decades in the effort to identify genomic regions, genes, and sequence variants associated with exercise behavior and exercise biology traits. This section reviews advances made over time and key laboratories and investigators involved in these studies. Candidate genes, genome-wide linkage scans, genome-wide association (GWA) studies, and contributions from combinations of transcriptomics and genomics are reviewed. Efforts to identify genetic differences between elite athletes and sedentary controls are also briefly summarized.
Candidate Genes
A candidate gene is a gene that has a theoretical relationship with the behavioral, physiological, or metabolic system regulating the trait of interest. Candidate genes for exercise biology traits have been defined on the basis of advances in exercise physiology studies and animal models and on purely theoretical grounds. Transgenic (overexpression of a gene or genes), knockdown (reduced expression level), and knockout (ablation of a gene or genes) mice have generated a number of candidate genes that were subsequently investigated for potential involvement in human variation. The expression level of a gene has also been used as a candidate phenotype against which DNA variants can be tested for associations. The complete transcriptome, which is the full set of ribonucleic acid (RNA) transcripts in a given cell or tissue, has been used to define new panels of candidate genes for further genomics studies (e.g., 72, 224).
Candidate genes were very prominent in the early phase of exercise genomics. Many of the earlier studies were quite simple in design and were launched primarily because of the availability of whole blood stored in freezers. They were generally case-control or cross-sectional cohort studies with unrelated subjects. In the case of continuous traits (e.g., V\od\O2max), the association with a candidate gene or marker is tested by comparing mean trait values across genotypes or between carriers and noncarriers of a specific allele. In the case-control design, testing for a relation between a trait and a candidate gene marker is based on the comparison of allele and genotype frequencies between two informative groups of subjects, one with the phenotype of interest (e.g., elite power and strength athletes - the "cases") and the other without the phenotype of interest (the "controls").
Special Case of Athletes Versus Controls
Luigi Gedda from the Gregor Mendel Institute of Medical Genetics and Twin Research at the University of Rome was perhaps the pioneer in the effort to understand the importance of genetic differences between athletes and nonathletes (67, 68) (figure 7.7). The initial efforts were based on surveys of Italian twins, specifically on 351 pairs of twins who were engaged in competitive sport. The results of the surveys indicated familial aggregation among athletes and the potential importance of zygosity in concordance of sport selection; participation in markedly different sports occurred in 85% of DZ twins in contrast to only 6% of MZ twins (68). The familial aggregation of athletes was also noted by others, such as Grebe (75, 76) of Germany, Linc and Fleischmann (117) of Czechoslovakia, and Jokl (92, 93), who at the time was in the United States. The work of Gedda and his longtime collaborator, Paolo Parisi, was the most systematic in this regard and focused on genealogical and twin methods. The research of Parisi continues today with the Italian Registry of Twin Athletes (154, 155). A higher prevalence of MZ twins among swimmers has been one of their findings (154). In a large sample of adult British female twins, athlete status (nonathlete vs. local-, county-, or national-level athlete) had a heritability of 0.66 (50).
Luigi Gedda (1902-2000), MD, Mendel Institute of Medical Genetics and Twin Research in Rome, right, and Paolo Parisi (1940 - ), PhD, professor of biology and rector, Italian University Sport and Movement, University of Rome "Foro Italico," left. Gedda was the first to confirm, through classic pedigree studies in the mid-1950s, the common knowledge that elite athletes often cluster in families and to then attempt to quantify the role of genetic factors using the twin concordance model. He studied a large sample of MZ and DZ twin pairs and found considerably higher concordance rates in the former than in the latter with respect to various aspects of sport participation, such as kind of sport practiced and performance level. In later decades, Gedda's longtime associate Paolo Parisi conducted epidemiological and cell genetics research, also through the aid of a special registry of Italian twin athletes, in order to explore the genetic basis of athletic performance. Of particular interest to him is the relation of physical activity to health, aging, and chronic disease. One major line of research of his institute focuses on the role of exercise-induced oxidative stress in genetic regulation processes.
The first documented attempt to identify differences in genetic markers for performance-related phenotypes dates to the late 1960s. A group of geneticists, taking advantage of the 1968 Olympic Games in Mexico, investigated common blood genetic markers in an attempt to discriminate between Olympic athletes and controls (45).
Interestingly, phenylthiocarbamide nontasters were underrepresented among the athletes. The effort to document genetic differences between elite athletes and sedentary controls was continued on the occasion of the 1976 Olympic Games in Montreal (37, 41). A slightly higher frequency of the A1 allele of the ABO blood group was observed in endurance athletes participating in the 1976 Summer Olympic Games than in reference populations (37). However, the other plasma and red blood cell markers (ABO, MNSs, Rhesus, Duffy, Kell, P, LDH, MDH, phosphoglucomutase, adenosine deaminase, adenylate kinase, esterase D, haptoglobin, transferrin, hemoglobin, glucose-6-phosphate dehydrogenase, and acid phosphatase) did not differ between athletes and controls (37, 41, 45). These early attempts were all based on polymorphisms in red blood cell antigens and enzymes. Later, skeletal muscle gene product variants were screened (17, 128) and selected enzyme markers were investigated for their putative effects on a variety of skeletal muscle and cardiorespiratory endurance indicators. Genetic variants of skeletal muscle creatine kinase (CKM) and adenylate kinase 1 (AK1) were screened for using isoelectric focusing in 295 subjects (16). A variant form of both enzymes was identified with an allele frequency of 1% (CKM) and 3.5% (AK1). There was no difference in V\od\O2max between the carriers of the variant alleles and matched controls homozygous for the nonvariant allele (16). None of these studies yielded reliably significant genomic predictors of performance or fitness.
Genomic differences between athletes and untrained controls began to be investigated in a more systematic fashion with the launch of the GENATHLETE study in the laboratory of Claude Bouchard at Laval University in 1993. The main collaborators on GENATHLETE included Louis Perusse, Marcel Boulay, and the late Jean-Aime Simoneau (all from Laval University), Rainer Rauramaa (Kuopio, Finland), and particularly Bernd Wolfahrt (from Germany). The study focused on DNA sequence differences between a panel that has now attained more than 300 elite endurance athletes with a V\od\O2max no lower than 75 ml·kg-1·min-1 and more than 300 sedentary controls with a V\od\O2max no higher than 50 ml·kg-1·min-1. The participants are all white males from Canada, Germany, Finland, and the United States. Single nucleotide polymorphisms (SNPs) in several genes have been investigated to date, but none have provided strong evidence for differences in allele and genotype frequencies between athletes and controls (16, 178, 184, 185, 245-247). However, a common variant and haplotype in the hypoxia inducible factor 1, alpha subunit (HIF1A) gene were found to be more prevalent in athletes compared with controls in a 2010 report based on the GENATHLETE cohort (54), an observation that was defined in an accompanying editorial as an important milestone (194).
Another effort to delineate the differences between athletes and nonathletes is under way in Spain under the leadership of Jonatan Ruiz and Alejandro Lucia. They have used samples of Spanish Caucasian endurance athletes (about 100), power athletes (about 50), and nonathlete controls. A number of differences at candidate genes between athletes and controls, as well as between endurance and power athletes, have been reported (34, 71, 190). Taking advantage of the concept of a total genotype score developed by Williams and Folland (238), Ruiz and colleagues in 2009 attempted to predict world-class endurance athlete status based on the frequency of variant alleles at 7 candidate genes genotyped in 43 Spanish endurance athletes and 123 controls (191).
Yannis Pitsiladis from the faculty of biomedical and life sciences at the University of Glasgow has taken advantage of striking performance differences at the elite level in athletes of various ethnic backgrounds to investigate the potential role of variation in nuclear and mitochondrial DNA (figure 7.8). For instance, distance runners from Kenya and Ethiopia and sprinters from Jamaica won 25% of all track and field medals at the 2008 Olympic Games in Beijing (166). The effort to impute ethnic differences in sport performance to genetic differences is clearly challenging, particularly because only about 10% of human genetic variation can be found between the major ethnic groups. Pitsiladis' laboratory has explored differences in sequence variants in mitochondrial DNA and in Y chromosome markers between Ethiopian athletes, Ethiopian controls, Kenyan athletes, and Kenyan controls. Mitochondrial DNA haplogroups found in Kenya were different from those found in Ethiopia (197). Differences in haplogroup distributions were observed between athletes and controls in Kenya but not in Ethiopia. The full significance of this observation needs to be established. Analyses of Y chromosome haplogroups in endurance athletes from Ethiopia revealed differences between them and samples from the more general Ethiopian population (145). Population stratification was ruled out as the explanation for such differences. One important conclusion reached by Pitsiladis and colleagues is that the clusters of Kenyan and Ethiopian elite runners are distinct from each other from a genetic point of view (166).
Yannis P. Pitsiladis (1967 - ), MMedSci, PhD, FACSM, integrative and systems biology research theme, faculty of biomedical and life sciences, University of Glasgow, Scotland. Pitsiladis is a reader in exercise physiology at the Institute of Biomedical and Life Sciences at the University of Glasgow and founding member (and previous director) of the International Centre for East African Running Science, set up to investigate the physiological, genetic, psychosocial, and economic determinants of the phenomenal success of East African distance runners in international athletics. Recent projects include the study of West African sprinters (including elite sprinters from Jamaica and the United States) and the study of world-class swimmers (e.g., why there are very few black swimmers). He is a visiting professor in medical physiology at Moi University (Eldoret, Kenya), Addis Ababa University (Addis Ababa, Ethiopia), and University of Technology (Kingston, Jamaica). Pitsiladis has a particular research interest in mitochondrial DNA and Y chromosome markers and their potential role in ethnic differences in performance.
Photo courtesy of Yannis P. Pitsiladis.
Two genes have received considerable attention in the exercise genomics literature: angiotensin I-converting enzyme (ACE) and actinin alpha 3 (ACTN3). Both have been strong favorites of exercise scientists over the past decade or so.
ACE Gene
Hugh Montgomery (1962 - ), MB, BS, BSc, FRCP, MD, FRGS, director of University College London Institute for Human Health and Performance; consultant intensivist at Whittington Hospital; and professor of intensive care medicine at University College London. Montgomery obtained his BSc degree in neuropharmacology and in circulatory and respiratory physiology in 1984 before graduating with a medical degree in 1987. He has since trained and accredited in general internal medicine, cardiology, and intensive care medicine. He is now professor of intensive care medicine at University College London, where he also directs the Institute for Human Health and Performance. In the early 1990s, he began using gene - environment interaction as a means to explore human physiology. Working with army recruits, he first identified a role for the angiotensin I-converting enzyme (ACE) I/D polymorphism in the regulation of human cardiac growth. This work was extended to broader measures of performance, including high-altitude mountaineering aptitude. Mechanistically, a role in the regulation of metabolic efficiency was suggested, leading to phase IV studies of ACE inhibition in the treatment of cancer cachexia. Studies of downstream gene variants (e.g., those of the bradykinin B2 receptor gene) have offered further mechanistic insight. Montgomery has a special interest in high-altitude performance: He was science lead for the Caudwell Xtreme Everest Expedition in 2007 and has identified genes under selection pressure in high-altitude populations.
The potential role of ACE sequence differences in human physical performance was first investigated in the 1990s by Hugh Montgomery from the University College London (figure 7.9). He and his coworkers reported in 1997 that 10 wk of physical training in British army recruits induced greater increases in left ventricular mass and septal and posterior wall thickness in the ACE D/D homozygotes than in the I allele carriers (141). A few years later, the same group of investigators confirmed the finding by reporting that the training-induced increase in left ventricular mass in another cohort of army recruits was 2.7 times greater in the D/D genotype compared with the I/I homozygotes (147). The I allele was associated with higher muscular endurance gains after 10 wk of physical training in British army recruits (142).
The story began in 1990 when it was reported that a 287 bp I/D polymorphism in intron 16 of the ACE gene was associated with plasma ACE activity (183). ACE activity was highest in D/D homozygotes and lowest in I/I homozygotes. More than 50 reports have subsequently dealt with the potential role of the ACE I/D genotype in some aspects of fitness or performance. Overall, the results are heterogeneous and often contradictory. For instance, in postmenopausal women, I/I homozygotes had a higher V\od\O2max than D/D homozygotes (79), whereas the opposite was observed in Chinese males (251). In the HERITAGE Family Study, no associations were found between the ACE I/D polymorphism and maximal and submaximal exercise V\od\O2 and power output phenotypes in healthy, sedentary blacks and whites (41).
This literature was recently reviewed by Montgomery and colleagues (206). In the aggregate, it appears that the ACE I/D polymorphism may contribute to human variation in skeletal and cardiac muscle growth and functional properties as well as in adaptation to hypoxia. However, its contribution to variation in human physical performance remains a matter of debate.
ACTN3 Gene
Kathryn North and colleagues from the Children's Hospital at Westmead in Australia discovered a common variant in the gene for actinin-3, a structural actin binding protein found in skeletal muscle fast-twitch fibers (figure 7.10). The polymorphism (R577X) replaces an arginine residue by a premature stop codon at position 577 and results in ACTN3 deficiency. About 16% of the world population is homozygous for the XX null genotype; the frequency of the null allele is highest in Caucasians and Asians and lowest in Africans (8). The first report on ACTN3 genotype and performance was from North's laboratory in 2003. It indicated that the frequency of the stop codon mutation was lower in sprinters than in controls and endurance athletes (248). Several studies have concluded that the stop codon variant (X577X) was lower in sprint and strength athletes than in nonathletes (55, 57, 153, 189, 192, 248), but other reports have been negative (149, 198, 249). Interestingly, a number of studies based on direct measures of muscle strength and power have also been published and the results are contradictory; that is, the X allele is negatively associated with these muscle phenotypes in some studies whereas the converse is found in others (39, 51, 66, 132, 133, 146, 150, 228). North has reviewed the biology of the ACTN3 polymorphism in recent publications (8, 120). In the aggregate, the data suggest that there is probably a role of the X allele in skeletal muscle function and muscle performance, but the data remain inconclusive at present. More studies with appropriate power and designs, as well as more extensive functional studies, are warranted.
Kathryn North (1960 - ), MD, FRACP, Director, Murdoch Childrens Research Institute, and David Danks Professor of Child Health Research at University of Melbourne, Australia. In the process of studying genes implicated in muscle disease, North and colleagues at the Children's Hospital at Westmead discovered a common variant in the actinin alpha 3 (ACTN3) gene. ACTN3 encodes a structural protein found in fast-twitch skeletal muscle fibers. The ACTN3 gene variant results in complete deficiency of actinin-3 in almost 20% of the general population. North showed that ACTN3 deficiency is rare in sprint athletes, suggesting that this protein plays a crucial role in the function of fast-twitch muscle fibers. North and her team developed a strain of mice engineered to be completely deficient in ACTN3 and showed that the muscle of these knockout mice displays an increase in oxidative metabolism. This metabolic shift could explain why ACTN3 deficiency is detrimental to sprint activities that require fast or glycolytic metabolism. Her analysis of deoxyribonucleic acid (DNA) samples from individuals from around the world suggests that the ACTN3 deficiency provided some benefit to the ancestors of modern Europeans and Asians after their migration out of Africa, resulting in its increase in frequency due to natural selection. The benefit provided by ACTN3 deficiency may have allowed them to adapt to the more hostile environments of Eurasia. North's group plans to use mouse and human studies to determine the effect of ACTN3 deficiency on muscle aging, response to exercise, and the progression of inherited muscle diseases such as the muscular dystrophies.
Other Candidate Genes
A series of studies has dealt with the contributions of other candidate genes to human variation in muscular strength and power. These genes were identified because of their biological relevance to muscle contractile and sarcomeric proteins, myogenesis and muscle regeneration, muscle mass atrophy and sarcopenia, hormonal regulation of muscle mass, energy transfer to sustain muscle contraction, and other properties. The evidence from candidate gene studies of muscle strength and power was recently reviewed by Thomis (220).
An example of such genes is the myostatin (MSTN) gene. Mutations in MSTN leading to inactive or defective gene product have been shown to double or even triple skeletal muscle mass in mice, cows, and sheep. Functional MSTN mutations are very rare in humans. However, a boy appeared extraordinarily muscular at birth and at 4.5 yr of age was described as muscular and very strong (196). It turned out that he was a homozygote for a G/A mutation located five nucleotides downstream of exon 1, which abolishes a normal splice donor site and activates a cryptic splice site further downstream in intron 1, resulting in a truncated, inactive myostatin peptide. A number of polymorphisms in MSTN have been investigated for their associations with muscle hypertrophy or muscle strength and power (40, 60, 107, 199, 231), but the overall findings have been inconsistent.
Another class of candidate genes of great interest for muscular strength and power is that of the insulin-like growth factors and related binding proteins. These molecules play important roles in muscle growth and repair and in muscle response to exercise. Polymorphisms in insulin-like growth factors 1 (IGF1) and 2 (IGF2) have been rather consistently associated with muscle strength and its response to training, as well as other relevant endophenotypes (52, 81, 108, 193, 195).
The laboratories of James Hagberg and Stephen Roth in the department of kinesiology at the University of Maryland in the United States have pioneered a number of candidate gene research avenues since the late 1990s (figure 7.11). Their efforts focused on sequence variants in ACE; nitric oxide synthase 3 (NOS3); angiotensinogen (AGT); ACTN3; angiotensin II receptor, type 1 (AGTR1); tumor necrosis factor (TNF); nuclear factor of kappa light polypeptide gene enhancer in B-cells 1 (NFKB1); activin A receptor, type IIB (ACVR2B); adenosine monophosphate deaminase 1 (AMPD1); vascular endothelial growth factor A (VEGFA); vitamin D receptor (VDR); and MSTN, among others (see 59, 78, 79, 81, 134, 156, 167). Hagberg has a strong interest in exercise blood pressure and other hemodynamic phenotypes and through most of his career has consistently focused on the role of exercise in health-related outcomes and therapeutic applications, with an emphasis on the importance of genetic differences at key genes. Roth, whose primary interest is in muscle size and strength, has contributed a primer on exercise genetics (187) and has a longstanding interest in the role of genetic variation in talent selection for athletic performance. Both have trained a good number of graduate students in exercise genetics and have been longtime contributors to the fitness and performance gene map series that was published in Medicine and Science in Sports and Exercise until 2009.
Stephen M. Roth (1973 - ), PhD, FACSM, associate professor, and James M. Hagberg (1950 - ), PhD, FACSM, professor, department of kinesiology, school of public health, University of Maryland. Hagberg completed his graduate studies at the University of Wisconsin. He has been on the faculty of a number of universities and at the University of Maryland for nearly 20 yr, where he is a distinguished scholar-teacher. He has been funded by the National Institute of Aging for genetics-based investigations and has published numerous papers identifying genetic markers that associate with the degree to which endurance-exercise training improves cardiovascular disease risk factors in older men and women. Stephen M. Roth completed graduate studies in exercise physiology at the University of Maryland in 2000 and postdoctoral training in human genetics at the University of Pittsburgh. In 2003 he was recruited back to the University of Maryland as director of the Functional Genomics Laboratory. He has been funded by the National Institutes of Health to perform a variety of genetics investigations. In addition to several research publications, Roth is author of a textbook titled Genetics Primer for Exercise Science and Health. The department of kinesiology at the University of Maryland was one of the first to develop a research focus in the area of exercise genomics. As a group, they have published more than 60 peer-reviewed publications in the areas of exercise genomics.
When the last version of the fitness and performance gene map was published based on the publications available by the end of 2007, there were 214 autosomal, 7 X chromosome, and 18 mitochondrial gene and other loci entries (31). Most of the entries were related to specific candidate genes and were supported by more than 350 peer-reviewed papers. With the exception of the ACE and ACTN3 common variants, few of the genes had been replicated in multiple studies. Moreover, after almost 25 yr of candidate gene studies in exercise biology, this line of research continues to be plagued by small sample sizes and lack of appropriate statistical power (31, 177). Studies with small sample sizes occasionally report positive findings, especially if they include several traits and perform multiple statistical tests for association. Fortunately, these positive findings are seldom replicated and usually fall into oblivion.
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Early German roots of exercise physiology
In 1719, Friedrich Hoffmann (1660-1742), a physician from Halle, obtained his doctoral degree with experimental investigations about the effects of physical exercise on the human cardiovascular system and on digestion.
Exercise Physiology Research in Germany 1700 to 1910
In 1719, Friedrich Hoffmann (1660-1742), a physician from Halle, obtained his doctoral degree with experimental investigations about the effects of physical exercise on the human cardiovascular system and on digestion. In 1796, the physician Christoph Wilhelm Hufeland (1762-1836) published a textbook about the significance of different types of physical exercise for human health and life expectancy (66).
In the 19th century, the physiologist Emil Dubois-Reymond (1818-1896) studied the role of gymnastics in the human body (21, 22). The physician and chemist Max von Pettenkofer (1818-1901) detected the existence of creatine in the skeletal muscle and described a strengthening of the circulatory system in connection with physical training (111).
The first ergometer in the present-day sense of the word was developed by the German physician Speck in 1883. When using this cranked ergometer, the test person was in the standing position (figure 4.1). The crank friction could be modified by pulling up a screw. Speck determined the resistance with weights hung on the crank. The number of revolutions could be determined by noting the number of turns of twine wound up around the crank axle. The exhaled air was collected in a double spirometer and the postexperimental air composition was determined, thus enabling conclusions to be drawn about the individual performance reaction (2, 125).
In 1887 the Viennese physician Friedrich Gaertner (1847-1917) presented a mechanically braked ergometer, based on Speck's equipment that could measure the work performed in kilogram-meter. This device, called the ergostat, later went into standard production (112).
The first heyday of exercise physiology began with the veterinarian Nathan Zuntz (1847-1920) in Berlin (figure 4.2), who developed the first motor-driven treadmill in 1889 (figure 4.3). His work is described in chapter 1 (142).
Of substantial significance in the application of aspects of exercise physiology in medicine were Adolf Theophil Ferdinand Hueppe (1852-1938) and Ferdinand August Schmidt (1852-1929). In 1899 Hueppe wrote a fundamental work titled A Textbook of Hygiene that covered the whole of the exercise physiology discipline of those days. This was followed by the work titled Hygiene of Physical Exercises, published in 1911. In 1893 Schmidt published the book Physical Exercise According to the Exercise Value, which deals with an overview of suitable physical exercises for different ages (122, 123).
From 1904 to 1906 Kuelbs examined the influence of physical training on the internal organs, particularly the heart. He took two dogs from the same litter and trained one of them 5 times/wk for about 2 h on a treadmill, which he had taken over from Zuntz; the other dog had a normal, everyday life. After 1 yr both animals were killed and all internal organs were measured and examined. Although both dogs had more or less the same body weight, the heart of the dog trained on the treadmill was approximately 33% larger than that of the untrained dog. Similar differences were also manifest in the weights of the liver, kidneys, adrenal glands, spleen, and lungs (77).
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Over the subsequent decades Arthur Mallwitz (1880-1968) became the most important promoter for German, and later international, sports medicine. He obtained his doctor's degree at Halle University (Saale) in 1908 with what is presumed to be the first ever dissertation in sports medicine. In his dissertation, titled Maximum Performances With Special Consideration of Sports Done at the Olympic Games, Mallwitz considered, above all, the investigations of Hueppe and Schmidt as well as those of Zuntz and his school. In 1910 a comprehensive book about exercise physiology in connection with numerous kinds of sports was edited by Weissbein (141).
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The first ergometer was developed by Speck in 1883. Gaertner produced it in series.
Hollmann W, Strueder HK, Predel HG, Tagarakis CVM. Spiroergometrie. Stuttgart, Schattauer, 2006.
Exercise Physiology Research in Germany 1911 to 1933
German Empire Committee for Scientific Research in Sport and Physical Exercise
The First Congress for Scientific Research in Sport and Physical Exercise took place in Oberhof, Germany, from September 20 to 23, 1912. The congress was conducted by the professor for internal medicine of the University Clinic Berlin Charité, Friedrich Kraus (1858-1936), and was chaired by Schmidt and Hueppe. Approximately 70 doctors participated (93). On September 21, 1912, the German Empire Committee for Scientific Research in Sport and Physical Exercise - the first national medical sport association worldwide - was founded under the chairmanship ofKraus, who was elected president.
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Nathan Zuntz (1847-1920).
Reprinted, by permission, from W. Hollmann and K. Tittel, 2008, History of German sports medicine (Gera: Druckhaus Gera), 15.
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The world's first motorized treadmill, developed by Zuntz and Lehmann in 1889 in Berlin. This apparatus was shown in the international hygiene exhibition in Dresden in 1911.
Hollmann W, Strueder HK, Predel HG, Tagarakis CVM. Spiroergometry. Stuttgart, Schattauer, 2006.
Period From 1913 to 1924
In 1913, Arthur Mallwitz was appointed the first full-time sport physician worldwide by the Prussian State Gymnastics Institute. Mallwitz then took up his office under the official designation of sport physician (94).
At the same time the physician and chemist Otto Meyerhof (1884-1951) recognized the regulating relationship between respiration rate and the suppression of glycolysis in muscles. He demonstrated that the consumption of one molecule of oxygen prevents the formation of two molecules of lactate. Meyerhof's findings supported the assumption that the enzymes fanning lactate also function aerobically but that the lactate formed is resynthesized to carbohydrate at the expense of the energy provided by respiration (98).
Hugo Wilhelm Knipping (1895-1984), physician and internist at Hamburg University, developed a gas metabolism apparatus for examination of humans at rest in 1924 and constructed a dynamo cranked ergometer in 1928. In 1929 he combined an enlarged gas metabolism apparatus for exercise examinations with the crank ergometer and designated the method as spiroergometry (73, 74). It was the genesis of precise and simple clinical exercise diagnostics. Engineering, however, was not able to construct the equipment to satisfy all technical requirements until 1949 (75, 76).
German Medical Association for the Promotion of Physical Exercise (1924-1933)
Because of the political confusion and economic difficulties after the finish of World War I in 1918, approximately 6 yr elapsed before research in sports medicine and thus exercise physiology was renewed in 1924. The founding of the German Physician Association for the Promotion of Physical Exercise in 1924 was the impetus for this.
In 1925 Max Rubner (1854-1932), director of the Robert Koch Institute in Berlin and an internationally recognized metabolism researcher, ascertained that the skeletal musculature in adults amounts to 43% of the total body mass and that the total musculoskeletal system inclusive of bones, heart, and lungs amounts to 61%. The greatest proportion of the musculature was allotted to the legs (56%) and the upper extremities (28%). The head and torso muscles contributed to 16% of the total body mass (120).
Approximately 3,200 kcal could meet the daily energy requirements for physical exercise for a 70 kg person whereas 2,600 calories was sufficient for simple office work. The metabolism of a farm worker during harvesting would require 4,300 kcal. The peak values of the daily calorie consumption for lumberjacks would amount to approximately 6,000 kcal for a 70 kg person. Long-distance racing cyclists, however, could reach a peak daily metabolic rate of 11,000 kcal. Rubner believed that the limiting factor for the uptake of calories in the human body was the intestinal system. A repeat of such great exertion over several days would inevitably lead to loss of body weight (119).
As early as 1925, Herbert Herxheimer (1894-1985) and others precisely described the psychic and physical effects of overtraining, including a decrease in maximal oxygen uptake, reduced appetite, tendency to sweat, shivering, jerky reflexes, and pronounced respiratory arrhythmia with a clear preponderance of the parasympathetic part. Obstipation and painful stomach spasms also could be observed. Herxheimer published all his sports medicine knowledge in his famous book in 1933.
Herxheimer also described the connection between heart size and distance running. He found an increase in the transverse diameters of the heart in the following ascending order: boxing, swimming, middle-distance running, long-distance running, marathon running, and long-distance skiing. Particularly large hearts would work with a large stroke volume. This would result in the corresponding bradycardia at rest. The blood pressure of endurance athletes would be low (39).
Ludwig Aschoff (1866-1942) in Freiburg ascertained that there is one physiological work hypertrophy of the heart muscle as an adaptation to increased muscular activity. The enlargement remains within moderate limits. Sport does not cause a pathological hypertrophy. If a conspicuous general hypertrophy of the heart exists, it is a matter of pathological circumstances (e.g., cardiac valve ailments, hypertony or glomerular-tubular cirrhosis of the kidney). It is impossible for sport to cause a fatality in an individual with a healthy heart. A muscular cardiac insufficiency is to be treated by taking it easy. Puberty is a dangerous period regarding possible functional damage of the heart through sport.
Another significant exercise physiologist of the 1920s was Richard Herbst (1893-1949) in KÃöenigsberg East Prussia. He conducted numerous experimental investigations on the behavior of maximum oxygen absorption in humans of different ages and in different training conditions. He published his findings in 1928, 4 yr after the first description of maximum oxygen uptake by Hill. According to Herbst (1928), endurance-trained subjects had a higher oxygen intake than did untrained subjects. Also, after reaching the maximum oxygen uptake value, ventilation could be increased still further. Herbst used the Douglas bag with the subsequent respiratory gas analysis method for runners and cyclists. Further, he examined running distances between 100 m and marathon using the Douglas bag and gas analysis. The values obtained at that time (e.g., marathon with an energy consumption of 3,050 kcal, 10 m sprint with an energy consumption of 50 kcal) agree with measurements made nowadays. Sustained running loads of more than 3 min were determined from the magnitude of the maximal oxygen uptake. Thus, these parameters were a measure of performance. The lung ventilation volume would still increase further after reaching the maximum oxygen absorption. Cardiac output is represented as the most important factor limiting physical performance (37).
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Harvard Fatigue Laboratory influential in promoting exercise physiology research
Despite its brief history (1927-1947), no physiology laboratory in America is more revered than the Harvard Fatigue Laboratory.
Despite its brief history (1927-1947), no physiology laboratory in America is more revered than the Harvard Fatigue Laboratory. Described as "the first laboratory for the comprehensive study of man" (5), it was perhaps more influential and effective in promoting scientific and collaborative research in exercise physiology (76). This chapter discusses the laboratory's contributions to the study of the acute and chronic effects of exercise and to the effects of altitude and temperature on the exercise response. This chapter includes information from the laboratory's extensive published record as well as from the perspective of the last surviving member of its faculty and staff (figure 3.1) (41).
G. Edgar Folk (1914-) of the University of Iowa in the United States who became a staff member of the Harvard Fatigue Laboratory in 1943. Folk remained at the Harvard Fatigue Laboratory until its closure in 1947. He subsequently spent six yr at Bowdoin College in Maine conducting research and teaching biology to undergraduate students. In 1953, he accepted an appointment in the department of physiology at the University of Iowa. Professor Folk continues to attend APS meetings, write manuscripts, and enjoy life as an elder statesman for physiology.
Harvard University (1920-1927)
In 1920, physiology at Harvard University was represented by four departments: physiology, comparative physiology, applied physiology, and physical chemistry. These departments were collectively known as the laboratories of physiology(53). Three years later, the department of industrial hygiene was transferred from the medical school to the recently established school of public health, facilitated by the efforts of Roger Lee (53). Subsequently, the department of industrial hygiene was renamed the department of applied physiology. At this time, Walter B. Cannon (1871-1945) was chairman of the department of physiology, David Edsall was dean of both the medical school and the school of public health, Lawrence Joseph Henderson (1888-1984) was director of the department of physical chemistry (figure 3.2), Wallace B. Donham was dean of the business school, and A. Laurence Lowell was president of the university (53). Also at this time, Dr. Arlie V. Bock was establishing a laboratory in Massachusetts General Hospital after being a physician in World War I, a Moseley Traveling Fellow in Sir Joseph Barcroft's laboratory for two years learning exercise protocols and blood-equilibration techniques, and after being a participant in Barcroft's high-altitude expedition in Peru (23) (figure 3.2).
David Bruce Dill (1891-1986) received his PhD in chemistry in 1925 from Stanford University and accepted a 2 yr National Research Council fellowship to work in the laboratory of L.J. Henderson to study the physical chemistry of proteins. However, after his arrival at Harvard, he was assigned to a Massachusetts General Hospital laboratory, where the senior staff physician was Dr. John H. Talbott. There he was reassigned to study with Dr. Bock the physiochemical properties of blood (46). When the fellowship was terminated, Dill was appointed as assistant professor of biochemistry in the school of public health, a position he retained until 1936. In addition, from 1927 to 1947, he held a professorship in the department of industrial hygiene at Harvard University (72). Although during his tenure at Harvard Henderson remained as director of the laboratory, it was Dill's leadership, organizational ability, and scientific insights that made the laboratory famous throughout the world. Between 1947 and 1961, Dill served as director of research for the U.S. Army Chemical Research and Development Laboratory. During this interval, he became president of the American Physiological Society (1950-1951) and later (1960-1961) was elected president of the American College of Sports Medicine (45, 74).
Henderson and the Establishment of the Harvard Fatigue Laboratory
Henderson, a recipient of an MD from Harvard in 1902, was professor of biological chemistry from 1919 until 1934 and the Abbot and James Lawrence professor of chemistry from 1934 until his death in 1942 (18) (figure 3.2). Besides chemistry and biology, Henderson had broad interests in sociology, psychology, anthropology, and the philosophy of Vilfredo Pareto, an Italian engineer and socialist (18, 46). He and Elton Mayo (a professor of industrial hygiene who, like Henderson, believed that workers should be studied in the workplace) developed the concept of establishing a laboratory to conduct research on industrial hazards (46). Such a laboratory would study the "group psychology, the social problems, and physiology of fatigue of normal man . . . not only as individual factors in determining physical and mental health, but more especially to determine their interrelatedness and the effect upon work" (46, p. 20).
With leadership from Henderson, the support of advisory and planning committees that included most of the previously mentioned deans and professors, the endorsement of President Lowell, and funding from the Laura Spelman Rockefeller Memorial and the Rockefeller Foundation, the Harvard Fatigue Laboratory was established in 1927 with Lawrence Joseph Henderson as its official director (46). According to Chapman, the term fatigue was selected because all parties believed it was important. However, because they could not agree on a definition, it did not force research activities into a specific departmental shape(19, p. 19). Its home was in the basement of Harvard Business School.
As noted, Dill was designated (although never officially appointed) to organize and direct the research program of the laboratory and quickly assumed the duties and responsibilities of Henderson. Hence, his curriculum vitae in the Mandeville Special Collections Library at the University of California in the United States lists him as the informal director of the laboratory between 1927 and 1946 (72). The Horvaths identified the senior members of the laboratory from 1927 to before World War II as Henderson, Dill, Bock, and Talbott (figure 3.2) (46).
Contributions to Undergraduate and Graduate Student Education
Although the education of undergraduate and graduate students was not a purpose for establishing the laboratory, the laboratory did provide opportunities for undergraduate and graduate students to be introduced to research and become involved with projects that all pertained to physiology and sometimes to exercise physiology. Although the laboratory offered no courses or degrees, it offered opportunities for students to conduct senior theses under the supervision of select faculty members. Twelve undergraduates were involved in activities of the laboratory. Henry Taylor became a renowned exercise physiologist at the University of Minnesota in the United States (figure 3.4). Richard Riley was recognized as an outstanding respiratory physiologist at Johns Hopkins University, and John Pappenheimer and Clifford Barger received acclaim as physiologists on the faculty of Harvard University (46). Sid Robinson and Steven Horvath (figures 3.5 and 3.6) conducted research for their PhD dissertations in the laboratory but received their degrees in biological sciences. Dill served as chairman of Robinson's committee but was unable to do so for Horvath because Horvath had married Dill's daughter (73). G. Edgar Folk Jr. received an MA from Harvard University in 1937 and served as a research associate in the laboratory from 1943 to 1947 (figure 3.1). In 1947, he received a PhD in the biological sciences with John Welch as his advisor (74). Additionally, Pappenheimer, Robinson, and Horvath served along with 13 other staff members as tutors for students in biochemistry (46).
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Advances in studies of genes associated with exercise behavior traits
Several research designs and technologies have been used over the past two decades in the effort to identify genomic regions, genes, and sequence variants associated with exercise behavior and exercise biology traits.
Genomics Studies
Several research designs and technologies have been used over the past two decades in the effort to identify genomic regions, genes, and sequence variants associated with exercise behavior and exercise biology traits. This section reviews advances made over time and key laboratories and investigators involved in these studies. Candidate genes, genome-wide linkage scans, genome-wide association (GWA) studies, and contributions from combinations of transcriptomics and genomics are reviewed. Efforts to identify genetic differences between elite athletes and sedentary controls are also briefly summarized.
Candidate Genes
A candidate gene is a gene that has a theoretical relationship with the behavioral, physiological, or metabolic system regulating the trait of interest. Candidate genes for exercise biology traits have been defined on the basis of advances in exercise physiology studies and animal models and on purely theoretical grounds. Transgenic (overexpression of a gene or genes), knockdown (reduced expression level), and knockout (ablation of a gene or genes) mice have generated a number of candidate genes that were subsequently investigated for potential involvement in human variation. The expression level of a gene has also been used as a candidate phenotype against which DNA variants can be tested for associations. The complete transcriptome, which is the full set of ribonucleic acid (RNA) transcripts in a given cell or tissue, has been used to define new panels of candidate genes for further genomics studies (e.g., 72, 224).
Candidate genes were very prominent in the early phase of exercise genomics. Many of the earlier studies were quite simple in design and were launched primarily because of the availability of whole blood stored in freezers. They were generally case-control or cross-sectional cohort studies with unrelated subjects. In the case of continuous traits (e.g., V\od\O2max), the association with a candidate gene or marker is tested by comparing mean trait values across genotypes or between carriers and noncarriers of a specific allele. In the case-control design, testing for a relation between a trait and a candidate gene marker is based on the comparison of allele and genotype frequencies between two informative groups of subjects, one with the phenotype of interest (e.g., elite power and strength athletes - the "cases") and the other without the phenotype of interest (the "controls").
Special Case of Athletes Versus Controls
Luigi Gedda from the Gregor Mendel Institute of Medical Genetics and Twin Research at the University of Rome was perhaps the pioneer in the effort to understand the importance of genetic differences between athletes and nonathletes (67, 68) (figure 7.7). The initial efforts were based on surveys of Italian twins, specifically on 351 pairs of twins who were engaged in competitive sport. The results of the surveys indicated familial aggregation among athletes and the potential importance of zygosity in concordance of sport selection; participation in markedly different sports occurred in 85% of DZ twins in contrast to only 6% of MZ twins (68). The familial aggregation of athletes was also noted by others, such as Grebe (75, 76) of Germany, Linc and Fleischmann (117) of Czechoslovakia, and Jokl (92, 93), who at the time was in the United States. The work of Gedda and his longtime collaborator, Paolo Parisi, was the most systematic in this regard and focused on genealogical and twin methods. The research of Parisi continues today with the Italian Registry of Twin Athletes (154, 155). A higher prevalence of MZ twins among swimmers has been one of their findings (154). In a large sample of adult British female twins, athlete status (nonathlete vs. local-, county-, or national-level athlete) had a heritability of 0.66 (50).
Luigi Gedda (1902-2000), MD, Mendel Institute of Medical Genetics and Twin Research in Rome, right, and Paolo Parisi (1940 - ), PhD, professor of biology and rector, Italian University Sport and Movement, University of Rome "Foro Italico," left. Gedda was the first to confirm, through classic pedigree studies in the mid-1950s, the common knowledge that elite athletes often cluster in families and to then attempt to quantify the role of genetic factors using the twin concordance model. He studied a large sample of MZ and DZ twin pairs and found considerably higher concordance rates in the former than in the latter with respect to various aspects of sport participation, such as kind of sport practiced and performance level. In later decades, Gedda's longtime associate Paolo Parisi conducted epidemiological and cell genetics research, also through the aid of a special registry of Italian twin athletes, in order to explore the genetic basis of athletic performance. Of particular interest to him is the relation of physical activity to health, aging, and chronic disease. One major line of research of his institute focuses on the role of exercise-induced oxidative stress in genetic regulation processes.
The first documented attempt to identify differences in genetic markers for performance-related phenotypes dates to the late 1960s. A group of geneticists, taking advantage of the 1968 Olympic Games in Mexico, investigated common blood genetic markers in an attempt to discriminate between Olympic athletes and controls (45).
Interestingly, phenylthiocarbamide nontasters were underrepresented among the athletes. The effort to document genetic differences between elite athletes and sedentary controls was continued on the occasion of the 1976 Olympic Games in Montreal (37, 41). A slightly higher frequency of the A1 allele of the ABO blood group was observed in endurance athletes participating in the 1976 Summer Olympic Games than in reference populations (37). However, the other plasma and red blood cell markers (ABO, MNSs, Rhesus, Duffy, Kell, P, LDH, MDH, phosphoglucomutase, adenosine deaminase, adenylate kinase, esterase D, haptoglobin, transferrin, hemoglobin, glucose-6-phosphate dehydrogenase, and acid phosphatase) did not differ between athletes and controls (37, 41, 45). These early attempts were all based on polymorphisms in red blood cell antigens and enzymes. Later, skeletal muscle gene product variants were screened (17, 128) and selected enzyme markers were investigated for their putative effects on a variety of skeletal muscle and cardiorespiratory endurance indicators. Genetic variants of skeletal muscle creatine kinase (CKM) and adenylate kinase 1 (AK1) were screened for using isoelectric focusing in 295 subjects (16). A variant form of both enzymes was identified with an allele frequency of 1% (CKM) and 3.5% (AK1). There was no difference in V\od\O2max between the carriers of the variant alleles and matched controls homozygous for the nonvariant allele (16). None of these studies yielded reliably significant genomic predictors of performance or fitness.
Genomic differences between athletes and untrained controls began to be investigated in a more systematic fashion with the launch of the GENATHLETE study in the laboratory of Claude Bouchard at Laval University in 1993. The main collaborators on GENATHLETE included Louis Perusse, Marcel Boulay, and the late Jean-Aime Simoneau (all from Laval University), Rainer Rauramaa (Kuopio, Finland), and particularly Bernd Wolfahrt (from Germany). The study focused on DNA sequence differences between a panel that has now attained more than 300 elite endurance athletes with a V\od\O2max no lower than 75 ml·kg-1·min-1 and more than 300 sedentary controls with a V\od\O2max no higher than 50 ml·kg-1·min-1. The participants are all white males from Canada, Germany, Finland, and the United States. Single nucleotide polymorphisms (SNPs) in several genes have been investigated to date, but none have provided strong evidence for differences in allele and genotype frequencies between athletes and controls (16, 178, 184, 185, 245-247). However, a common variant and haplotype in the hypoxia inducible factor 1, alpha subunit (HIF1A) gene were found to be more prevalent in athletes compared with controls in a 2010 report based on the GENATHLETE cohort (54), an observation that was defined in an accompanying editorial as an important milestone (194).
Another effort to delineate the differences between athletes and nonathletes is under way in Spain under the leadership of Jonatan Ruiz and Alejandro Lucia. They have used samples of Spanish Caucasian endurance athletes (about 100), power athletes (about 50), and nonathlete controls. A number of differences at candidate genes between athletes and controls, as well as between endurance and power athletes, have been reported (34, 71, 190). Taking advantage of the concept of a total genotype score developed by Williams and Folland (238), Ruiz and colleagues in 2009 attempted to predict world-class endurance athlete status based on the frequency of variant alleles at 7 candidate genes genotyped in 43 Spanish endurance athletes and 123 controls (191).
Yannis Pitsiladis from the faculty of biomedical and life sciences at the University of Glasgow has taken advantage of striking performance differences at the elite level in athletes of various ethnic backgrounds to investigate the potential role of variation in nuclear and mitochondrial DNA (figure 7.8). For instance, distance runners from Kenya and Ethiopia and sprinters from Jamaica won 25% of all track and field medals at the 2008 Olympic Games in Beijing (166). The effort to impute ethnic differences in sport performance to genetic differences is clearly challenging, particularly because only about 10% of human genetic variation can be found between the major ethnic groups. Pitsiladis' laboratory has explored differences in sequence variants in mitochondrial DNA and in Y chromosome markers between Ethiopian athletes, Ethiopian controls, Kenyan athletes, and Kenyan controls. Mitochondrial DNA haplogroups found in Kenya were different from those found in Ethiopia (197). Differences in haplogroup distributions were observed between athletes and controls in Kenya but not in Ethiopia. The full significance of this observation needs to be established. Analyses of Y chromosome haplogroups in endurance athletes from Ethiopia revealed differences between them and samples from the more general Ethiopian population (145). Population stratification was ruled out as the explanation for such differences. One important conclusion reached by Pitsiladis and colleagues is that the clusters of Kenyan and Ethiopian elite runners are distinct from each other from a genetic point of view (166).
Yannis P. Pitsiladis (1967 - ), MMedSci, PhD, FACSM, integrative and systems biology research theme, faculty of biomedical and life sciences, University of Glasgow, Scotland. Pitsiladis is a reader in exercise physiology at the Institute of Biomedical and Life Sciences at the University of Glasgow and founding member (and previous director) of the International Centre for East African Running Science, set up to investigate the physiological, genetic, psychosocial, and economic determinants of the phenomenal success of East African distance runners in international athletics. Recent projects include the study of West African sprinters (including elite sprinters from Jamaica and the United States) and the study of world-class swimmers (e.g., why there are very few black swimmers). He is a visiting professor in medical physiology at Moi University (Eldoret, Kenya), Addis Ababa University (Addis Ababa, Ethiopia), and University of Technology (Kingston, Jamaica). Pitsiladis has a particular research interest in mitochondrial DNA and Y chromosome markers and their potential role in ethnic differences in performance.
Photo courtesy of Yannis P. Pitsiladis.
Two genes have received considerable attention in the exercise genomics literature: angiotensin I-converting enzyme (ACE) and actinin alpha 3 (ACTN3). Both have been strong favorites of exercise scientists over the past decade or so.
ACE Gene
Hugh Montgomery (1962 - ), MB, BS, BSc, FRCP, MD, FRGS, director of University College London Institute for Human Health and Performance; consultant intensivist at Whittington Hospital; and professor of intensive care medicine at University College London. Montgomery obtained his BSc degree in neuropharmacology and in circulatory and respiratory physiology in 1984 before graduating with a medical degree in 1987. He has since trained and accredited in general internal medicine, cardiology, and intensive care medicine. He is now professor of intensive care medicine at University College London, where he also directs the Institute for Human Health and Performance. In the early 1990s, he began using gene - environment interaction as a means to explore human physiology. Working with army recruits, he first identified a role for the angiotensin I-converting enzyme (ACE) I/D polymorphism in the regulation of human cardiac growth. This work was extended to broader measures of performance, including high-altitude mountaineering aptitude. Mechanistically, a role in the regulation of metabolic efficiency was suggested, leading to phase IV studies of ACE inhibition in the treatment of cancer cachexia. Studies of downstream gene variants (e.g., those of the bradykinin B2 receptor gene) have offered further mechanistic insight. Montgomery has a special interest in high-altitude performance: He was science lead for the Caudwell Xtreme Everest Expedition in 2007 and has identified genes under selection pressure in high-altitude populations.
The potential role of ACE sequence differences in human physical performance was first investigated in the 1990s by Hugh Montgomery from the University College London (figure 7.9). He and his coworkers reported in 1997 that 10 wk of physical training in British army recruits induced greater increases in left ventricular mass and septal and posterior wall thickness in the ACE D/D homozygotes than in the I allele carriers (141). A few years later, the same group of investigators confirmed the finding by reporting that the training-induced increase in left ventricular mass in another cohort of army recruits was 2.7 times greater in the D/D genotype compared with the I/I homozygotes (147). The I allele was associated with higher muscular endurance gains after 10 wk of physical training in British army recruits (142).
The story began in 1990 when it was reported that a 287 bp I/D polymorphism in intron 16 of the ACE gene was associated with plasma ACE activity (183). ACE activity was highest in D/D homozygotes and lowest in I/I homozygotes. More than 50 reports have subsequently dealt with the potential role of the ACE I/D genotype in some aspects of fitness or performance. Overall, the results are heterogeneous and often contradictory. For instance, in postmenopausal women, I/I homozygotes had a higher V\od\O2max than D/D homozygotes (79), whereas the opposite was observed in Chinese males (251). In the HERITAGE Family Study, no associations were found between the ACE I/D polymorphism and maximal and submaximal exercise V\od\O2 and power output phenotypes in healthy, sedentary blacks and whites (41).
This literature was recently reviewed by Montgomery and colleagues (206). In the aggregate, it appears that the ACE I/D polymorphism may contribute to human variation in skeletal and cardiac muscle growth and functional properties as well as in adaptation to hypoxia. However, its contribution to variation in human physical performance remains a matter of debate.
ACTN3 Gene
Kathryn North and colleagues from the Children's Hospital at Westmead in Australia discovered a common variant in the gene for actinin-3, a structural actin binding protein found in skeletal muscle fast-twitch fibers (figure 7.10). The polymorphism (R577X) replaces an arginine residue by a premature stop codon at position 577 and results in ACTN3 deficiency. About 16% of the world population is homozygous for the XX null genotype; the frequency of the null allele is highest in Caucasians and Asians and lowest in Africans (8). The first report on ACTN3 genotype and performance was from North's laboratory in 2003. It indicated that the frequency of the stop codon mutation was lower in sprinters than in controls and endurance athletes (248). Several studies have concluded that the stop codon variant (X577X) was lower in sprint and strength athletes than in nonathletes (55, 57, 153, 189, 192, 248), but other reports have been negative (149, 198, 249). Interestingly, a number of studies based on direct measures of muscle strength and power have also been published and the results are contradictory; that is, the X allele is negatively associated with these muscle phenotypes in some studies whereas the converse is found in others (39, 51, 66, 132, 133, 146, 150, 228). North has reviewed the biology of the ACTN3 polymorphism in recent publications (8, 120). In the aggregate, the data suggest that there is probably a role of the X allele in skeletal muscle function and muscle performance, but the data remain inconclusive at present. More studies with appropriate power and designs, as well as more extensive functional studies, are warranted.
Kathryn North (1960 - ), MD, FRACP, Director, Murdoch Childrens Research Institute, and David Danks Professor of Child Health Research at University of Melbourne, Australia. In the process of studying genes implicated in muscle disease, North and colleagues at the Children's Hospital at Westmead discovered a common variant in the actinin alpha 3 (ACTN3) gene. ACTN3 encodes a structural protein found in fast-twitch skeletal muscle fibers. The ACTN3 gene variant results in complete deficiency of actinin-3 in almost 20% of the general population. North showed that ACTN3 deficiency is rare in sprint athletes, suggesting that this protein plays a crucial role in the function of fast-twitch muscle fibers. North and her team developed a strain of mice engineered to be completely deficient in ACTN3 and showed that the muscle of these knockout mice displays an increase in oxidative metabolism. This metabolic shift could explain why ACTN3 deficiency is detrimental to sprint activities that require fast or glycolytic metabolism. Her analysis of deoxyribonucleic acid (DNA) samples from individuals from around the world suggests that the ACTN3 deficiency provided some benefit to the ancestors of modern Europeans and Asians after their migration out of Africa, resulting in its increase in frequency due to natural selection. The benefit provided by ACTN3 deficiency may have allowed them to adapt to the more hostile environments of Eurasia. North's group plans to use mouse and human studies to determine the effect of ACTN3 deficiency on muscle aging, response to exercise, and the progression of inherited muscle diseases such as the muscular dystrophies.
Other Candidate Genes
A series of studies has dealt with the contributions of other candidate genes to human variation in muscular strength and power. These genes were identified because of their biological relevance to muscle contractile and sarcomeric proteins, myogenesis and muscle regeneration, muscle mass atrophy and sarcopenia, hormonal regulation of muscle mass, energy transfer to sustain muscle contraction, and other properties. The evidence from candidate gene studies of muscle strength and power was recently reviewed by Thomis (220).
An example of such genes is the myostatin (MSTN) gene. Mutations in MSTN leading to inactive or defective gene product have been shown to double or even triple skeletal muscle mass in mice, cows, and sheep. Functional MSTN mutations are very rare in humans. However, a boy appeared extraordinarily muscular at birth and at 4.5 yr of age was described as muscular and very strong (196). It turned out that he was a homozygote for a G/A mutation located five nucleotides downstream of exon 1, which abolishes a normal splice donor site and activates a cryptic splice site further downstream in intron 1, resulting in a truncated, inactive myostatin peptide. A number of polymorphisms in MSTN have been investigated for their associations with muscle hypertrophy or muscle strength and power (40, 60, 107, 199, 231), but the overall findings have been inconsistent.
Another class of candidate genes of great interest for muscular strength and power is that of the insulin-like growth factors and related binding proteins. These molecules play important roles in muscle growth and repair and in muscle response to exercise. Polymorphisms in insulin-like growth factors 1 (IGF1) and 2 (IGF2) have been rather consistently associated with muscle strength and its response to training, as well as other relevant endophenotypes (52, 81, 108, 193, 195).
The laboratories of James Hagberg and Stephen Roth in the department of kinesiology at the University of Maryland in the United States have pioneered a number of candidate gene research avenues since the late 1990s (figure 7.11). Their efforts focused on sequence variants in ACE; nitric oxide synthase 3 (NOS3); angiotensinogen (AGT); ACTN3; angiotensin II receptor, type 1 (AGTR1); tumor necrosis factor (TNF); nuclear factor of kappa light polypeptide gene enhancer in B-cells 1 (NFKB1); activin A receptor, type IIB (ACVR2B); adenosine monophosphate deaminase 1 (AMPD1); vascular endothelial growth factor A (VEGFA); vitamin D receptor (VDR); and MSTN, among others (see 59, 78, 79, 81, 134, 156, 167). Hagberg has a strong interest in exercise blood pressure and other hemodynamic phenotypes and through most of his career has consistently focused on the role of exercise in health-related outcomes and therapeutic applications, with an emphasis on the importance of genetic differences at key genes. Roth, whose primary interest is in muscle size and strength, has contributed a primer on exercise genetics (187) and has a longstanding interest in the role of genetic variation in talent selection for athletic performance. Both have trained a good number of graduate students in exercise genetics and have been longtime contributors to the fitness and performance gene map series that was published in Medicine and Science in Sports and Exercise until 2009.
Stephen M. Roth (1973 - ), PhD, FACSM, associate professor, and James M. Hagberg (1950 - ), PhD, FACSM, professor, department of kinesiology, school of public health, University of Maryland. Hagberg completed his graduate studies at the University of Wisconsin. He has been on the faculty of a number of universities and at the University of Maryland for nearly 20 yr, where he is a distinguished scholar-teacher. He has been funded by the National Institute of Aging for genetics-based investigations and has published numerous papers identifying genetic markers that associate with the degree to which endurance-exercise training improves cardiovascular disease risk factors in older men and women. Stephen M. Roth completed graduate studies in exercise physiology at the University of Maryland in 2000 and postdoctoral training in human genetics at the University of Pittsburgh. In 2003 he was recruited back to the University of Maryland as director of the Functional Genomics Laboratory. He has been funded by the National Institutes of Health to perform a variety of genetics investigations. In addition to several research publications, Roth is author of a textbook titled Genetics Primer for Exercise Science and Health. The department of kinesiology at the University of Maryland was one of the first to develop a research focus in the area of exercise genomics. As a group, they have published more than 60 peer-reviewed publications in the areas of exercise genomics.
When the last version of the fitness and performance gene map was published based on the publications available by the end of 2007, there were 214 autosomal, 7 X chromosome, and 18 mitochondrial gene and other loci entries (31). Most of the entries were related to specific candidate genes and were supported by more than 350 peer-reviewed papers. With the exception of the ACE and ACTN3 common variants, few of the genes had been replicated in multiple studies. Moreover, after almost 25 yr of candidate gene studies in exercise biology, this line of research continues to be plagued by small sample sizes and lack of appropriate statistical power (31, 177). Studies with small sample sizes occasionally report positive findings, especially if they include several traits and perform multiple statistical tests for association. Fortunately, these positive findings are seldom replicated and usually fall into oblivion.
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Early German roots of exercise physiology
In 1719, Friedrich Hoffmann (1660-1742), a physician from Halle, obtained his doctoral degree with experimental investigations about the effects of physical exercise on the human cardiovascular system and on digestion.
Exercise Physiology Research in Germany 1700 to 1910
In 1719, Friedrich Hoffmann (1660-1742), a physician from Halle, obtained his doctoral degree with experimental investigations about the effects of physical exercise on the human cardiovascular system and on digestion. In 1796, the physician Christoph Wilhelm Hufeland (1762-1836) published a textbook about the significance of different types of physical exercise for human health and life expectancy (66).
In the 19th century, the physiologist Emil Dubois-Reymond (1818-1896) studied the role of gymnastics in the human body (21, 22). The physician and chemist Max von Pettenkofer (1818-1901) detected the existence of creatine in the skeletal muscle and described a strengthening of the circulatory system in connection with physical training (111).
The first ergometer in the present-day sense of the word was developed by the German physician Speck in 1883. When using this cranked ergometer, the test person was in the standing position (figure 4.1). The crank friction could be modified by pulling up a screw. Speck determined the resistance with weights hung on the crank. The number of revolutions could be determined by noting the number of turns of twine wound up around the crank axle. The exhaled air was collected in a double spirometer and the postexperimental air composition was determined, thus enabling conclusions to be drawn about the individual performance reaction (2, 125).
In 1887 the Viennese physician Friedrich Gaertner (1847-1917) presented a mechanically braked ergometer, based on Speck's equipment that could measure the work performed in kilogram-meter. This device, called the ergostat, later went into standard production (112).
The first heyday of exercise physiology began with the veterinarian Nathan Zuntz (1847-1920) in Berlin (figure 4.2), who developed the first motor-driven treadmill in 1889 (figure 4.3). His work is described in chapter 1 (142).
Of substantial significance in the application of aspects of exercise physiology in medicine were Adolf Theophil Ferdinand Hueppe (1852-1938) and Ferdinand August Schmidt (1852-1929). In 1899 Hueppe wrote a fundamental work titled A Textbook of Hygiene that covered the whole of the exercise physiology discipline of those days. This was followed by the work titled Hygiene of Physical Exercises, published in 1911. In 1893 Schmidt published the book Physical Exercise According to the Exercise Value, which deals with an overview of suitable physical exercises for different ages (122, 123).
From 1904 to 1906 Kuelbs examined the influence of physical training on the internal organs, particularly the heart. He took two dogs from the same litter and trained one of them 5 times/wk for about 2 h on a treadmill, which he had taken over from Zuntz; the other dog had a normal, everyday life. After 1 yr both animals were killed and all internal organs were measured and examined. Although both dogs had more or less the same body weight, the heart of the dog trained on the treadmill was approximately 33% larger than that of the untrained dog. Similar differences were also manifest in the weights of the liver, kidneys, adrenal glands, spleen, and lungs (77).
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Over the subsequent decades Arthur Mallwitz (1880-1968) became the most important promoter for German, and later international, sports medicine. He obtained his doctor's degree at Halle University (Saale) in 1908 with what is presumed to be the first ever dissertation in sports medicine. In his dissertation, titled Maximum Performances With Special Consideration of Sports Done at the Olympic Games, Mallwitz considered, above all, the investigations of Hueppe and Schmidt as well as those of Zuntz and his school. In 1910 a comprehensive book about exercise physiology in connection with numerous kinds of sports was edited by Weissbein (141).
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The first ergometer was developed by Speck in 1883. Gaertner produced it in series.
Hollmann W, Strueder HK, Predel HG, Tagarakis CVM. Spiroergometrie. Stuttgart, Schattauer, 2006.
Exercise Physiology Research in Germany 1911 to 1933
German Empire Committee for Scientific Research in Sport and Physical Exercise
The First Congress for Scientific Research in Sport and Physical Exercise took place in Oberhof, Germany, from September 20 to 23, 1912. The congress was conducted by the professor for internal medicine of the University Clinic Berlin Charité, Friedrich Kraus (1858-1936), and was chaired by Schmidt and Hueppe. Approximately 70 doctors participated (93). On September 21, 1912, the German Empire Committee for Scientific Research in Sport and Physical Exercise - the first national medical sport association worldwide - was founded under the chairmanship ofKraus, who was elected president.
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Nathan Zuntz (1847-1920).
Reprinted, by permission, from W. Hollmann and K. Tittel, 2008, History of German sports medicine (Gera: Druckhaus Gera), 15.
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The world's first motorized treadmill, developed by Zuntz and Lehmann in 1889 in Berlin. This apparatus was shown in the international hygiene exhibition in Dresden in 1911.
Hollmann W, Strueder HK, Predel HG, Tagarakis CVM. Spiroergometry. Stuttgart, Schattauer, 2006.
Period From 1913 to 1924
In 1913, Arthur Mallwitz was appointed the first full-time sport physician worldwide by the Prussian State Gymnastics Institute. Mallwitz then took up his office under the official designation of sport physician (94).
At the same time the physician and chemist Otto Meyerhof (1884-1951) recognized the regulating relationship between respiration rate and the suppression of glycolysis in muscles. He demonstrated that the consumption of one molecule of oxygen prevents the formation of two molecules of lactate. Meyerhof's findings supported the assumption that the enzymes fanning lactate also function aerobically but that the lactate formed is resynthesized to carbohydrate at the expense of the energy provided by respiration (98).
Hugo Wilhelm Knipping (1895-1984), physician and internist at Hamburg University, developed a gas metabolism apparatus for examination of humans at rest in 1924 and constructed a dynamo cranked ergometer in 1928. In 1929 he combined an enlarged gas metabolism apparatus for exercise examinations with the crank ergometer and designated the method as spiroergometry (73, 74). It was the genesis of precise and simple clinical exercise diagnostics. Engineering, however, was not able to construct the equipment to satisfy all technical requirements until 1949 (75, 76).
German Medical Association for the Promotion of Physical Exercise (1924-1933)
Because of the political confusion and economic difficulties after the finish of World War I in 1918, approximately 6 yr elapsed before research in sports medicine and thus exercise physiology was renewed in 1924. The founding of the German Physician Association for the Promotion of Physical Exercise in 1924 was the impetus for this.
In 1925 Max Rubner (1854-1932), director of the Robert Koch Institute in Berlin and an internationally recognized metabolism researcher, ascertained that the skeletal musculature in adults amounts to 43% of the total body mass and that the total musculoskeletal system inclusive of bones, heart, and lungs amounts to 61%. The greatest proportion of the musculature was allotted to the legs (56%) and the upper extremities (28%). The head and torso muscles contributed to 16% of the total body mass (120).
Approximately 3,200 kcal could meet the daily energy requirements for physical exercise for a 70 kg person whereas 2,600 calories was sufficient for simple office work. The metabolism of a farm worker during harvesting would require 4,300 kcal. The peak values of the daily calorie consumption for lumberjacks would amount to approximately 6,000 kcal for a 70 kg person. Long-distance racing cyclists, however, could reach a peak daily metabolic rate of 11,000 kcal. Rubner believed that the limiting factor for the uptake of calories in the human body was the intestinal system. A repeat of such great exertion over several days would inevitably lead to loss of body weight (119).
As early as 1925, Herbert Herxheimer (1894-1985) and others precisely described the psychic and physical effects of overtraining, including a decrease in maximal oxygen uptake, reduced appetite, tendency to sweat, shivering, jerky reflexes, and pronounced respiratory arrhythmia with a clear preponderance of the parasympathetic part. Obstipation and painful stomach spasms also could be observed. Herxheimer published all his sports medicine knowledge in his famous book in 1933.
Herxheimer also described the connection between heart size and distance running. He found an increase in the transverse diameters of the heart in the following ascending order: boxing, swimming, middle-distance running, long-distance running, marathon running, and long-distance skiing. Particularly large hearts would work with a large stroke volume. This would result in the corresponding bradycardia at rest. The blood pressure of endurance athletes would be low (39).
Ludwig Aschoff (1866-1942) in Freiburg ascertained that there is one physiological work hypertrophy of the heart muscle as an adaptation to increased muscular activity. The enlargement remains within moderate limits. Sport does not cause a pathological hypertrophy. If a conspicuous general hypertrophy of the heart exists, it is a matter of pathological circumstances (e.g., cardiac valve ailments, hypertony or glomerular-tubular cirrhosis of the kidney). It is impossible for sport to cause a fatality in an individual with a healthy heart. A muscular cardiac insufficiency is to be treated by taking it easy. Puberty is a dangerous period regarding possible functional damage of the heart through sport.
Another significant exercise physiologist of the 1920s was Richard Herbst (1893-1949) in KÃöenigsberg East Prussia. He conducted numerous experimental investigations on the behavior of maximum oxygen absorption in humans of different ages and in different training conditions. He published his findings in 1928, 4 yr after the first description of maximum oxygen uptake by Hill. According to Herbst (1928), endurance-trained subjects had a higher oxygen intake than did untrained subjects. Also, after reaching the maximum oxygen uptake value, ventilation could be increased still further. Herbst used the Douglas bag with the subsequent respiratory gas analysis method for runners and cyclists. Further, he examined running distances between 100 m and marathon using the Douglas bag and gas analysis. The values obtained at that time (e.g., marathon with an energy consumption of 3,050 kcal, 10 m sprint with an energy consumption of 50 kcal) agree with measurements made nowadays. Sustained running loads of more than 3 min were determined from the magnitude of the maximal oxygen uptake. Thus, these parameters were a measure of performance. The lung ventilation volume would still increase further after reaching the maximum oxygen absorption. Cardiac output is represented as the most important factor limiting physical performance (37).
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Harvard Fatigue Laboratory influential in promoting exercise physiology research
Despite its brief history (1927-1947), no physiology laboratory in America is more revered than the Harvard Fatigue Laboratory.
Despite its brief history (1927-1947), no physiology laboratory in America is more revered than the Harvard Fatigue Laboratory. Described as "the first laboratory for the comprehensive study of man" (5), it was perhaps more influential and effective in promoting scientific and collaborative research in exercise physiology (76). This chapter discusses the laboratory's contributions to the study of the acute and chronic effects of exercise and to the effects of altitude and temperature on the exercise response. This chapter includes information from the laboratory's extensive published record as well as from the perspective of the last surviving member of its faculty and staff (figure 3.1) (41).
G. Edgar Folk (1914-) of the University of Iowa in the United States who became a staff member of the Harvard Fatigue Laboratory in 1943. Folk remained at the Harvard Fatigue Laboratory until its closure in 1947. He subsequently spent six yr at Bowdoin College in Maine conducting research and teaching biology to undergraduate students. In 1953, he accepted an appointment in the department of physiology at the University of Iowa. Professor Folk continues to attend APS meetings, write manuscripts, and enjoy life as an elder statesman for physiology.
Harvard University (1920-1927)
In 1920, physiology at Harvard University was represented by four departments: physiology, comparative physiology, applied physiology, and physical chemistry. These departments were collectively known as the laboratories of physiology(53). Three years later, the department of industrial hygiene was transferred from the medical school to the recently established school of public health, facilitated by the efforts of Roger Lee (53). Subsequently, the department of industrial hygiene was renamed the department of applied physiology. At this time, Walter B. Cannon (1871-1945) was chairman of the department of physiology, David Edsall was dean of both the medical school and the school of public health, Lawrence Joseph Henderson (1888-1984) was director of the department of physical chemistry (figure 3.2), Wallace B. Donham was dean of the business school, and A. Laurence Lowell was president of the university (53). Also at this time, Dr. Arlie V. Bock was establishing a laboratory in Massachusetts General Hospital after being a physician in World War I, a Moseley Traveling Fellow in Sir Joseph Barcroft's laboratory for two years learning exercise protocols and blood-equilibration techniques, and after being a participant in Barcroft's high-altitude expedition in Peru (23) (figure 3.2).
David Bruce Dill (1891-1986) received his PhD in chemistry in 1925 from Stanford University and accepted a 2 yr National Research Council fellowship to work in the laboratory of L.J. Henderson to study the physical chemistry of proteins. However, after his arrival at Harvard, he was assigned to a Massachusetts General Hospital laboratory, where the senior staff physician was Dr. John H. Talbott. There he was reassigned to study with Dr. Bock the physiochemical properties of blood (46). When the fellowship was terminated, Dill was appointed as assistant professor of biochemistry in the school of public health, a position he retained until 1936. In addition, from 1927 to 1947, he held a professorship in the department of industrial hygiene at Harvard University (72). Although during his tenure at Harvard Henderson remained as director of the laboratory, it was Dill's leadership, organizational ability, and scientific insights that made the laboratory famous throughout the world. Between 1947 and 1961, Dill served as director of research for the U.S. Army Chemical Research and Development Laboratory. During this interval, he became president of the American Physiological Society (1950-1951) and later (1960-1961) was elected president of the American College of Sports Medicine (45, 74).
Henderson and the Establishment of the Harvard Fatigue Laboratory
Henderson, a recipient of an MD from Harvard in 1902, was professor of biological chemistry from 1919 until 1934 and the Abbot and James Lawrence professor of chemistry from 1934 until his death in 1942 (18) (figure 3.2). Besides chemistry and biology, Henderson had broad interests in sociology, psychology, anthropology, and the philosophy of Vilfredo Pareto, an Italian engineer and socialist (18, 46). He and Elton Mayo (a professor of industrial hygiene who, like Henderson, believed that workers should be studied in the workplace) developed the concept of establishing a laboratory to conduct research on industrial hazards (46). Such a laboratory would study the "group psychology, the social problems, and physiology of fatigue of normal man . . . not only as individual factors in determining physical and mental health, but more especially to determine their interrelatedness and the effect upon work" (46, p. 20).
With leadership from Henderson, the support of advisory and planning committees that included most of the previously mentioned deans and professors, the endorsement of President Lowell, and funding from the Laura Spelman Rockefeller Memorial and the Rockefeller Foundation, the Harvard Fatigue Laboratory was established in 1927 with Lawrence Joseph Henderson as its official director (46). According to Chapman, the term fatigue was selected because all parties believed it was important. However, because they could not agree on a definition, it did not force research activities into a specific departmental shape(19, p. 19). Its home was in the basement of Harvard Business School.
As noted, Dill was designated (although never officially appointed) to organize and direct the research program of the laboratory and quickly assumed the duties and responsibilities of Henderson. Hence, his curriculum vitae in the Mandeville Special Collections Library at the University of California in the United States lists him as the informal director of the laboratory between 1927 and 1946 (72). The Horvaths identified the senior members of the laboratory from 1927 to before World War II as Henderson, Dill, Bock, and Talbott (figure 3.2) (46).
Contributions to Undergraduate and Graduate Student Education
Although the education of undergraduate and graduate students was not a purpose for establishing the laboratory, the laboratory did provide opportunities for undergraduate and graduate students to be introduced to research and become involved with projects that all pertained to physiology and sometimes to exercise physiology. Although the laboratory offered no courses or degrees, it offered opportunities for students to conduct senior theses under the supervision of select faculty members. Twelve undergraduates were involved in activities of the laboratory. Henry Taylor became a renowned exercise physiologist at the University of Minnesota in the United States (figure 3.4). Richard Riley was recognized as an outstanding respiratory physiologist at Johns Hopkins University, and John Pappenheimer and Clifford Barger received acclaim as physiologists on the faculty of Harvard University (46). Sid Robinson and Steven Horvath (figures 3.5 and 3.6) conducted research for their PhD dissertations in the laboratory but received their degrees in biological sciences. Dill served as chairman of Robinson's committee but was unable to do so for Horvath because Horvath had married Dill's daughter (73). G. Edgar Folk Jr. received an MA from Harvard University in 1937 and served as a research associate in the laboratory from 1943 to 1947 (figure 3.1). In 1947, he received a PhD in the biological sciences with John Welch as his advisor (74). Additionally, Pappenheimer, Robinson, and Horvath served along with 13 other staff members as tutors for students in biochemistry (46).
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Advances in studies of genes associated with exercise behavior traits
Several research designs and technologies have been used over the past two decades in the effort to identify genomic regions, genes, and sequence variants associated with exercise behavior and exercise biology traits.
Genomics Studies
Several research designs and technologies have been used over the past two decades in the effort to identify genomic regions, genes, and sequence variants associated with exercise behavior and exercise biology traits. This section reviews advances made over time and key laboratories and investigators involved in these studies. Candidate genes, genome-wide linkage scans, genome-wide association (GWA) studies, and contributions from combinations of transcriptomics and genomics are reviewed. Efforts to identify genetic differences between elite athletes and sedentary controls are also briefly summarized.
Candidate Genes
A candidate gene is a gene that has a theoretical relationship with the behavioral, physiological, or metabolic system regulating the trait of interest. Candidate genes for exercise biology traits have been defined on the basis of advances in exercise physiology studies and animal models and on purely theoretical grounds. Transgenic (overexpression of a gene or genes), knockdown (reduced expression level), and knockout (ablation of a gene or genes) mice have generated a number of candidate genes that were subsequently investigated for potential involvement in human variation. The expression level of a gene has also been used as a candidate phenotype against which DNA variants can be tested for associations. The complete transcriptome, which is the full set of ribonucleic acid (RNA) transcripts in a given cell or tissue, has been used to define new panels of candidate genes for further genomics studies (e.g., 72, 224).
Candidate genes were very prominent in the early phase of exercise genomics. Many of the earlier studies were quite simple in design and were launched primarily because of the availability of whole blood stored in freezers. They were generally case-control or cross-sectional cohort studies with unrelated subjects. In the case of continuous traits (e.g., V\od\O2max), the association with a candidate gene or marker is tested by comparing mean trait values across genotypes or between carriers and noncarriers of a specific allele. In the case-control design, testing for a relation between a trait and a candidate gene marker is based on the comparison of allele and genotype frequencies between two informative groups of subjects, one with the phenotype of interest (e.g., elite power and strength athletes - the "cases") and the other without the phenotype of interest (the "controls").
Special Case of Athletes Versus Controls
Luigi Gedda from the Gregor Mendel Institute of Medical Genetics and Twin Research at the University of Rome was perhaps the pioneer in the effort to understand the importance of genetic differences between athletes and nonathletes (67, 68) (figure 7.7). The initial efforts were based on surveys of Italian twins, specifically on 351 pairs of twins who were engaged in competitive sport. The results of the surveys indicated familial aggregation among athletes and the potential importance of zygosity in concordance of sport selection; participation in markedly different sports occurred in 85% of DZ twins in contrast to only 6% of MZ twins (68). The familial aggregation of athletes was also noted by others, such as Grebe (75, 76) of Germany, Linc and Fleischmann (117) of Czechoslovakia, and Jokl (92, 93), who at the time was in the United States. The work of Gedda and his longtime collaborator, Paolo Parisi, was the most systematic in this regard and focused on genealogical and twin methods. The research of Parisi continues today with the Italian Registry of Twin Athletes (154, 155). A higher prevalence of MZ twins among swimmers has been one of their findings (154). In a large sample of adult British female twins, athlete status (nonathlete vs. local-, county-, or national-level athlete) had a heritability of 0.66 (50).
Luigi Gedda (1902-2000), MD, Mendel Institute of Medical Genetics and Twin Research in Rome, right, and Paolo Parisi (1940 - ), PhD, professor of biology and rector, Italian University Sport and Movement, University of Rome "Foro Italico," left. Gedda was the first to confirm, through classic pedigree studies in the mid-1950s, the common knowledge that elite athletes often cluster in families and to then attempt to quantify the role of genetic factors using the twin concordance model. He studied a large sample of MZ and DZ twin pairs and found considerably higher concordance rates in the former than in the latter with respect to various aspects of sport participation, such as kind of sport practiced and performance level. In later decades, Gedda's longtime associate Paolo Parisi conducted epidemiological and cell genetics research, also through the aid of a special registry of Italian twin athletes, in order to explore the genetic basis of athletic performance. Of particular interest to him is the relation of physical activity to health, aging, and chronic disease. One major line of research of his institute focuses on the role of exercise-induced oxidative stress in genetic regulation processes.
The first documented attempt to identify differences in genetic markers for performance-related phenotypes dates to the late 1960s. A group of geneticists, taking advantage of the 1968 Olympic Games in Mexico, investigated common blood genetic markers in an attempt to discriminate between Olympic athletes and controls (45).
Interestingly, phenylthiocarbamide nontasters were underrepresented among the athletes. The effort to document genetic differences between elite athletes and sedentary controls was continued on the occasion of the 1976 Olympic Games in Montreal (37, 41). A slightly higher frequency of the A1 allele of the ABO blood group was observed in endurance athletes participating in the 1976 Summer Olympic Games than in reference populations (37). However, the other plasma and red blood cell markers (ABO, MNSs, Rhesus, Duffy, Kell, P, LDH, MDH, phosphoglucomutase, adenosine deaminase, adenylate kinase, esterase D, haptoglobin, transferrin, hemoglobin, glucose-6-phosphate dehydrogenase, and acid phosphatase) did not differ between athletes and controls (37, 41, 45). These early attempts were all based on polymorphisms in red blood cell antigens and enzymes. Later, skeletal muscle gene product variants were screened (17, 128) and selected enzyme markers were investigated for their putative effects on a variety of skeletal muscle and cardiorespiratory endurance indicators. Genetic variants of skeletal muscle creatine kinase (CKM) and adenylate kinase 1 (AK1) were screened for using isoelectric focusing in 295 subjects (16). A variant form of both enzymes was identified with an allele frequency of 1% (CKM) and 3.5% (AK1). There was no difference in V\od\O2max between the carriers of the variant alleles and matched controls homozygous for the nonvariant allele (16). None of these studies yielded reliably significant genomic predictors of performance or fitness.
Genomic differences between athletes and untrained controls began to be investigated in a more systematic fashion with the launch of the GENATHLETE study in the laboratory of Claude Bouchard at Laval University in 1993. The main collaborators on GENATHLETE included Louis Perusse, Marcel Boulay, and the late Jean-Aime Simoneau (all from Laval University), Rainer Rauramaa (Kuopio, Finland), and particularly Bernd Wolfahrt (from Germany). The study focused on DNA sequence differences between a panel that has now attained more than 300 elite endurance athletes with a V\od\O2max no lower than 75 ml·kg-1·min-1 and more than 300 sedentary controls with a V\od\O2max no higher than 50 ml·kg-1·min-1. The participants are all white males from Canada, Germany, Finland, and the United States. Single nucleotide polymorphisms (SNPs) in several genes have been investigated to date, but none have provided strong evidence for differences in allele and genotype frequencies between athletes and controls (16, 178, 184, 185, 245-247). However, a common variant and haplotype in the hypoxia inducible factor 1, alpha subunit (HIF1A) gene were found to be more prevalent in athletes compared with controls in a 2010 report based on the GENATHLETE cohort (54), an observation that was defined in an accompanying editorial as an important milestone (194).
Another effort to delineate the differences between athletes and nonathletes is under way in Spain under the leadership of Jonatan Ruiz and Alejandro Lucia. They have used samples of Spanish Caucasian endurance athletes (about 100), power athletes (about 50), and nonathlete controls. A number of differences at candidate genes between athletes and controls, as well as between endurance and power athletes, have been reported (34, 71, 190). Taking advantage of the concept of a total genotype score developed by Williams and Folland (238), Ruiz and colleagues in 2009 attempted to predict world-class endurance athlete status based on the frequency of variant alleles at 7 candidate genes genotyped in 43 Spanish endurance athletes and 123 controls (191).
Yannis Pitsiladis from the faculty of biomedical and life sciences at the University of Glasgow has taken advantage of striking performance differences at the elite level in athletes of various ethnic backgrounds to investigate the potential role of variation in nuclear and mitochondrial DNA (figure 7.8). For instance, distance runners from Kenya and Ethiopia and sprinters from Jamaica won 25% of all track and field medals at the 2008 Olympic Games in Beijing (166). The effort to impute ethnic differences in sport performance to genetic differences is clearly challenging, particularly because only about 10% of human genetic variation can be found between the major ethnic groups. Pitsiladis' laboratory has explored differences in sequence variants in mitochondrial DNA and in Y chromosome markers between Ethiopian athletes, Ethiopian controls, Kenyan athletes, and Kenyan controls. Mitochondrial DNA haplogroups found in Kenya were different from those found in Ethiopia (197). Differences in haplogroup distributions were observed between athletes and controls in Kenya but not in Ethiopia. The full significance of this observation needs to be established. Analyses of Y chromosome haplogroups in endurance athletes from Ethiopia revealed differences between them and samples from the more general Ethiopian population (145). Population stratification was ruled out as the explanation for such differences. One important conclusion reached by Pitsiladis and colleagues is that the clusters of Kenyan and Ethiopian elite runners are distinct from each other from a genetic point of view (166).
Yannis P. Pitsiladis (1967 - ), MMedSci, PhD, FACSM, integrative and systems biology research theme, faculty of biomedical and life sciences, University of Glasgow, Scotland. Pitsiladis is a reader in exercise physiology at the Institute of Biomedical and Life Sciences at the University of Glasgow and founding member (and previous director) of the International Centre for East African Running Science, set up to investigate the physiological, genetic, psychosocial, and economic determinants of the phenomenal success of East African distance runners in international athletics. Recent projects include the study of West African sprinters (including elite sprinters from Jamaica and the United States) and the study of world-class swimmers (e.g., why there are very few black swimmers). He is a visiting professor in medical physiology at Moi University (Eldoret, Kenya), Addis Ababa University (Addis Ababa, Ethiopia), and University of Technology (Kingston, Jamaica). Pitsiladis has a particular research interest in mitochondrial DNA and Y chromosome markers and their potential role in ethnic differences in performance.
Photo courtesy of Yannis P. Pitsiladis.
Two genes have received considerable attention in the exercise genomics literature: angiotensin I-converting enzyme (ACE) and actinin alpha 3 (ACTN3). Both have been strong favorites of exercise scientists over the past decade or so.
ACE Gene
Hugh Montgomery (1962 - ), MB, BS, BSc, FRCP, MD, FRGS, director of University College London Institute for Human Health and Performance; consultant intensivist at Whittington Hospital; and professor of intensive care medicine at University College London. Montgomery obtained his BSc degree in neuropharmacology and in circulatory and respiratory physiology in 1984 before graduating with a medical degree in 1987. He has since trained and accredited in general internal medicine, cardiology, and intensive care medicine. He is now professor of intensive care medicine at University College London, where he also directs the Institute for Human Health and Performance. In the early 1990s, he began using gene - environment interaction as a means to explore human physiology. Working with army recruits, he first identified a role for the angiotensin I-converting enzyme (ACE) I/D polymorphism in the regulation of human cardiac growth. This work was extended to broader measures of performance, including high-altitude mountaineering aptitude. Mechanistically, a role in the regulation of metabolic efficiency was suggested, leading to phase IV studies of ACE inhibition in the treatment of cancer cachexia. Studies of downstream gene variants (e.g., those of the bradykinin B2 receptor gene) have offered further mechanistic insight. Montgomery has a special interest in high-altitude performance: He was science lead for the Caudwell Xtreme Everest Expedition in 2007 and has identified genes under selection pressure in high-altitude populations.
The potential role of ACE sequence differences in human physical performance was first investigated in the 1990s by Hugh Montgomery from the University College London (figure 7.9). He and his coworkers reported in 1997 that 10 wk of physical training in British army recruits induced greater increases in left ventricular mass and septal and posterior wall thickness in the ACE D/D homozygotes than in the I allele carriers (141). A few years later, the same group of investigators confirmed the finding by reporting that the training-induced increase in left ventricular mass in another cohort of army recruits was 2.7 times greater in the D/D genotype compared with the I/I homozygotes (147). The I allele was associated with higher muscular endurance gains after 10 wk of physical training in British army recruits (142).
The story began in 1990 when it was reported that a 287 bp I/D polymorphism in intron 16 of the ACE gene was associated with plasma ACE activity (183). ACE activity was highest in D/D homozygotes and lowest in I/I homozygotes. More than 50 reports have subsequently dealt with the potential role of the ACE I/D genotype in some aspects of fitness or performance. Overall, the results are heterogeneous and often contradictory. For instance, in postmenopausal women, I/I homozygotes had a higher V\od\O2max than D/D homozygotes (79), whereas the opposite was observed in Chinese males (251). In the HERITAGE Family Study, no associations were found between the ACE I/D polymorphism and maximal and submaximal exercise V\od\O2 and power output phenotypes in healthy, sedentary blacks and whites (41).
This literature was recently reviewed by Montgomery and colleagues (206). In the aggregate, it appears that the ACE I/D polymorphism may contribute to human variation in skeletal and cardiac muscle growth and functional properties as well as in adaptation to hypoxia. However, its contribution to variation in human physical performance remains a matter of debate.
ACTN3 Gene
Kathryn North and colleagues from the Children's Hospital at Westmead in Australia discovered a common variant in the gene for actinin-3, a structural actin binding protein found in skeletal muscle fast-twitch fibers (figure 7.10). The polymorphism (R577X) replaces an arginine residue by a premature stop codon at position 577 and results in ACTN3 deficiency. About 16% of the world population is homozygous for the XX null genotype; the frequency of the null allele is highest in Caucasians and Asians and lowest in Africans (8). The first report on ACTN3 genotype and performance was from North's laboratory in 2003. It indicated that the frequency of the stop codon mutation was lower in sprinters than in controls and endurance athletes (248). Several studies have concluded that the stop codon variant (X577X) was lower in sprint and strength athletes than in nonathletes (55, 57, 153, 189, 192, 248), but other reports have been negative (149, 198, 249). Interestingly, a number of studies based on direct measures of muscle strength and power have also been published and the results are contradictory; that is, the X allele is negatively associated with these muscle phenotypes in some studies whereas the converse is found in others (39, 51, 66, 132, 133, 146, 150, 228). North has reviewed the biology of the ACTN3 polymorphism in recent publications (8, 120). In the aggregate, the data suggest that there is probably a role of the X allele in skeletal muscle function and muscle performance, but the data remain inconclusive at present. More studies with appropriate power and designs, as well as more extensive functional studies, are warranted.
Kathryn North (1960 - ), MD, FRACP, Director, Murdoch Childrens Research Institute, and David Danks Professor of Child Health Research at University of Melbourne, Australia. In the process of studying genes implicated in muscle disease, North and colleagues at the Children's Hospital at Westmead discovered a common variant in the actinin alpha 3 (ACTN3) gene. ACTN3 encodes a structural protein found in fast-twitch skeletal muscle fibers. The ACTN3 gene variant results in complete deficiency of actinin-3 in almost 20% of the general population. North showed that ACTN3 deficiency is rare in sprint athletes, suggesting that this protein plays a crucial role in the function of fast-twitch muscle fibers. North and her team developed a strain of mice engineered to be completely deficient in ACTN3 and showed that the muscle of these knockout mice displays an increase in oxidative metabolism. This metabolic shift could explain why ACTN3 deficiency is detrimental to sprint activities that require fast or glycolytic metabolism. Her analysis of deoxyribonucleic acid (DNA) samples from individuals from around the world suggests that the ACTN3 deficiency provided some benefit to the ancestors of modern Europeans and Asians after their migration out of Africa, resulting in its increase in frequency due to natural selection. The benefit provided by ACTN3 deficiency may have allowed them to adapt to the more hostile environments of Eurasia. North's group plans to use mouse and human studies to determine the effect of ACTN3 deficiency on muscle aging, response to exercise, and the progression of inherited muscle diseases such as the muscular dystrophies.
Other Candidate Genes
A series of studies has dealt with the contributions of other candidate genes to human variation in muscular strength and power. These genes were identified because of their biological relevance to muscle contractile and sarcomeric proteins, myogenesis and muscle regeneration, muscle mass atrophy and sarcopenia, hormonal regulation of muscle mass, energy transfer to sustain muscle contraction, and other properties. The evidence from candidate gene studies of muscle strength and power was recently reviewed by Thomis (220).
An example of such genes is the myostatin (MSTN) gene. Mutations in MSTN leading to inactive or defective gene product have been shown to double or even triple skeletal muscle mass in mice, cows, and sheep. Functional MSTN mutations are very rare in humans. However, a boy appeared extraordinarily muscular at birth and at 4.5 yr of age was described as muscular and very strong (196). It turned out that he was a homozygote for a G/A mutation located five nucleotides downstream of exon 1, which abolishes a normal splice donor site and activates a cryptic splice site further downstream in intron 1, resulting in a truncated, inactive myostatin peptide. A number of polymorphisms in MSTN have been investigated for their associations with muscle hypertrophy or muscle strength and power (40, 60, 107, 199, 231), but the overall findings have been inconsistent.
Another class of candidate genes of great interest for muscular strength and power is that of the insulin-like growth factors and related binding proteins. These molecules play important roles in muscle growth and repair and in muscle response to exercise. Polymorphisms in insulin-like growth factors 1 (IGF1) and 2 (IGF2) have been rather consistently associated with muscle strength and its response to training, as well as other relevant endophenotypes (52, 81, 108, 193, 195).
The laboratories of James Hagberg and Stephen Roth in the department of kinesiology at the University of Maryland in the United States have pioneered a number of candidate gene research avenues since the late 1990s (figure 7.11). Their efforts focused on sequence variants in ACE; nitric oxide synthase 3 (NOS3); angiotensinogen (AGT); ACTN3; angiotensin II receptor, type 1 (AGTR1); tumor necrosis factor (TNF); nuclear factor of kappa light polypeptide gene enhancer in B-cells 1 (NFKB1); activin A receptor, type IIB (ACVR2B); adenosine monophosphate deaminase 1 (AMPD1); vascular endothelial growth factor A (VEGFA); vitamin D receptor (VDR); and MSTN, among others (see 59, 78, 79, 81, 134, 156, 167). Hagberg has a strong interest in exercise blood pressure and other hemodynamic phenotypes and through most of his career has consistently focused on the role of exercise in health-related outcomes and therapeutic applications, with an emphasis on the importance of genetic differences at key genes. Roth, whose primary interest is in muscle size and strength, has contributed a primer on exercise genetics (187) and has a longstanding interest in the role of genetic variation in talent selection for athletic performance. Both have trained a good number of graduate students in exercise genetics and have been longtime contributors to the fitness and performance gene map series that was published in Medicine and Science in Sports and Exercise until 2009.
Stephen M. Roth (1973 - ), PhD, FACSM, associate professor, and James M. Hagberg (1950 - ), PhD, FACSM, professor, department of kinesiology, school of public health, University of Maryland. Hagberg completed his graduate studies at the University of Wisconsin. He has been on the faculty of a number of universities and at the University of Maryland for nearly 20 yr, where he is a distinguished scholar-teacher. He has been funded by the National Institute of Aging for genetics-based investigations and has published numerous papers identifying genetic markers that associate with the degree to which endurance-exercise training improves cardiovascular disease risk factors in older men and women. Stephen M. Roth completed graduate studies in exercise physiology at the University of Maryland in 2000 and postdoctoral training in human genetics at the University of Pittsburgh. In 2003 he was recruited back to the University of Maryland as director of the Functional Genomics Laboratory. He has been funded by the National Institutes of Health to perform a variety of genetics investigations. In addition to several research publications, Roth is author of a textbook titled Genetics Primer for Exercise Science and Health. The department of kinesiology at the University of Maryland was one of the first to develop a research focus in the area of exercise genomics. As a group, they have published more than 60 peer-reviewed publications in the areas of exercise genomics.
When the last version of the fitness and performance gene map was published based on the publications available by the end of 2007, there were 214 autosomal, 7 X chromosome, and 18 mitochondrial gene and other loci entries (31). Most of the entries were related to specific candidate genes and were supported by more than 350 peer-reviewed papers. With the exception of the ACE and ACTN3 common variants, few of the genes had been replicated in multiple studies. Moreover, after almost 25 yr of candidate gene studies in exercise biology, this line of research continues to be plagued by small sample sizes and lack of appropriate statistical power (31, 177). Studies with small sample sizes occasionally report positive findings, especially if they include several traits and perform multiple statistical tests for association. Fortunately, these positive findings are seldom replicated and usually fall into oblivion.
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Early German roots of exercise physiology
In 1719, Friedrich Hoffmann (1660-1742), a physician from Halle, obtained his doctoral degree with experimental investigations about the effects of physical exercise on the human cardiovascular system and on digestion.
Exercise Physiology Research in Germany 1700 to 1910
In 1719, Friedrich Hoffmann (1660-1742), a physician from Halle, obtained his doctoral degree with experimental investigations about the effects of physical exercise on the human cardiovascular system and on digestion. In 1796, the physician Christoph Wilhelm Hufeland (1762-1836) published a textbook about the significance of different types of physical exercise for human health and life expectancy (66).
In the 19th century, the physiologist Emil Dubois-Reymond (1818-1896) studied the role of gymnastics in the human body (21, 22). The physician and chemist Max von Pettenkofer (1818-1901) detected the existence of creatine in the skeletal muscle and described a strengthening of the circulatory system in connection with physical training (111).
The first ergometer in the present-day sense of the word was developed by the German physician Speck in 1883. When using this cranked ergometer, the test person was in the standing position (figure 4.1). The crank friction could be modified by pulling up a screw. Speck determined the resistance with weights hung on the crank. The number of revolutions could be determined by noting the number of turns of twine wound up around the crank axle. The exhaled air was collected in a double spirometer and the postexperimental air composition was determined, thus enabling conclusions to be drawn about the individual performance reaction (2, 125).
In 1887 the Viennese physician Friedrich Gaertner (1847-1917) presented a mechanically braked ergometer, based on Speck's equipment that could measure the work performed in kilogram-meter. This device, called the ergostat, later went into standard production (112).
The first heyday of exercise physiology began with the veterinarian Nathan Zuntz (1847-1920) in Berlin (figure 4.2), who developed the first motor-driven treadmill in 1889 (figure 4.3). His work is described in chapter 1 (142).
Of substantial significance in the application of aspects of exercise physiology in medicine were Adolf Theophil Ferdinand Hueppe (1852-1938) and Ferdinand August Schmidt (1852-1929). In 1899 Hueppe wrote a fundamental work titled A Textbook of Hygiene that covered the whole of the exercise physiology discipline of those days. This was followed by the work titled Hygiene of Physical Exercises, published in 1911. In 1893 Schmidt published the book Physical Exercise According to the Exercise Value, which deals with an overview of suitable physical exercises for different ages (122, 123).
From 1904 to 1906 Kuelbs examined the influence of physical training on the internal organs, particularly the heart. He took two dogs from the same litter and trained one of them 5 times/wk for about 2 h on a treadmill, which he had taken over from Zuntz; the other dog had a normal, everyday life. After 1 yr both animals were killed and all internal organs were measured and examined. Although both dogs had more or less the same body weight, the heart of the dog trained on the treadmill was approximately 33% larger than that of the untrained dog. Similar differences were also manifest in the weights of the liver, kidneys, adrenal glands, spleen, and lungs (77).
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Over the subsequent decades Arthur Mallwitz (1880-1968) became the most important promoter for German, and later international, sports medicine. He obtained his doctor's degree at Halle University (Saale) in 1908 with what is presumed to be the first ever dissertation in sports medicine. In his dissertation, titled Maximum Performances With Special Consideration of Sports Done at the Olympic Games, Mallwitz considered, above all, the investigations of Hueppe and Schmidt as well as those of Zuntz and his school. In 1910 a comprehensive book about exercise physiology in connection with numerous kinds of sports was edited by Weissbein (141).
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The first ergometer was developed by Speck in 1883. Gaertner produced it in series.
Hollmann W, Strueder HK, Predel HG, Tagarakis CVM. Spiroergometrie. Stuttgart, Schattauer, 2006.
Exercise Physiology Research in Germany 1911 to 1933
German Empire Committee for Scientific Research in Sport and Physical Exercise
The First Congress for Scientific Research in Sport and Physical Exercise took place in Oberhof, Germany, from September 20 to 23, 1912. The congress was conducted by the professor for internal medicine of the University Clinic Berlin Charité, Friedrich Kraus (1858-1936), and was chaired by Schmidt and Hueppe. Approximately 70 doctors participated (93). On September 21, 1912, the German Empire Committee for Scientific Research in Sport and Physical Exercise - the first national medical sport association worldwide - was founded under the chairmanship ofKraus, who was elected president.
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Nathan Zuntz (1847-1920).
Reprinted, by permission, from W. Hollmann and K. Tittel, 2008, History of German sports medicine (Gera: Druckhaus Gera), 15.
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The world's first motorized treadmill, developed by Zuntz and Lehmann in 1889 in Berlin. This apparatus was shown in the international hygiene exhibition in Dresden in 1911.
Hollmann W, Strueder HK, Predel HG, Tagarakis CVM. Spiroergometry. Stuttgart, Schattauer, 2006.
Period From 1913 to 1924
In 1913, Arthur Mallwitz was appointed the first full-time sport physician worldwide by the Prussian State Gymnastics Institute. Mallwitz then took up his office under the official designation of sport physician (94).
At the same time the physician and chemist Otto Meyerhof (1884-1951) recognized the regulating relationship between respiration rate and the suppression of glycolysis in muscles. He demonstrated that the consumption of one molecule of oxygen prevents the formation of two molecules of lactate. Meyerhof's findings supported the assumption that the enzymes fanning lactate also function aerobically but that the lactate formed is resynthesized to carbohydrate at the expense of the energy provided by respiration (98).
Hugo Wilhelm Knipping (1895-1984), physician and internist at Hamburg University, developed a gas metabolism apparatus for examination of humans at rest in 1924 and constructed a dynamo cranked ergometer in 1928. In 1929 he combined an enlarged gas metabolism apparatus for exercise examinations with the crank ergometer and designated the method as spiroergometry (73, 74). It was the genesis of precise and simple clinical exercise diagnostics. Engineering, however, was not able to construct the equipment to satisfy all technical requirements until 1949 (75, 76).
German Medical Association for the Promotion of Physical Exercise (1924-1933)
Because of the political confusion and economic difficulties after the finish of World War I in 1918, approximately 6 yr elapsed before research in sports medicine and thus exercise physiology was renewed in 1924. The founding of the German Physician Association for the Promotion of Physical Exercise in 1924 was the impetus for this.
In 1925 Max Rubner (1854-1932), director of the Robert Koch Institute in Berlin and an internationally recognized metabolism researcher, ascertained that the skeletal musculature in adults amounts to 43% of the total body mass and that the total musculoskeletal system inclusive of bones, heart, and lungs amounts to 61%. The greatest proportion of the musculature was allotted to the legs (56%) and the upper extremities (28%). The head and torso muscles contributed to 16% of the total body mass (120).
Approximately 3,200 kcal could meet the daily energy requirements for physical exercise for a 70 kg person whereas 2,600 calories was sufficient for simple office work. The metabolism of a farm worker during harvesting would require 4,300 kcal. The peak values of the daily calorie consumption for lumberjacks would amount to approximately 6,000 kcal for a 70 kg person. Long-distance racing cyclists, however, could reach a peak daily metabolic rate of 11,000 kcal. Rubner believed that the limiting factor for the uptake of calories in the human body was the intestinal system. A repeat of such great exertion over several days would inevitably lead to loss of body weight (119).
As early as 1925, Herbert Herxheimer (1894-1985) and others precisely described the psychic and physical effects of overtraining, including a decrease in maximal oxygen uptake, reduced appetite, tendency to sweat, shivering, jerky reflexes, and pronounced respiratory arrhythmia with a clear preponderance of the parasympathetic part. Obstipation and painful stomach spasms also could be observed. Herxheimer published all his sports medicine knowledge in his famous book in 1933.
Herxheimer also described the connection between heart size and distance running. He found an increase in the transverse diameters of the heart in the following ascending order: boxing, swimming, middle-distance running, long-distance running, marathon running, and long-distance skiing. Particularly large hearts would work with a large stroke volume. This would result in the corresponding bradycardia at rest. The blood pressure of endurance athletes would be low (39).
Ludwig Aschoff (1866-1942) in Freiburg ascertained that there is one physiological work hypertrophy of the heart muscle as an adaptation to increased muscular activity. The enlargement remains within moderate limits. Sport does not cause a pathological hypertrophy. If a conspicuous general hypertrophy of the heart exists, it is a matter of pathological circumstances (e.g., cardiac valve ailments, hypertony or glomerular-tubular cirrhosis of the kidney). It is impossible for sport to cause a fatality in an individual with a healthy heart. A muscular cardiac insufficiency is to be treated by taking it easy. Puberty is a dangerous period regarding possible functional damage of the heart through sport.
Another significant exercise physiologist of the 1920s was Richard Herbst (1893-1949) in KÃöenigsberg East Prussia. He conducted numerous experimental investigations on the behavior of maximum oxygen absorption in humans of different ages and in different training conditions. He published his findings in 1928, 4 yr after the first description of maximum oxygen uptake by Hill. According to Herbst (1928), endurance-trained subjects had a higher oxygen intake than did untrained subjects. Also, after reaching the maximum oxygen uptake value, ventilation could be increased still further. Herbst used the Douglas bag with the subsequent respiratory gas analysis method for runners and cyclists. Further, he examined running distances between 100 m and marathon using the Douglas bag and gas analysis. The values obtained at that time (e.g., marathon with an energy consumption of 3,050 kcal, 10 m sprint with an energy consumption of 50 kcal) agree with measurements made nowadays. Sustained running loads of more than 3 min were determined from the magnitude of the maximal oxygen uptake. Thus, these parameters were a measure of performance. The lung ventilation volume would still increase further after reaching the maximum oxygen absorption. Cardiac output is represented as the most important factor limiting physical performance (37).
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Harvard Fatigue Laboratory influential in promoting exercise physiology research
Despite its brief history (1927-1947), no physiology laboratory in America is more revered than the Harvard Fatigue Laboratory.
Despite its brief history (1927-1947), no physiology laboratory in America is more revered than the Harvard Fatigue Laboratory. Described as "the first laboratory for the comprehensive study of man" (5), it was perhaps more influential and effective in promoting scientific and collaborative research in exercise physiology (76). This chapter discusses the laboratory's contributions to the study of the acute and chronic effects of exercise and to the effects of altitude and temperature on the exercise response. This chapter includes information from the laboratory's extensive published record as well as from the perspective of the last surviving member of its faculty and staff (figure 3.1) (41).
G. Edgar Folk (1914-) of the University of Iowa in the United States who became a staff member of the Harvard Fatigue Laboratory in 1943. Folk remained at the Harvard Fatigue Laboratory until its closure in 1947. He subsequently spent six yr at Bowdoin College in Maine conducting research and teaching biology to undergraduate students. In 1953, he accepted an appointment in the department of physiology at the University of Iowa. Professor Folk continues to attend APS meetings, write manuscripts, and enjoy life as an elder statesman for physiology.
Harvard University (1920-1927)
In 1920, physiology at Harvard University was represented by four departments: physiology, comparative physiology, applied physiology, and physical chemistry. These departments were collectively known as the laboratories of physiology(53). Three years later, the department of industrial hygiene was transferred from the medical school to the recently established school of public health, facilitated by the efforts of Roger Lee (53). Subsequently, the department of industrial hygiene was renamed the department of applied physiology. At this time, Walter B. Cannon (1871-1945) was chairman of the department of physiology, David Edsall was dean of both the medical school and the school of public health, Lawrence Joseph Henderson (1888-1984) was director of the department of physical chemistry (figure 3.2), Wallace B. Donham was dean of the business school, and A. Laurence Lowell was president of the university (53). Also at this time, Dr. Arlie V. Bock was establishing a laboratory in Massachusetts General Hospital after being a physician in World War I, a Moseley Traveling Fellow in Sir Joseph Barcroft's laboratory for two years learning exercise protocols and blood-equilibration techniques, and after being a participant in Barcroft's high-altitude expedition in Peru (23) (figure 3.2).
David Bruce Dill (1891-1986) received his PhD in chemistry in 1925 from Stanford University and accepted a 2 yr National Research Council fellowship to work in the laboratory of L.J. Henderson to study the physical chemistry of proteins. However, after his arrival at Harvard, he was assigned to a Massachusetts General Hospital laboratory, where the senior staff physician was Dr. John H. Talbott. There he was reassigned to study with Dr. Bock the physiochemical properties of blood (46). When the fellowship was terminated, Dill was appointed as assistant professor of biochemistry in the school of public health, a position he retained until 1936. In addition, from 1927 to 1947, he held a professorship in the department of industrial hygiene at Harvard University (72). Although during his tenure at Harvard Henderson remained as director of the laboratory, it was Dill's leadership, organizational ability, and scientific insights that made the laboratory famous throughout the world. Between 1947 and 1961, Dill served as director of research for the U.S. Army Chemical Research and Development Laboratory. During this interval, he became president of the American Physiological Society (1950-1951) and later (1960-1961) was elected president of the American College of Sports Medicine (45, 74).
Henderson and the Establishment of the Harvard Fatigue Laboratory
Henderson, a recipient of an MD from Harvard in 1902, was professor of biological chemistry from 1919 until 1934 and the Abbot and James Lawrence professor of chemistry from 1934 until his death in 1942 (18) (figure 3.2). Besides chemistry and biology, Henderson had broad interests in sociology, psychology, anthropology, and the philosophy of Vilfredo Pareto, an Italian engineer and socialist (18, 46). He and Elton Mayo (a professor of industrial hygiene who, like Henderson, believed that workers should be studied in the workplace) developed the concept of establishing a laboratory to conduct research on industrial hazards (46). Such a laboratory would study the "group psychology, the social problems, and physiology of fatigue of normal man . . . not only as individual factors in determining physical and mental health, but more especially to determine their interrelatedness and the effect upon work" (46, p. 20).
With leadership from Henderson, the support of advisory and planning committees that included most of the previously mentioned deans and professors, the endorsement of President Lowell, and funding from the Laura Spelman Rockefeller Memorial and the Rockefeller Foundation, the Harvard Fatigue Laboratory was established in 1927 with Lawrence Joseph Henderson as its official director (46). According to Chapman, the term fatigue was selected because all parties believed it was important. However, because they could not agree on a definition, it did not force research activities into a specific departmental shape(19, p. 19). Its home was in the basement of Harvard Business School.
As noted, Dill was designated (although never officially appointed) to organize and direct the research program of the laboratory and quickly assumed the duties and responsibilities of Henderson. Hence, his curriculum vitae in the Mandeville Special Collections Library at the University of California in the United States lists him as the informal director of the laboratory between 1927 and 1946 (72). The Horvaths identified the senior members of the laboratory from 1927 to before World War II as Henderson, Dill, Bock, and Talbott (figure 3.2) (46).
Contributions to Undergraduate and Graduate Student Education
Although the education of undergraduate and graduate students was not a purpose for establishing the laboratory, the laboratory did provide opportunities for undergraduate and graduate students to be introduced to research and become involved with projects that all pertained to physiology and sometimes to exercise physiology. Although the laboratory offered no courses or degrees, it offered opportunities for students to conduct senior theses under the supervision of select faculty members. Twelve undergraduates were involved in activities of the laboratory. Henry Taylor became a renowned exercise physiologist at the University of Minnesota in the United States (figure 3.4). Richard Riley was recognized as an outstanding respiratory physiologist at Johns Hopkins University, and John Pappenheimer and Clifford Barger received acclaim as physiologists on the faculty of Harvard University (46). Sid Robinson and Steven Horvath (figures 3.5 and 3.6) conducted research for their PhD dissertations in the laboratory but received their degrees in biological sciences. Dill served as chairman of Robinson's committee but was unable to do so for Horvath because Horvath had married Dill's daughter (73). G. Edgar Folk Jr. received an MA from Harvard University in 1937 and served as a research associate in the laboratory from 1943 to 1947 (figure 3.1). In 1947, he received a PhD in the biological sciences with John Welch as his advisor (74). Additionally, Pappenheimer, Robinson, and Horvath served along with 13 other staff members as tutors for students in biochemistry (46).
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Advances in studies of genes associated with exercise behavior traits
Several research designs and technologies have been used over the past two decades in the effort to identify genomic regions, genes, and sequence variants associated with exercise behavior and exercise biology traits.
Genomics Studies
Several research designs and technologies have been used over the past two decades in the effort to identify genomic regions, genes, and sequence variants associated with exercise behavior and exercise biology traits. This section reviews advances made over time and key laboratories and investigators involved in these studies. Candidate genes, genome-wide linkage scans, genome-wide association (GWA) studies, and contributions from combinations of transcriptomics and genomics are reviewed. Efforts to identify genetic differences between elite athletes and sedentary controls are also briefly summarized.
Candidate Genes
A candidate gene is a gene that has a theoretical relationship with the behavioral, physiological, or metabolic system regulating the trait of interest. Candidate genes for exercise biology traits have been defined on the basis of advances in exercise physiology studies and animal models and on purely theoretical grounds. Transgenic (overexpression of a gene or genes), knockdown (reduced expression level), and knockout (ablation of a gene or genes) mice have generated a number of candidate genes that were subsequently investigated for potential involvement in human variation. The expression level of a gene has also been used as a candidate phenotype against which DNA variants can be tested for associations. The complete transcriptome, which is the full set of ribonucleic acid (RNA) transcripts in a given cell or tissue, has been used to define new panels of candidate genes for further genomics studies (e.g., 72, 224).
Candidate genes were very prominent in the early phase of exercise genomics. Many of the earlier studies were quite simple in design and were launched primarily because of the availability of whole blood stored in freezers. They were generally case-control or cross-sectional cohort studies with unrelated subjects. In the case of continuous traits (e.g., V\od\O2max), the association with a candidate gene or marker is tested by comparing mean trait values across genotypes or between carriers and noncarriers of a specific allele. In the case-control design, testing for a relation between a trait and a candidate gene marker is based on the comparison of allele and genotype frequencies between two informative groups of subjects, one with the phenotype of interest (e.g., elite power and strength athletes - the "cases") and the other without the phenotype of interest (the "controls").
Special Case of Athletes Versus Controls
Luigi Gedda from the Gregor Mendel Institute of Medical Genetics and Twin Research at the University of Rome was perhaps the pioneer in the effort to understand the importance of genetic differences between athletes and nonathletes (67, 68) (figure 7.7). The initial efforts were based on surveys of Italian twins, specifically on 351 pairs of twins who were engaged in competitive sport. The results of the surveys indicated familial aggregation among athletes and the potential importance of zygosity in concordance of sport selection; participation in markedly different sports occurred in 85% of DZ twins in contrast to only 6% of MZ twins (68). The familial aggregation of athletes was also noted by others, such as Grebe (75, 76) of Germany, Linc and Fleischmann (117) of Czechoslovakia, and Jokl (92, 93), who at the time was in the United States. The work of Gedda and his longtime collaborator, Paolo Parisi, was the most systematic in this regard and focused on genealogical and twin methods. The research of Parisi continues today with the Italian Registry of Twin Athletes (154, 155). A higher prevalence of MZ twins among swimmers has been one of their findings (154). In a large sample of adult British female twins, athlete status (nonathlete vs. local-, county-, or national-level athlete) had a heritability of 0.66 (50).
Luigi Gedda (1902-2000), MD, Mendel Institute of Medical Genetics and Twin Research in Rome, right, and Paolo Parisi (1940 - ), PhD, professor of biology and rector, Italian University Sport and Movement, University of Rome "Foro Italico," left. Gedda was the first to confirm, through classic pedigree studies in the mid-1950s, the common knowledge that elite athletes often cluster in families and to then attempt to quantify the role of genetic factors using the twin concordance model. He studied a large sample of MZ and DZ twin pairs and found considerably higher concordance rates in the former than in the latter with respect to various aspects of sport participation, such as kind of sport practiced and performance level. In later decades, Gedda's longtime associate Paolo Parisi conducted epidemiological and cell genetics research, also through the aid of a special registry of Italian twin athletes, in order to explore the genetic basis of athletic performance. Of particular interest to him is the relation of physical activity to health, aging, and chronic disease. One major line of research of his institute focuses on the role of exercise-induced oxidative stress in genetic regulation processes.
The first documented attempt to identify differences in genetic markers for performance-related phenotypes dates to the late 1960s. A group of geneticists, taking advantage of the 1968 Olympic Games in Mexico, investigated common blood genetic markers in an attempt to discriminate between Olympic athletes and controls (45).
Interestingly, phenylthiocarbamide nontasters were underrepresented among the athletes. The effort to document genetic differences between elite athletes and sedentary controls was continued on the occasion of the 1976 Olympic Games in Montreal (37, 41). A slightly higher frequency of the A1 allele of the ABO blood group was observed in endurance athletes participating in the 1976 Summer Olympic Games than in reference populations (37). However, the other plasma and red blood cell markers (ABO, MNSs, Rhesus, Duffy, Kell, P, LDH, MDH, phosphoglucomutase, adenosine deaminase, adenylate kinase, esterase D, haptoglobin, transferrin, hemoglobin, glucose-6-phosphate dehydrogenase, and acid phosphatase) did not differ between athletes and controls (37, 41, 45). These early attempts were all based on polymorphisms in red blood cell antigens and enzymes. Later, skeletal muscle gene product variants were screened (17, 128) and selected enzyme markers were investigated for their putative effects on a variety of skeletal muscle and cardiorespiratory endurance indicators. Genetic variants of skeletal muscle creatine kinase (CKM) and adenylate kinase 1 (AK1) were screened for using isoelectric focusing in 295 subjects (16). A variant form of both enzymes was identified with an allele frequency of 1% (CKM) and 3.5% (AK1). There was no difference in V\od\O2max between the carriers of the variant alleles and matched controls homozygous for the nonvariant allele (16). None of these studies yielded reliably significant genomic predictors of performance or fitness.
Genomic differences between athletes and untrained controls began to be investigated in a more systematic fashion with the launch of the GENATHLETE study in the laboratory of Claude Bouchard at Laval University in 1993. The main collaborators on GENATHLETE included Louis Perusse, Marcel Boulay, and the late Jean-Aime Simoneau (all from Laval University), Rainer Rauramaa (Kuopio, Finland), and particularly Bernd Wolfahrt (from Germany). The study focused on DNA sequence differences between a panel that has now attained more than 300 elite endurance athletes with a V\od\O2max no lower than 75 ml·kg-1·min-1 and more than 300 sedentary controls with a V\od\O2max no higher than 50 ml·kg-1·min-1. The participants are all white males from Canada, Germany, Finland, and the United States. Single nucleotide polymorphisms (SNPs) in several genes have been investigated to date, but none have provided strong evidence for differences in allele and genotype frequencies between athletes and controls (16, 178, 184, 185, 245-247). However, a common variant and haplotype in the hypoxia inducible factor 1, alpha subunit (HIF1A) gene were found to be more prevalent in athletes compared with controls in a 2010 report based on the GENATHLETE cohort (54), an observation that was defined in an accompanying editorial as an important milestone (194).
Another effort to delineate the differences between athletes and nonathletes is under way in Spain under the leadership of Jonatan Ruiz and Alejandro Lucia. They have used samples of Spanish Caucasian endurance athletes (about 100), power athletes (about 50), and nonathlete controls. A number of differences at candidate genes between athletes and controls, as well as between endurance and power athletes, have been reported (34, 71, 190). Taking advantage of the concept of a total genotype score developed by Williams and Folland (238), Ruiz and colleagues in 2009 attempted to predict world-class endurance athlete status based on the frequency of variant alleles at 7 candidate genes genotyped in 43 Spanish endurance athletes and 123 controls (191).
Yannis Pitsiladis from the faculty of biomedical and life sciences at the University of Glasgow has taken advantage of striking performance differences at the elite level in athletes of various ethnic backgrounds to investigate the potential role of variation in nuclear and mitochondrial DNA (figure 7.8). For instance, distance runners from Kenya and Ethiopia and sprinters from Jamaica won 25% of all track and field medals at the 2008 Olympic Games in Beijing (166). The effort to impute ethnic differences in sport performance to genetic differences is clearly challenging, particularly because only about 10% of human genetic variation can be found between the major ethnic groups. Pitsiladis' laboratory has explored differences in sequence variants in mitochondrial DNA and in Y chromosome markers between Ethiopian athletes, Ethiopian controls, Kenyan athletes, and Kenyan controls. Mitochondrial DNA haplogroups found in Kenya were different from those found in Ethiopia (197). Differences in haplogroup distributions were observed between athletes and controls in Kenya but not in Ethiopia. The full significance of this observation needs to be established. Analyses of Y chromosome haplogroups in endurance athletes from Ethiopia revealed differences between them and samples from the more general Ethiopian population (145). Population stratification was ruled out as the explanation for such differences. One important conclusion reached by Pitsiladis and colleagues is that the clusters of Kenyan and Ethiopian elite runners are distinct from each other from a genetic point of view (166).
Yannis P. Pitsiladis (1967 - ), MMedSci, PhD, FACSM, integrative and systems biology research theme, faculty of biomedical and life sciences, University of Glasgow, Scotland. Pitsiladis is a reader in exercise physiology at the Institute of Biomedical and Life Sciences at the University of Glasgow and founding member (and previous director) of the International Centre for East African Running Science, set up to investigate the physiological, genetic, psychosocial, and economic determinants of the phenomenal success of East African distance runners in international athletics. Recent projects include the study of West African sprinters (including elite sprinters from Jamaica and the United States) and the study of world-class swimmers (e.g., why there are very few black swimmers). He is a visiting professor in medical physiology at Moi University (Eldoret, Kenya), Addis Ababa University (Addis Ababa, Ethiopia), and University of Technology (Kingston, Jamaica). Pitsiladis has a particular research interest in mitochondrial DNA and Y chromosome markers and their potential role in ethnic differences in performance.
Photo courtesy of Yannis P. Pitsiladis.
Two genes have received considerable attention in the exercise genomics literature: angiotensin I-converting enzyme (ACE) and actinin alpha 3 (ACTN3). Both have been strong favorites of exercise scientists over the past decade or so.
ACE Gene
Hugh Montgomery (1962 - ), MB, BS, BSc, FRCP, MD, FRGS, director of University College London Institute for Human Health and Performance; consultant intensivist at Whittington Hospital; and professor of intensive care medicine at University College London. Montgomery obtained his BSc degree in neuropharmacology and in circulatory and respiratory physiology in 1984 before graduating with a medical degree in 1987. He has since trained and accredited in general internal medicine, cardiology, and intensive care medicine. He is now professor of intensive care medicine at University College London, where he also directs the Institute for Human Health and Performance. In the early 1990s, he began using gene - environment interaction as a means to explore human physiology. Working with army recruits, he first identified a role for the angiotensin I-converting enzyme (ACE) I/D polymorphism in the regulation of human cardiac growth. This work was extended to broader measures of performance, including high-altitude mountaineering aptitude. Mechanistically, a role in the regulation of metabolic efficiency was suggested, leading to phase IV studies of ACE inhibition in the treatment of cancer cachexia. Studies of downstream gene variants (e.g., those of the bradykinin B2 receptor gene) have offered further mechanistic insight. Montgomery has a special interest in high-altitude performance: He was science lead for the Caudwell Xtreme Everest Expedition in 2007 and has identified genes under selection pressure in high-altitude populations.
The potential role of ACE sequence differences in human physical performance was first investigated in the 1990s by Hugh Montgomery from the University College London (figure 7.9). He and his coworkers reported in 1997 that 10 wk of physical training in British army recruits induced greater increases in left ventricular mass and septal and posterior wall thickness in the ACE D/D homozygotes than in the I allele carriers (141). A few years later, the same group of investigators confirmed the finding by reporting that the training-induced increase in left ventricular mass in another cohort of army recruits was 2.7 times greater in the D/D genotype compared with the I/I homozygotes (147). The I allele was associated with higher muscular endurance gains after 10 wk of physical training in British army recruits (142).
The story began in 1990 when it was reported that a 287 bp I/D polymorphism in intron 16 of the ACE gene was associated with plasma ACE activity (183). ACE activity was highest in D/D homozygotes and lowest in I/I homozygotes. More than 50 reports have subsequently dealt with the potential role of the ACE I/D genotype in some aspects of fitness or performance. Overall, the results are heterogeneous and often contradictory. For instance, in postmenopausal women, I/I homozygotes had a higher V\od\O2max than D/D homozygotes (79), whereas the opposite was observed in Chinese males (251). In the HERITAGE Family Study, no associations were found between the ACE I/D polymorphism and maximal and submaximal exercise V\od\O2 and power output phenotypes in healthy, sedentary blacks and whites (41).
This literature was recently reviewed by Montgomery and colleagues (206). In the aggregate, it appears that the ACE I/D polymorphism may contribute to human variation in skeletal and cardiac muscle growth and functional properties as well as in adaptation to hypoxia. However, its contribution to variation in human physical performance remains a matter of debate.
ACTN3 Gene
Kathryn North and colleagues from the Children's Hospital at Westmead in Australia discovered a common variant in the gene for actinin-3, a structural actin binding protein found in skeletal muscle fast-twitch fibers (figure 7.10). The polymorphism (R577X) replaces an arginine residue by a premature stop codon at position 577 and results in ACTN3 deficiency. About 16% of the world population is homozygous for the XX null genotype; the frequency of the null allele is highest in Caucasians and Asians and lowest in Africans (8). The first report on ACTN3 genotype and performance was from North's laboratory in 2003. It indicated that the frequency of the stop codon mutation was lower in sprinters than in controls and endurance athletes (248). Several studies have concluded that the stop codon variant (X577X) was lower in sprint and strength athletes than in nonathletes (55, 57, 153, 189, 192, 248), but other reports have been negative (149, 198, 249). Interestingly, a number of studies based on direct measures of muscle strength and power have also been published and the results are contradictory; that is, the X allele is negatively associated with these muscle phenotypes in some studies whereas the converse is found in others (39, 51, 66, 132, 133, 146, 150, 228). North has reviewed the biology of the ACTN3 polymorphism in recent publications (8, 120). In the aggregate, the data suggest that there is probably a role of the X allele in skeletal muscle function and muscle performance, but the data remain inconclusive at present. More studies with appropriate power and designs, as well as more extensive functional studies, are warranted.
Kathryn North (1960 - ), MD, FRACP, Director, Murdoch Childrens Research Institute, and David Danks Professor of Child Health Research at University of Melbourne, Australia. In the process of studying genes implicated in muscle disease, North and colleagues at the Children's Hospital at Westmead discovered a common variant in the actinin alpha 3 (ACTN3) gene. ACTN3 encodes a structural protein found in fast-twitch skeletal muscle fibers. The ACTN3 gene variant results in complete deficiency of actinin-3 in almost 20% of the general population. North showed that ACTN3 deficiency is rare in sprint athletes, suggesting that this protein plays a crucial role in the function of fast-twitch muscle fibers. North and her team developed a strain of mice engineered to be completely deficient in ACTN3 and showed that the muscle of these knockout mice displays an increase in oxidative metabolism. This metabolic shift could explain why ACTN3 deficiency is detrimental to sprint activities that require fast or glycolytic metabolism. Her analysis of deoxyribonucleic acid (DNA) samples from individuals from around the world suggests that the ACTN3 deficiency provided some benefit to the ancestors of modern Europeans and Asians after their migration out of Africa, resulting in its increase in frequency due to natural selection. The benefit provided by ACTN3 deficiency may have allowed them to adapt to the more hostile environments of Eurasia. North's group plans to use mouse and human studies to determine the effect of ACTN3 deficiency on muscle aging, response to exercise, and the progression of inherited muscle diseases such as the muscular dystrophies.
Other Candidate Genes
A series of studies has dealt with the contributions of other candidate genes to human variation in muscular strength and power. These genes were identified because of their biological relevance to muscle contractile and sarcomeric proteins, myogenesis and muscle regeneration, muscle mass atrophy and sarcopenia, hormonal regulation of muscle mass, energy transfer to sustain muscle contraction, and other properties. The evidence from candidate gene studies of muscle strength and power was recently reviewed by Thomis (220).
An example of such genes is the myostatin (MSTN) gene. Mutations in MSTN leading to inactive or defective gene product have been shown to double or even triple skeletal muscle mass in mice, cows, and sheep. Functional MSTN mutations are very rare in humans. However, a boy appeared extraordinarily muscular at birth and at 4.5 yr of age was described as muscular and very strong (196). It turned out that he was a homozygote for a G/A mutation located five nucleotides downstream of exon 1, which abolishes a normal splice donor site and activates a cryptic splice site further downstream in intron 1, resulting in a truncated, inactive myostatin peptide. A number of polymorphisms in MSTN have been investigated for their associations with muscle hypertrophy or muscle strength and power (40, 60, 107, 199, 231), but the overall findings have been inconsistent.
Another class of candidate genes of great interest for muscular strength and power is that of the insulin-like growth factors and related binding proteins. These molecules play important roles in muscle growth and repair and in muscle response to exercise. Polymorphisms in insulin-like growth factors 1 (IGF1) and 2 (IGF2) have been rather consistently associated with muscle strength and its response to training, as well as other relevant endophenotypes (52, 81, 108, 193, 195).
The laboratories of James Hagberg and Stephen Roth in the department of kinesiology at the University of Maryland in the United States have pioneered a number of candidate gene research avenues since the late 1990s (figure 7.11). Their efforts focused on sequence variants in ACE; nitric oxide synthase 3 (NOS3); angiotensinogen (AGT); ACTN3; angiotensin II receptor, type 1 (AGTR1); tumor necrosis factor (TNF); nuclear factor of kappa light polypeptide gene enhancer in B-cells 1 (NFKB1); activin A receptor, type IIB (ACVR2B); adenosine monophosphate deaminase 1 (AMPD1); vascular endothelial growth factor A (VEGFA); vitamin D receptor (VDR); and MSTN, among others (see 59, 78, 79, 81, 134, 156, 167). Hagberg has a strong interest in exercise blood pressure and other hemodynamic phenotypes and through most of his career has consistently focused on the role of exercise in health-related outcomes and therapeutic applications, with an emphasis on the importance of genetic differences at key genes. Roth, whose primary interest is in muscle size and strength, has contributed a primer on exercise genetics (187) and has a longstanding interest in the role of genetic variation in talent selection for athletic performance. Both have trained a good number of graduate students in exercise genetics and have been longtime contributors to the fitness and performance gene map series that was published in Medicine and Science in Sports and Exercise until 2009.
Stephen M. Roth (1973 - ), PhD, FACSM, associate professor, and James M. Hagberg (1950 - ), PhD, FACSM, professor, department of kinesiology, school of public health, University of Maryland. Hagberg completed his graduate studies at the University of Wisconsin. He has been on the faculty of a number of universities and at the University of Maryland for nearly 20 yr, where he is a distinguished scholar-teacher. He has been funded by the National Institute of Aging for genetics-based investigations and has published numerous papers identifying genetic markers that associate with the degree to which endurance-exercise training improves cardiovascular disease risk factors in older men and women. Stephen M. Roth completed graduate studies in exercise physiology at the University of Maryland in 2000 and postdoctoral training in human genetics at the University of Pittsburgh. In 2003 he was recruited back to the University of Maryland as director of the Functional Genomics Laboratory. He has been funded by the National Institutes of Health to perform a variety of genetics investigations. In addition to several research publications, Roth is author of a textbook titled Genetics Primer for Exercise Science and Health. The department of kinesiology at the University of Maryland was one of the first to develop a research focus in the area of exercise genomics. As a group, they have published more than 60 peer-reviewed publications in the areas of exercise genomics.
When the last version of the fitness and performance gene map was published based on the publications available by the end of 2007, there were 214 autosomal, 7 X chromosome, and 18 mitochondrial gene and other loci entries (31). Most of the entries were related to specific candidate genes and were supported by more than 350 peer-reviewed papers. With the exception of the ACE and ACTN3 common variants, few of the genes had been replicated in multiple studies. Moreover, after almost 25 yr of candidate gene studies in exercise biology, this line of research continues to be plagued by small sample sizes and lack of appropriate statistical power (31, 177). Studies with small sample sizes occasionally report positive findings, especially if they include several traits and perform multiple statistical tests for association. Fortunately, these positive findings are seldom replicated and usually fall into oblivion.
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Early German roots of exercise physiology
In 1719, Friedrich Hoffmann (1660-1742), a physician from Halle, obtained his doctoral degree with experimental investigations about the effects of physical exercise on the human cardiovascular system and on digestion.
Exercise Physiology Research in Germany 1700 to 1910
In 1719, Friedrich Hoffmann (1660-1742), a physician from Halle, obtained his doctoral degree with experimental investigations about the effects of physical exercise on the human cardiovascular system and on digestion. In 1796, the physician Christoph Wilhelm Hufeland (1762-1836) published a textbook about the significance of different types of physical exercise for human health and life expectancy (66).
In the 19th century, the physiologist Emil Dubois-Reymond (1818-1896) studied the role of gymnastics in the human body (21, 22). The physician and chemist Max von Pettenkofer (1818-1901) detected the existence of creatine in the skeletal muscle and described a strengthening of the circulatory system in connection with physical training (111).
The first ergometer in the present-day sense of the word was developed by the German physician Speck in 1883. When using this cranked ergometer, the test person was in the standing position (figure 4.1). The crank friction could be modified by pulling up a screw. Speck determined the resistance with weights hung on the crank. The number of revolutions could be determined by noting the number of turns of twine wound up around the crank axle. The exhaled air was collected in a double spirometer and the postexperimental air composition was determined, thus enabling conclusions to be drawn about the individual performance reaction (2, 125).
In 1887 the Viennese physician Friedrich Gaertner (1847-1917) presented a mechanically braked ergometer, based on Speck's equipment that could measure the work performed in kilogram-meter. This device, called the ergostat, later went into standard production (112).
The first heyday of exercise physiology began with the veterinarian Nathan Zuntz (1847-1920) in Berlin (figure 4.2), who developed the first motor-driven treadmill in 1889 (figure 4.3). His work is described in chapter 1 (142).
Of substantial significance in the application of aspects of exercise physiology in medicine were Adolf Theophil Ferdinand Hueppe (1852-1938) and Ferdinand August Schmidt (1852-1929). In 1899 Hueppe wrote a fundamental work titled A Textbook of Hygiene that covered the whole of the exercise physiology discipline of those days. This was followed by the work titled Hygiene of Physical Exercises, published in 1911. In 1893 Schmidt published the book Physical Exercise According to the Exercise Value, which deals with an overview of suitable physical exercises for different ages (122, 123).
From 1904 to 1906 Kuelbs examined the influence of physical training on the internal organs, particularly the heart. He took two dogs from the same litter and trained one of them 5 times/wk for about 2 h on a treadmill, which he had taken over from Zuntz; the other dog had a normal, everyday life. After 1 yr both animals were killed and all internal organs were measured and examined. Although both dogs had more or less the same body weight, the heart of the dog trained on the treadmill was approximately 33% larger than that of the untrained dog. Similar differences were also manifest in the weights of the liver, kidneys, adrenal glands, spleen, and lungs (77).
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Over the subsequent decades Arthur Mallwitz (1880-1968) became the most important promoter for German, and later international, sports medicine. He obtained his doctor's degree at Halle University (Saale) in 1908 with what is presumed to be the first ever dissertation in sports medicine. In his dissertation, titled Maximum Performances With Special Consideration of Sports Done at the Olympic Games, Mallwitz considered, above all, the investigations of Hueppe and Schmidt as well as those of Zuntz and his school. In 1910 a comprehensive book about exercise physiology in connection with numerous kinds of sports was edited by Weissbein (141).
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The first ergometer was developed by Speck in 1883. Gaertner produced it in series.
Hollmann W, Strueder HK, Predel HG, Tagarakis CVM. Spiroergometrie. Stuttgart, Schattauer, 2006.
Exercise Physiology Research in Germany 1911 to 1933
German Empire Committee for Scientific Research in Sport and Physical Exercise
The First Congress for Scientific Research in Sport and Physical Exercise took place in Oberhof, Germany, from September 20 to 23, 1912. The congress was conducted by the professor for internal medicine of the University Clinic Berlin Charité, Friedrich Kraus (1858-1936), and was chaired by Schmidt and Hueppe. Approximately 70 doctors participated (93). On September 21, 1912, the German Empire Committee for Scientific Research in Sport and Physical Exercise - the first national medical sport association worldwide - was founded under the chairmanship ofKraus, who was elected president.
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Nathan Zuntz (1847-1920).
Reprinted, by permission, from W. Hollmann and K. Tittel, 2008, History of German sports medicine (Gera: Druckhaus Gera), 15.
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The world's first motorized treadmill, developed by Zuntz and Lehmann in 1889 in Berlin. This apparatus was shown in the international hygiene exhibition in Dresden in 1911.
Hollmann W, Strueder HK, Predel HG, Tagarakis CVM. Spiroergometry. Stuttgart, Schattauer, 2006.
Period From 1913 to 1924
In 1913, Arthur Mallwitz was appointed the first full-time sport physician worldwide by the Prussian State Gymnastics Institute. Mallwitz then took up his office under the official designation of sport physician (94).
At the same time the physician and chemist Otto Meyerhof (1884-1951) recognized the regulating relationship between respiration rate and the suppression of glycolysis in muscles. He demonstrated that the consumption of one molecule of oxygen prevents the formation of two molecules of lactate. Meyerhof's findings supported the assumption that the enzymes fanning lactate also function aerobically but that the lactate formed is resynthesized to carbohydrate at the expense of the energy provided by respiration (98).
Hugo Wilhelm Knipping (1895-1984), physician and internist at Hamburg University, developed a gas metabolism apparatus for examination of humans at rest in 1924 and constructed a dynamo cranked ergometer in 1928. In 1929 he combined an enlarged gas metabolism apparatus for exercise examinations with the crank ergometer and designated the method as spiroergometry (73, 74). It was the genesis of precise and simple clinical exercise diagnostics. Engineering, however, was not able to construct the equipment to satisfy all technical requirements until 1949 (75, 76).
German Medical Association for the Promotion of Physical Exercise (1924-1933)
Because of the political confusion and economic difficulties after the finish of World War I in 1918, approximately 6 yr elapsed before research in sports medicine and thus exercise physiology was renewed in 1924. The founding of the German Physician Association for the Promotion of Physical Exercise in 1924 was the impetus for this.
In 1925 Max Rubner (1854-1932), director of the Robert Koch Institute in Berlin and an internationally recognized metabolism researcher, ascertained that the skeletal musculature in adults amounts to 43% of the total body mass and that the total musculoskeletal system inclusive of bones, heart, and lungs amounts to 61%. The greatest proportion of the musculature was allotted to the legs (56%) and the upper extremities (28%). The head and torso muscles contributed to 16% of the total body mass (120).
Approximately 3,200 kcal could meet the daily energy requirements for physical exercise for a 70 kg person whereas 2,600 calories was sufficient for simple office work. The metabolism of a farm worker during harvesting would require 4,300 kcal. The peak values of the daily calorie consumption for lumberjacks would amount to approximately 6,000 kcal for a 70 kg person. Long-distance racing cyclists, however, could reach a peak daily metabolic rate of 11,000 kcal. Rubner believed that the limiting factor for the uptake of calories in the human body was the intestinal system. A repeat of such great exertion over several days would inevitably lead to loss of body weight (119).
As early as 1925, Herbert Herxheimer (1894-1985) and others precisely described the psychic and physical effects of overtraining, including a decrease in maximal oxygen uptake, reduced appetite, tendency to sweat, shivering, jerky reflexes, and pronounced respiratory arrhythmia with a clear preponderance of the parasympathetic part. Obstipation and painful stomach spasms also could be observed. Herxheimer published all his sports medicine knowledge in his famous book in 1933.
Herxheimer also described the connection between heart size and distance running. He found an increase in the transverse diameters of the heart in the following ascending order: boxing, swimming, middle-distance running, long-distance running, marathon running, and long-distance skiing. Particularly large hearts would work with a large stroke volume. This would result in the corresponding bradycardia at rest. The blood pressure of endurance athletes would be low (39).
Ludwig Aschoff (1866-1942) in Freiburg ascertained that there is one physiological work hypertrophy of the heart muscle as an adaptation to increased muscular activity. The enlargement remains within moderate limits. Sport does not cause a pathological hypertrophy. If a conspicuous general hypertrophy of the heart exists, it is a matter of pathological circumstances (e.g., cardiac valve ailments, hypertony or glomerular-tubular cirrhosis of the kidney). It is impossible for sport to cause a fatality in an individual with a healthy heart. A muscular cardiac insufficiency is to be treated by taking it easy. Puberty is a dangerous period regarding possible functional damage of the heart through sport.
Another significant exercise physiologist of the 1920s was Richard Herbst (1893-1949) in KÃöenigsberg East Prussia. He conducted numerous experimental investigations on the behavior of maximum oxygen absorption in humans of different ages and in different training conditions. He published his findings in 1928, 4 yr after the first description of maximum oxygen uptake by Hill. According to Herbst (1928), endurance-trained subjects had a higher oxygen intake than did untrained subjects. Also, after reaching the maximum oxygen uptake value, ventilation could be increased still further. Herbst used the Douglas bag with the subsequent respiratory gas analysis method for runners and cyclists. Further, he examined running distances between 100 m and marathon using the Douglas bag and gas analysis. The values obtained at that time (e.g., marathon with an energy consumption of 3,050 kcal, 10 m sprint with an energy consumption of 50 kcal) agree with measurements made nowadays. Sustained running loads of more than 3 min were determined from the magnitude of the maximal oxygen uptake. Thus, these parameters were a measure of performance. The lung ventilation volume would still increase further after reaching the maximum oxygen absorption. Cardiac output is represented as the most important factor limiting physical performance (37).
Read more from History of Exercise Physiology by Charles M. Tipton, PhD.
Harvard Fatigue Laboratory influential in promoting exercise physiology research
Despite its brief history (1927-1947), no physiology laboratory in America is more revered than the Harvard Fatigue Laboratory.
Despite its brief history (1927-1947), no physiology laboratory in America is more revered than the Harvard Fatigue Laboratory. Described as "the first laboratory for the comprehensive study of man" (5), it was perhaps more influential and effective in promoting scientific and collaborative research in exercise physiology (76). This chapter discusses the laboratory's contributions to the study of the acute and chronic effects of exercise and to the effects of altitude and temperature on the exercise response. This chapter includes information from the laboratory's extensive published record as well as from the perspective of the last surviving member of its faculty and staff (figure 3.1) (41).
G. Edgar Folk (1914-) of the University of Iowa in the United States who became a staff member of the Harvard Fatigue Laboratory in 1943. Folk remained at the Harvard Fatigue Laboratory until its closure in 1947. He subsequently spent six yr at Bowdoin College in Maine conducting research and teaching biology to undergraduate students. In 1953, he accepted an appointment in the department of physiology at the University of Iowa. Professor Folk continues to attend APS meetings, write manuscripts, and enjoy life as an elder statesman for physiology.
Harvard University (1920-1927)
In 1920, physiology at Harvard University was represented by four departments: physiology, comparative physiology, applied physiology, and physical chemistry. These departments were collectively known as the laboratories of physiology(53). Three years later, the department of industrial hygiene was transferred from the medical school to the recently established school of public health, facilitated by the efforts of Roger Lee (53). Subsequently, the department of industrial hygiene was renamed the department of applied physiology. At this time, Walter B. Cannon (1871-1945) was chairman of the department of physiology, David Edsall was dean of both the medical school and the school of public health, Lawrence Joseph Henderson (1888-1984) was director of the department of physical chemistry (figure 3.2), Wallace B. Donham was dean of the business school, and A. Laurence Lowell was president of the university (53). Also at this time, Dr. Arlie V. Bock was establishing a laboratory in Massachusetts General Hospital after being a physician in World War I, a Moseley Traveling Fellow in Sir Joseph Barcroft's laboratory for two years learning exercise protocols and blood-equilibration techniques, and after being a participant in Barcroft's high-altitude expedition in Peru (23) (figure 3.2).
David Bruce Dill (1891-1986) received his PhD in chemistry in 1925 from Stanford University and accepted a 2 yr National Research Council fellowship to work in the laboratory of L.J. Henderson to study the physical chemistry of proteins. However, after his arrival at Harvard, he was assigned to a Massachusetts General Hospital laboratory, where the senior staff physician was Dr. John H. Talbott. There he was reassigned to study with Dr. Bock the physiochemical properties of blood (46). When the fellowship was terminated, Dill was appointed as assistant professor of biochemistry in the school of public health, a position he retained until 1936. In addition, from 1927 to 1947, he held a professorship in the department of industrial hygiene at Harvard University (72). Although during his tenure at Harvard Henderson remained as director of the laboratory, it was Dill's leadership, organizational ability, and scientific insights that made the laboratory famous throughout the world. Between 1947 and 1961, Dill served as director of research for the U.S. Army Chemical Research and Development Laboratory. During this interval, he became president of the American Physiological Society (1950-1951) and later (1960-1961) was elected president of the American College of Sports Medicine (45, 74).
Henderson and the Establishment of the Harvard Fatigue Laboratory
Henderson, a recipient of an MD from Harvard in 1902, was professor of biological chemistry from 1919 until 1934 and the Abbot and James Lawrence professor of chemistry from 1934 until his death in 1942 (18) (figure 3.2). Besides chemistry and biology, Henderson had broad interests in sociology, psychology, anthropology, and the philosophy of Vilfredo Pareto, an Italian engineer and socialist (18, 46). He and Elton Mayo (a professor of industrial hygiene who, like Henderson, believed that workers should be studied in the workplace) developed the concept of establishing a laboratory to conduct research on industrial hazards (46). Such a laboratory would study the "group psychology, the social problems, and physiology of fatigue of normal man . . . not only as individual factors in determining physical and mental health, but more especially to determine their interrelatedness and the effect upon work" (46, p. 20).
With leadership from Henderson, the support of advisory and planning committees that included most of the previously mentioned deans and professors, the endorsement of President Lowell, and funding from the Laura Spelman Rockefeller Memorial and the Rockefeller Foundation, the Harvard Fatigue Laboratory was established in 1927 with Lawrence Joseph Henderson as its official director (46). According to Chapman, the term fatigue was selected because all parties believed it was important. However, because they could not agree on a definition, it did not force research activities into a specific departmental shape(19, p. 19). Its home was in the basement of Harvard Business School.
As noted, Dill was designated (although never officially appointed) to organize and direct the research program of the laboratory and quickly assumed the duties and responsibilities of Henderson. Hence, his curriculum vitae in the Mandeville Special Collections Library at the University of California in the United States lists him as the informal director of the laboratory between 1927 and 1946 (72). The Horvaths identified the senior members of the laboratory from 1927 to before World War II as Henderson, Dill, Bock, and Talbott (figure 3.2) (46).
Contributions to Undergraduate and Graduate Student Education
Although the education of undergraduate and graduate students was not a purpose for establishing the laboratory, the laboratory did provide opportunities for undergraduate and graduate students to be introduced to research and become involved with projects that all pertained to physiology and sometimes to exercise physiology. Although the laboratory offered no courses or degrees, it offered opportunities for students to conduct senior theses under the supervision of select faculty members. Twelve undergraduates were involved in activities of the laboratory. Henry Taylor became a renowned exercise physiologist at the University of Minnesota in the United States (figure 3.4). Richard Riley was recognized as an outstanding respiratory physiologist at Johns Hopkins University, and John Pappenheimer and Clifford Barger received acclaim as physiologists on the faculty of Harvard University (46). Sid Robinson and Steven Horvath (figures 3.5 and 3.6) conducted research for their PhD dissertations in the laboratory but received their degrees in biological sciences. Dill served as chairman of Robinson's committee but was unable to do so for Horvath because Horvath had married Dill's daughter (73). G. Edgar Folk Jr. received an MA from Harvard University in 1937 and served as a research associate in the laboratory from 1943 to 1947 (figure 3.1). In 1947, he received a PhD in the biological sciences with John Welch as his advisor (74). Additionally, Pappenheimer, Robinson, and Horvath served along with 13 other staff members as tutors for students in biochemistry (46).
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Advances in studies of genes associated with exercise behavior traits
Several research designs and technologies have been used over the past two decades in the effort to identify genomic regions, genes, and sequence variants associated with exercise behavior and exercise biology traits.
Genomics Studies
Several research designs and technologies have been used over the past two decades in the effort to identify genomic regions, genes, and sequence variants associated with exercise behavior and exercise biology traits. This section reviews advances made over time and key laboratories and investigators involved in these studies. Candidate genes, genome-wide linkage scans, genome-wide association (GWA) studies, and contributions from combinations of transcriptomics and genomics are reviewed. Efforts to identify genetic differences between elite athletes and sedentary controls are also briefly summarized.
Candidate Genes
A candidate gene is a gene that has a theoretical relationship with the behavioral, physiological, or metabolic system regulating the trait of interest. Candidate genes for exercise biology traits have been defined on the basis of advances in exercise physiology studies and animal models and on purely theoretical grounds. Transgenic (overexpression of a gene or genes), knockdown (reduced expression level), and knockout (ablation of a gene or genes) mice have generated a number of candidate genes that were subsequently investigated for potential involvement in human variation. The expression level of a gene has also been used as a candidate phenotype against which DNA variants can be tested for associations. The complete transcriptome, which is the full set of ribonucleic acid (RNA) transcripts in a given cell or tissue, has been used to define new panels of candidate genes for further genomics studies (e.g., 72, 224).
Candidate genes were very prominent in the early phase of exercise genomics. Many of the earlier studies were quite simple in design and were launched primarily because of the availability of whole blood stored in freezers. They were generally case-control or cross-sectional cohort studies with unrelated subjects. In the case of continuous traits (e.g., V\od\O2max), the association with a candidate gene or marker is tested by comparing mean trait values across genotypes or between carriers and noncarriers of a specific allele. In the case-control design, testing for a relation between a trait and a candidate gene marker is based on the comparison of allele and genotype frequencies between two informative groups of subjects, one with the phenotype of interest (e.g., elite power and strength athletes - the "cases") and the other without the phenotype of interest (the "controls").
Special Case of Athletes Versus Controls
Luigi Gedda from the Gregor Mendel Institute of Medical Genetics and Twin Research at the University of Rome was perhaps the pioneer in the effort to understand the importance of genetic differences between athletes and nonathletes (67, 68) (figure 7.7). The initial efforts were based on surveys of Italian twins, specifically on 351 pairs of twins who were engaged in competitive sport. The results of the surveys indicated familial aggregation among athletes and the potential importance of zygosity in concordance of sport selection; participation in markedly different sports occurred in 85% of DZ twins in contrast to only 6% of MZ twins (68). The familial aggregation of athletes was also noted by others, such as Grebe (75, 76) of Germany, Linc and Fleischmann (117) of Czechoslovakia, and Jokl (92, 93), who at the time was in the United States. The work of Gedda and his longtime collaborator, Paolo Parisi, was the most systematic in this regard and focused on genealogical and twin methods. The research of Parisi continues today with the Italian Registry of Twin Athletes (154, 155). A higher prevalence of MZ twins among swimmers has been one of their findings (154). In a large sample of adult British female twins, athlete status (nonathlete vs. local-, county-, or national-level athlete) had a heritability of 0.66 (50).
Luigi Gedda (1902-2000), MD, Mendel Institute of Medical Genetics and Twin Research in Rome, right, and Paolo Parisi (1940 - ), PhD, professor of biology and rector, Italian University Sport and Movement, University of Rome "Foro Italico," left. Gedda was the first to confirm, through classic pedigree studies in the mid-1950s, the common knowledge that elite athletes often cluster in families and to then attempt to quantify the role of genetic factors using the twin concordance model. He studied a large sample of MZ and DZ twin pairs and found considerably higher concordance rates in the former than in the latter with respect to various aspects of sport participation, such as kind of sport practiced and performance level. In later decades, Gedda's longtime associate Paolo Parisi conducted epidemiological and cell genetics research, also through the aid of a special registry of Italian twin athletes, in order to explore the genetic basis of athletic performance. Of particular interest to him is the relation of physical activity to health, aging, and chronic disease. One major line of research of his institute focuses on the role of exercise-induced oxidative stress in genetic regulation processes.
The first documented attempt to identify differences in genetic markers for performance-related phenotypes dates to the late 1960s. A group of geneticists, taking advantage of the 1968 Olympic Games in Mexico, investigated common blood genetic markers in an attempt to discriminate between Olympic athletes and controls (45).
Interestingly, phenylthiocarbamide nontasters were underrepresented among the athletes. The effort to document genetic differences between elite athletes and sedentary controls was continued on the occasion of the 1976 Olympic Games in Montreal (37, 41). A slightly higher frequency of the A1 allele of the ABO blood group was observed in endurance athletes participating in the 1976 Summer Olympic Games than in reference populations (37). However, the other plasma and red blood cell markers (ABO, MNSs, Rhesus, Duffy, Kell, P, LDH, MDH, phosphoglucomutase, adenosine deaminase, adenylate kinase, esterase D, haptoglobin, transferrin, hemoglobin, glucose-6-phosphate dehydrogenase, and acid phosphatase) did not differ between athletes and controls (37, 41, 45). These early attempts were all based on polymorphisms in red blood cell antigens and enzymes. Later, skeletal muscle gene product variants were screened (17, 128) and selected enzyme markers were investigated for their putative effects on a variety of skeletal muscle and cardiorespiratory endurance indicators. Genetic variants of skeletal muscle creatine kinase (CKM) and adenylate kinase 1 (AK1) were screened for using isoelectric focusing in 295 subjects (16). A variant form of both enzymes was identified with an allele frequency of 1% (CKM) and 3.5% (AK1). There was no difference in V\od\O2max between the carriers of the variant alleles and matched controls homozygous for the nonvariant allele (16). None of these studies yielded reliably significant genomic predictors of performance or fitness.
Genomic differences between athletes and untrained controls began to be investigated in a more systematic fashion with the launch of the GENATHLETE study in the laboratory of Claude Bouchard at Laval University in 1993. The main collaborators on GENATHLETE included Louis Perusse, Marcel Boulay, and the late Jean-Aime Simoneau (all from Laval University), Rainer Rauramaa (Kuopio, Finland), and particularly Bernd Wolfahrt (from Germany). The study focused on DNA sequence differences between a panel that has now attained more than 300 elite endurance athletes with a V\od\O2max no lower than 75 ml·kg-1·min-1 and more than 300 sedentary controls with a V\od\O2max no higher than 50 ml·kg-1·min-1. The participants are all white males from Canada, Germany, Finland, and the United States. Single nucleotide polymorphisms (SNPs) in several genes have been investigated to date, but none have provided strong evidence for differences in allele and genotype frequencies between athletes and controls (16, 178, 184, 185, 245-247). However, a common variant and haplotype in the hypoxia inducible factor 1, alpha subunit (HIF1A) gene were found to be more prevalent in athletes compared with controls in a 2010 report based on the GENATHLETE cohort (54), an observation that was defined in an accompanying editorial as an important milestone (194).
Another effort to delineate the differences between athletes and nonathletes is under way in Spain under the leadership of Jonatan Ruiz and Alejandro Lucia. They have used samples of Spanish Caucasian endurance athletes (about 100), power athletes (about 50), and nonathlete controls. A number of differences at candidate genes between athletes and controls, as well as between endurance and power athletes, have been reported (34, 71, 190). Taking advantage of the concept of a total genotype score developed by Williams and Folland (238), Ruiz and colleagues in 2009 attempted to predict world-class endurance athlete status based on the frequency of variant alleles at 7 candidate genes genotyped in 43 Spanish endurance athletes and 123 controls (191).
Yannis Pitsiladis from the faculty of biomedical and life sciences at the University of Glasgow has taken advantage of striking performance differences at the elite level in athletes of various ethnic backgrounds to investigate the potential role of variation in nuclear and mitochondrial DNA (figure 7.8). For instance, distance runners from Kenya and Ethiopia and sprinters from Jamaica won 25% of all track and field medals at the 2008 Olympic Games in Beijing (166). The effort to impute ethnic differences in sport performance to genetic differences is clearly challenging, particularly because only about 10% of human genetic variation can be found between the major ethnic groups. Pitsiladis' laboratory has explored differences in sequence variants in mitochondrial DNA and in Y chromosome markers between Ethiopian athletes, Ethiopian controls, Kenyan athletes, and Kenyan controls. Mitochondrial DNA haplogroups found in Kenya were different from those found in Ethiopia (197). Differences in haplogroup distributions were observed between athletes and controls in Kenya but not in Ethiopia. The full significance of this observation needs to be established. Analyses of Y chromosome haplogroups in endurance athletes from Ethiopia revealed differences between them and samples from the more general Ethiopian population (145). Population stratification was ruled out as the explanation for such differences. One important conclusion reached by Pitsiladis and colleagues is that the clusters of Kenyan and Ethiopian elite runners are distinct from each other from a genetic point of view (166).
Yannis P. Pitsiladis (1967 - ), MMedSci, PhD, FACSM, integrative and systems biology research theme, faculty of biomedical and life sciences, University of Glasgow, Scotland. Pitsiladis is a reader in exercise physiology at the Institute of Biomedical and Life Sciences at the University of Glasgow and founding member (and previous director) of the International Centre for East African Running Science, set up to investigate the physiological, genetic, psychosocial, and economic determinants of the phenomenal success of East African distance runners in international athletics. Recent projects include the study of West African sprinters (including elite sprinters from Jamaica and the United States) and the study of world-class swimmers (e.g., why there are very few black swimmers). He is a visiting professor in medical physiology at Moi University (Eldoret, Kenya), Addis Ababa University (Addis Ababa, Ethiopia), and University of Technology (Kingston, Jamaica). Pitsiladis has a particular research interest in mitochondrial DNA and Y chromosome markers and their potential role in ethnic differences in performance.
Photo courtesy of Yannis P. Pitsiladis.
Two genes have received considerable attention in the exercise genomics literature: angiotensin I-converting enzyme (ACE) and actinin alpha 3 (ACTN3). Both have been strong favorites of exercise scientists over the past decade or so.
ACE Gene
Hugh Montgomery (1962 - ), MB, BS, BSc, FRCP, MD, FRGS, director of University College London Institute for Human Health and Performance; consultant intensivist at Whittington Hospital; and professor of intensive care medicine at University College London. Montgomery obtained his BSc degree in neuropharmacology and in circulatory and respiratory physiology in 1984 before graduating with a medical degree in 1987. He has since trained and accredited in general internal medicine, cardiology, and intensive care medicine. He is now professor of intensive care medicine at University College London, where he also directs the Institute for Human Health and Performance. In the early 1990s, he began using gene - environment interaction as a means to explore human physiology. Working with army recruits, he first identified a role for the angiotensin I-converting enzyme (ACE) I/D polymorphism in the regulation of human cardiac growth. This work was extended to broader measures of performance, including high-altitude mountaineering aptitude. Mechanistically, a role in the regulation of metabolic efficiency was suggested, leading to phase IV studies of ACE inhibition in the treatment of cancer cachexia. Studies of downstream gene variants (e.g., those of the bradykinin B2 receptor gene) have offered further mechanistic insight. Montgomery has a special interest in high-altitude performance: He was science lead for the Caudwell Xtreme Everest Expedition in 2007 and has identified genes under selection pressure in high-altitude populations.
The potential role of ACE sequence differences in human physical performance was first investigated in the 1990s by Hugh Montgomery from the University College London (figure 7.9). He and his coworkers reported in 1997 that 10 wk of physical training in British army recruits induced greater increases in left ventricular mass and septal and posterior wall thickness in the ACE D/D homozygotes than in the I allele carriers (141). A few years later, the same group of investigators confirmed the finding by reporting that the training-induced increase in left ventricular mass in another cohort of army recruits was 2.7 times greater in the D/D genotype compared with the I/I homozygotes (147). The I allele was associated with higher muscular endurance gains after 10 wk of physical training in British army recruits (142).
The story began in 1990 when it was reported that a 287 bp I/D polymorphism in intron 16 of the ACE gene was associated with plasma ACE activity (183). ACE activity was highest in D/D homozygotes and lowest in I/I homozygotes. More than 50 reports have subsequently dealt with the potential role of the ACE I/D genotype in some aspects of fitness or performance. Overall, the results are heterogeneous and often contradictory. For instance, in postmenopausal women, I/I homozygotes had a higher V\od\O2max than D/D homozygotes (79), whereas the opposite was observed in Chinese males (251). In the HERITAGE Family Study, no associations were found between the ACE I/D polymorphism and maximal and submaximal exercise V\od\O2 and power output phenotypes in healthy, sedentary blacks and whites (41).
This literature was recently reviewed by Montgomery and colleagues (206). In the aggregate, it appears that the ACE I/D polymorphism may contribute to human variation in skeletal and cardiac muscle growth and functional properties as well as in adaptation to hypoxia. However, its contribution to variation in human physical performance remains a matter of debate.
ACTN3 Gene
Kathryn North and colleagues from the Children's Hospital at Westmead in Australia discovered a common variant in the gene for actinin-3, a structural actin binding protein found in skeletal muscle fast-twitch fibers (figure 7.10). The polymorphism (R577X) replaces an arginine residue by a premature stop codon at position 577 and results in ACTN3 deficiency. About 16% of the world population is homozygous for the XX null genotype; the frequency of the null allele is highest in Caucasians and Asians and lowest in Africans (8). The first report on ACTN3 genotype and performance was from North's laboratory in 2003. It indicated that the frequency of the stop codon mutation was lower in sprinters than in controls and endurance athletes (248). Several studies have concluded that the stop codon variant (X577X) was lower in sprint and strength athletes than in nonathletes (55, 57, 153, 189, 192, 248), but other reports have been negative (149, 198, 249). Interestingly, a number of studies based on direct measures of muscle strength and power have also been published and the results are contradictory; that is, the X allele is negatively associated with these muscle phenotypes in some studies whereas the converse is found in others (39, 51, 66, 132, 133, 146, 150, 228). North has reviewed the biology of the ACTN3 polymorphism in recent publications (8, 120). In the aggregate, the data suggest that there is probably a role of the X allele in skeletal muscle function and muscle performance, but the data remain inconclusive at present. More studies with appropriate power and designs, as well as more extensive functional studies, are warranted.
Kathryn North (1960 - ), MD, FRACP, Director, Murdoch Childrens Research Institute, and David Danks Professor of Child Health Research at University of Melbourne, Australia. In the process of studying genes implicated in muscle disease, North and colleagues at the Children's Hospital at Westmead discovered a common variant in the actinin alpha 3 (ACTN3) gene. ACTN3 encodes a structural protein found in fast-twitch skeletal muscle fibers. The ACTN3 gene variant results in complete deficiency of actinin-3 in almost 20% of the general population. North showed that ACTN3 deficiency is rare in sprint athletes, suggesting that this protein plays a crucial role in the function of fast-twitch muscle fibers. North and her team developed a strain of mice engineered to be completely deficient in ACTN3 and showed that the muscle of these knockout mice displays an increase in oxidative metabolism. This metabolic shift could explain why ACTN3 deficiency is detrimental to sprint activities that require fast or glycolytic metabolism. Her analysis of deoxyribonucleic acid (DNA) samples from individuals from around the world suggests that the ACTN3 deficiency provided some benefit to the ancestors of modern Europeans and Asians after their migration out of Africa, resulting in its increase in frequency due to natural selection. The benefit provided by ACTN3 deficiency may have allowed them to adapt to the more hostile environments of Eurasia. North's group plans to use mouse and human studies to determine the effect of ACTN3 deficiency on muscle aging, response to exercise, and the progression of inherited muscle diseases such as the muscular dystrophies.
Other Candidate Genes
A series of studies has dealt with the contributions of other candidate genes to human variation in muscular strength and power. These genes were identified because of their biological relevance to muscle contractile and sarcomeric proteins, myogenesis and muscle regeneration, muscle mass atrophy and sarcopenia, hormonal regulation of muscle mass, energy transfer to sustain muscle contraction, and other properties. The evidence from candidate gene studies of muscle strength and power was recently reviewed by Thomis (220).
An example of such genes is the myostatin (MSTN) gene. Mutations in MSTN leading to inactive or defective gene product have been shown to double or even triple skeletal muscle mass in mice, cows, and sheep. Functional MSTN mutations are very rare in humans. However, a boy appeared extraordinarily muscular at birth and at 4.5 yr of age was described as muscular and very strong (196). It turned out that he was a homozygote for a G/A mutation located five nucleotides downstream of exon 1, which abolishes a normal splice donor site and activates a cryptic splice site further downstream in intron 1, resulting in a truncated, inactive myostatin peptide. A number of polymorphisms in MSTN have been investigated for their associations with muscle hypertrophy or muscle strength and power (40, 60, 107, 199, 231), but the overall findings have been inconsistent.
Another class of candidate genes of great interest for muscular strength and power is that of the insulin-like growth factors and related binding proteins. These molecules play important roles in muscle growth and repair and in muscle response to exercise. Polymorphisms in insulin-like growth factors 1 (IGF1) and 2 (IGF2) have been rather consistently associated with muscle strength and its response to training, as well as other relevant endophenotypes (52, 81, 108, 193, 195).
The laboratories of James Hagberg and Stephen Roth in the department of kinesiology at the University of Maryland in the United States have pioneered a number of candidate gene research avenues since the late 1990s (figure 7.11). Their efforts focused on sequence variants in ACE; nitric oxide synthase 3 (NOS3); angiotensinogen (AGT); ACTN3; angiotensin II receptor, type 1 (AGTR1); tumor necrosis factor (TNF); nuclear factor of kappa light polypeptide gene enhancer in B-cells 1 (NFKB1); activin A receptor, type IIB (ACVR2B); adenosine monophosphate deaminase 1 (AMPD1); vascular endothelial growth factor A (VEGFA); vitamin D receptor (VDR); and MSTN, among others (see 59, 78, 79, 81, 134, 156, 167). Hagberg has a strong interest in exercise blood pressure and other hemodynamic phenotypes and through most of his career has consistently focused on the role of exercise in health-related outcomes and therapeutic applications, with an emphasis on the importance of genetic differences at key genes. Roth, whose primary interest is in muscle size and strength, has contributed a primer on exercise genetics (187) and has a longstanding interest in the role of genetic variation in talent selection for athletic performance. Both have trained a good number of graduate students in exercise genetics and have been longtime contributors to the fitness and performance gene map series that was published in Medicine and Science in Sports and Exercise until 2009.
Stephen M. Roth (1973 - ), PhD, FACSM, associate professor, and James M. Hagberg (1950 - ), PhD, FACSM, professor, department of kinesiology, school of public health, University of Maryland. Hagberg completed his graduate studies at the University of Wisconsin. He has been on the faculty of a number of universities and at the University of Maryland for nearly 20 yr, where he is a distinguished scholar-teacher. He has been funded by the National Institute of Aging for genetics-based investigations and has published numerous papers identifying genetic markers that associate with the degree to which endurance-exercise training improves cardiovascular disease risk factors in older men and women. Stephen M. Roth completed graduate studies in exercise physiology at the University of Maryland in 2000 and postdoctoral training in human genetics at the University of Pittsburgh. In 2003 he was recruited back to the University of Maryland as director of the Functional Genomics Laboratory. He has been funded by the National Institutes of Health to perform a variety of genetics investigations. In addition to several research publications, Roth is author of a textbook titled Genetics Primer for Exercise Science and Health. The department of kinesiology at the University of Maryland was one of the first to develop a research focus in the area of exercise genomics. As a group, they have published more than 60 peer-reviewed publications in the areas of exercise genomics.
When the last version of the fitness and performance gene map was published based on the publications available by the end of 2007, there were 214 autosomal, 7 X chromosome, and 18 mitochondrial gene and other loci entries (31). Most of the entries were related to specific candidate genes and were supported by more than 350 peer-reviewed papers. With the exception of the ACE and ACTN3 common variants, few of the genes had been replicated in multiple studies. Moreover, after almost 25 yr of candidate gene studies in exercise biology, this line of research continues to be plagued by small sample sizes and lack of appropriate statistical power (31, 177). Studies with small sample sizes occasionally report positive findings, especially if they include several traits and perform multiple statistical tests for association. Fortunately, these positive findings are seldom replicated and usually fall into oblivion.
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Early German roots of exercise physiology
In 1719, Friedrich Hoffmann (1660-1742), a physician from Halle, obtained his doctoral degree with experimental investigations about the effects of physical exercise on the human cardiovascular system and on digestion.
Exercise Physiology Research in Germany 1700 to 1910
In 1719, Friedrich Hoffmann (1660-1742), a physician from Halle, obtained his doctoral degree with experimental investigations about the effects of physical exercise on the human cardiovascular system and on digestion. In 1796, the physician Christoph Wilhelm Hufeland (1762-1836) published a textbook about the significance of different types of physical exercise for human health and life expectancy (66).
In the 19th century, the physiologist Emil Dubois-Reymond (1818-1896) studied the role of gymnastics in the human body (21, 22). The physician and chemist Max von Pettenkofer (1818-1901) detected the existence of creatine in the skeletal muscle and described a strengthening of the circulatory system in connection with physical training (111).
The first ergometer in the present-day sense of the word was developed by the German physician Speck in 1883. When using this cranked ergometer, the test person was in the standing position (figure 4.1). The crank friction could be modified by pulling up a screw. Speck determined the resistance with weights hung on the crank. The number of revolutions could be determined by noting the number of turns of twine wound up around the crank axle. The exhaled air was collected in a double spirometer and the postexperimental air composition was determined, thus enabling conclusions to be drawn about the individual performance reaction (2, 125).
In 1887 the Viennese physician Friedrich Gaertner (1847-1917) presented a mechanically braked ergometer, based on Speck's equipment that could measure the work performed in kilogram-meter. This device, called the ergostat, later went into standard production (112).
The first heyday of exercise physiology began with the veterinarian Nathan Zuntz (1847-1920) in Berlin (figure 4.2), who developed the first motor-driven treadmill in 1889 (figure 4.3). His work is described in chapter 1 (142).
Of substantial significance in the application of aspects of exercise physiology in medicine were Adolf Theophil Ferdinand Hueppe (1852-1938) and Ferdinand August Schmidt (1852-1929). In 1899 Hueppe wrote a fundamental work titled A Textbook of Hygiene that covered the whole of the exercise physiology discipline of those days. This was followed by the work titled Hygiene of Physical Exercises, published in 1911. In 1893 Schmidt published the book Physical Exercise According to the Exercise Value, which deals with an overview of suitable physical exercises for different ages (122, 123).
From 1904 to 1906 Kuelbs examined the influence of physical training on the internal organs, particularly the heart. He took two dogs from the same litter and trained one of them 5 times/wk for about 2 h on a treadmill, which he had taken over from Zuntz; the other dog had a normal, everyday life. After 1 yr both animals were killed and all internal organs were measured and examined. Although both dogs had more or less the same body weight, the heart of the dog trained on the treadmill was approximately 33% larger than that of the untrained dog. Similar differences were also manifest in the weights of the liver, kidneys, adrenal glands, spleen, and lungs (77).
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Over the subsequent decades Arthur Mallwitz (1880-1968) became the most important promoter for German, and later international, sports medicine. He obtained his doctor's degree at Halle University (Saale) in 1908 with what is presumed to be the first ever dissertation in sports medicine. In his dissertation, titled Maximum Performances With Special Consideration of Sports Done at the Olympic Games, Mallwitz considered, above all, the investigations of Hueppe and Schmidt as well as those of Zuntz and his school. In 1910 a comprehensive book about exercise physiology in connection with numerous kinds of sports was edited by Weissbein (141).
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The first ergometer was developed by Speck in 1883. Gaertner produced it in series.
Hollmann W, Strueder HK, Predel HG, Tagarakis CVM. Spiroergometrie. Stuttgart, Schattauer, 2006.
Exercise Physiology Research in Germany 1911 to 1933
German Empire Committee for Scientific Research in Sport and Physical Exercise
The First Congress for Scientific Research in Sport and Physical Exercise took place in Oberhof, Germany, from September 20 to 23, 1912. The congress was conducted by the professor for internal medicine of the University Clinic Berlin Charité, Friedrich Kraus (1858-1936), and was chaired by Schmidt and Hueppe. Approximately 70 doctors participated (93). On September 21, 1912, the German Empire Committee for Scientific Research in Sport and Physical Exercise - the first national medical sport association worldwide - was founded under the chairmanship ofKraus, who was elected president.
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Nathan Zuntz (1847-1920).
Reprinted, by permission, from W. Hollmann and K. Tittel, 2008, History of German sports medicine (Gera: Druckhaus Gera), 15.
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The world's first motorized treadmill, developed by Zuntz and Lehmann in 1889 in Berlin. This apparatus was shown in the international hygiene exhibition in Dresden in 1911.
Hollmann W, Strueder HK, Predel HG, Tagarakis CVM. Spiroergometry. Stuttgart, Schattauer, 2006.
Period From 1913 to 1924
In 1913, Arthur Mallwitz was appointed the first full-time sport physician worldwide by the Prussian State Gymnastics Institute. Mallwitz then took up his office under the official designation of sport physician (94).
At the same time the physician and chemist Otto Meyerhof (1884-1951) recognized the regulating relationship between respiration rate and the suppression of glycolysis in muscles. He demonstrated that the consumption of one molecule of oxygen prevents the formation of two molecules of lactate. Meyerhof's findings supported the assumption that the enzymes fanning lactate also function aerobically but that the lactate formed is resynthesized to carbohydrate at the expense of the energy provided by respiration (98).
Hugo Wilhelm Knipping (1895-1984), physician and internist at Hamburg University, developed a gas metabolism apparatus for examination of humans at rest in 1924 and constructed a dynamo cranked ergometer in 1928. In 1929 he combined an enlarged gas metabolism apparatus for exercise examinations with the crank ergometer and designated the method as spiroergometry (73, 74). It was the genesis of precise and simple clinical exercise diagnostics. Engineering, however, was not able to construct the equipment to satisfy all technical requirements until 1949 (75, 76).
German Medical Association for the Promotion of Physical Exercise (1924-1933)
Because of the political confusion and economic difficulties after the finish of World War I in 1918, approximately 6 yr elapsed before research in sports medicine and thus exercise physiology was renewed in 1924. The founding of the German Physician Association for the Promotion of Physical Exercise in 1924 was the impetus for this.
In 1925 Max Rubner (1854-1932), director of the Robert Koch Institute in Berlin and an internationally recognized metabolism researcher, ascertained that the skeletal musculature in adults amounts to 43% of the total body mass and that the total musculoskeletal system inclusive of bones, heart, and lungs amounts to 61%. The greatest proportion of the musculature was allotted to the legs (56%) and the upper extremities (28%). The head and torso muscles contributed to 16% of the total body mass (120).
Approximately 3,200 kcal could meet the daily energy requirements for physical exercise for a 70 kg person whereas 2,600 calories was sufficient for simple office work. The metabolism of a farm worker during harvesting would require 4,300 kcal. The peak values of the daily calorie consumption for lumberjacks would amount to approximately 6,000 kcal for a 70 kg person. Long-distance racing cyclists, however, could reach a peak daily metabolic rate of 11,000 kcal. Rubner believed that the limiting factor for the uptake of calories in the human body was the intestinal system. A repeat of such great exertion over several days would inevitably lead to loss of body weight (119).
As early as 1925, Herbert Herxheimer (1894-1985) and others precisely described the psychic and physical effects of overtraining, including a decrease in maximal oxygen uptake, reduced appetite, tendency to sweat, shivering, jerky reflexes, and pronounced respiratory arrhythmia with a clear preponderance of the parasympathetic part. Obstipation and painful stomach spasms also could be observed. Herxheimer published all his sports medicine knowledge in his famous book in 1933.
Herxheimer also described the connection between heart size and distance running. He found an increase in the transverse diameters of the heart in the following ascending order: boxing, swimming, middle-distance running, long-distance running, marathon running, and long-distance skiing. Particularly large hearts would work with a large stroke volume. This would result in the corresponding bradycardia at rest. The blood pressure of endurance athletes would be low (39).
Ludwig Aschoff (1866-1942) in Freiburg ascertained that there is one physiological work hypertrophy of the heart muscle as an adaptation to increased muscular activity. The enlargement remains within moderate limits. Sport does not cause a pathological hypertrophy. If a conspicuous general hypertrophy of the heart exists, it is a matter of pathological circumstances (e.g., cardiac valve ailments, hypertony or glomerular-tubular cirrhosis of the kidney). It is impossible for sport to cause a fatality in an individual with a healthy heart. A muscular cardiac insufficiency is to be treated by taking it easy. Puberty is a dangerous period regarding possible functional damage of the heart through sport.
Another significant exercise physiologist of the 1920s was Richard Herbst (1893-1949) in KÃöenigsberg East Prussia. He conducted numerous experimental investigations on the behavior of maximum oxygen absorption in humans of different ages and in different training conditions. He published his findings in 1928, 4 yr after the first description of maximum oxygen uptake by Hill. According to Herbst (1928), endurance-trained subjects had a higher oxygen intake than did untrained subjects. Also, after reaching the maximum oxygen uptake value, ventilation could be increased still further. Herbst used the Douglas bag with the subsequent respiratory gas analysis method for runners and cyclists. Further, he examined running distances between 100 m and marathon using the Douglas bag and gas analysis. The values obtained at that time (e.g., marathon with an energy consumption of 3,050 kcal, 10 m sprint with an energy consumption of 50 kcal) agree with measurements made nowadays. Sustained running loads of more than 3 min were determined from the magnitude of the maximal oxygen uptake. Thus, these parameters were a measure of performance. The lung ventilation volume would still increase further after reaching the maximum oxygen absorption. Cardiac output is represented as the most important factor limiting physical performance (37).
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Harvard Fatigue Laboratory influential in promoting exercise physiology research
Despite its brief history (1927-1947), no physiology laboratory in America is more revered than the Harvard Fatigue Laboratory.
Despite its brief history (1927-1947), no physiology laboratory in America is more revered than the Harvard Fatigue Laboratory. Described as "the first laboratory for the comprehensive study of man" (5), it was perhaps more influential and effective in promoting scientific and collaborative research in exercise physiology (76). This chapter discusses the laboratory's contributions to the study of the acute and chronic effects of exercise and to the effects of altitude and temperature on the exercise response. This chapter includes information from the laboratory's extensive published record as well as from the perspective of the last surviving member of its faculty and staff (figure 3.1) (41).
G. Edgar Folk (1914-) of the University of Iowa in the United States who became a staff member of the Harvard Fatigue Laboratory in 1943. Folk remained at the Harvard Fatigue Laboratory until its closure in 1947. He subsequently spent six yr at Bowdoin College in Maine conducting research and teaching biology to undergraduate students. In 1953, he accepted an appointment in the department of physiology at the University of Iowa. Professor Folk continues to attend APS meetings, write manuscripts, and enjoy life as an elder statesman for physiology.
Harvard University (1920-1927)
In 1920, physiology at Harvard University was represented by four departments: physiology, comparative physiology, applied physiology, and physical chemistry. These departments were collectively known as the laboratories of physiology(53). Three years later, the department of industrial hygiene was transferred from the medical school to the recently established school of public health, facilitated by the efforts of Roger Lee (53). Subsequently, the department of industrial hygiene was renamed the department of applied physiology. At this time, Walter B. Cannon (1871-1945) was chairman of the department of physiology, David Edsall was dean of both the medical school and the school of public health, Lawrence Joseph Henderson (1888-1984) was director of the department of physical chemistry (figure 3.2), Wallace B. Donham was dean of the business school, and A. Laurence Lowell was president of the university (53). Also at this time, Dr. Arlie V. Bock was establishing a laboratory in Massachusetts General Hospital after being a physician in World War I, a Moseley Traveling Fellow in Sir Joseph Barcroft's laboratory for two years learning exercise protocols and blood-equilibration techniques, and after being a participant in Barcroft's high-altitude expedition in Peru (23) (figure 3.2).
David Bruce Dill (1891-1986) received his PhD in chemistry in 1925 from Stanford University and accepted a 2 yr National Research Council fellowship to work in the laboratory of L.J. Henderson to study the physical chemistry of proteins. However, after his arrival at Harvard, he was assigned to a Massachusetts General Hospital laboratory, where the senior staff physician was Dr. John H. Talbott. There he was reassigned to study with Dr. Bock the physiochemical properties of blood (46). When the fellowship was terminated, Dill was appointed as assistant professor of biochemistry in the school of public health, a position he retained until 1936. In addition, from 1927 to 1947, he held a professorship in the department of industrial hygiene at Harvard University (72). Although during his tenure at Harvard Henderson remained as director of the laboratory, it was Dill's leadership, organizational ability, and scientific insights that made the laboratory famous throughout the world. Between 1947 and 1961, Dill served as director of research for the U.S. Army Chemical Research and Development Laboratory. During this interval, he became president of the American Physiological Society (1950-1951) and later (1960-1961) was elected president of the American College of Sports Medicine (45, 74).
Henderson and the Establishment of the Harvard Fatigue Laboratory
Henderson, a recipient of an MD from Harvard in 1902, was professor of biological chemistry from 1919 until 1934 and the Abbot and James Lawrence professor of chemistry from 1934 until his death in 1942 (18) (figure 3.2). Besides chemistry and biology, Henderson had broad interests in sociology, psychology, anthropology, and the philosophy of Vilfredo Pareto, an Italian engineer and socialist (18, 46). He and Elton Mayo (a professor of industrial hygiene who, like Henderson, believed that workers should be studied in the workplace) developed the concept of establishing a laboratory to conduct research on industrial hazards (46). Such a laboratory would study the "group psychology, the social problems, and physiology of fatigue of normal man . . . not only as individual factors in determining physical and mental health, but more especially to determine their interrelatedness and the effect upon work" (46, p. 20).
With leadership from Henderson, the support of advisory and planning committees that included most of the previously mentioned deans and professors, the endorsement of President Lowell, and funding from the Laura Spelman Rockefeller Memorial and the Rockefeller Foundation, the Harvard Fatigue Laboratory was established in 1927 with Lawrence Joseph Henderson as its official director (46). According to Chapman, the term fatigue was selected because all parties believed it was important. However, because they could not agree on a definition, it did not force research activities into a specific departmental shape(19, p. 19). Its home was in the basement of Harvard Business School.
As noted, Dill was designated (although never officially appointed) to organize and direct the research program of the laboratory and quickly assumed the duties and responsibilities of Henderson. Hence, his curriculum vitae in the Mandeville Special Collections Library at the University of California in the United States lists him as the informal director of the laboratory between 1927 and 1946 (72). The Horvaths identified the senior members of the laboratory from 1927 to before World War II as Henderson, Dill, Bock, and Talbott (figure 3.2) (46).
Contributions to Undergraduate and Graduate Student Education
Although the education of undergraduate and graduate students was not a purpose for establishing the laboratory, the laboratory did provide opportunities for undergraduate and graduate students to be introduced to research and become involved with projects that all pertained to physiology and sometimes to exercise physiology. Although the laboratory offered no courses or degrees, it offered opportunities for students to conduct senior theses under the supervision of select faculty members. Twelve undergraduates were involved in activities of the laboratory. Henry Taylor became a renowned exercise physiologist at the University of Minnesota in the United States (figure 3.4). Richard Riley was recognized as an outstanding respiratory physiologist at Johns Hopkins University, and John Pappenheimer and Clifford Barger received acclaim as physiologists on the faculty of Harvard University (46). Sid Robinson and Steven Horvath (figures 3.5 and 3.6) conducted research for their PhD dissertations in the laboratory but received their degrees in biological sciences. Dill served as chairman of Robinson's committee but was unable to do so for Horvath because Horvath had married Dill's daughter (73). G. Edgar Folk Jr. received an MA from Harvard University in 1937 and served as a research associate in the laboratory from 1943 to 1947 (figure 3.1). In 1947, he received a PhD in the biological sciences with John Welch as his advisor (74). Additionally, Pappenheimer, Robinson, and Horvath served along with 13 other staff members as tutors for students in biochemistry (46).
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Advances in studies of genes associated with exercise behavior traits
Several research designs and technologies have been used over the past two decades in the effort to identify genomic regions, genes, and sequence variants associated with exercise behavior and exercise biology traits.
Genomics Studies
Several research designs and technologies have been used over the past two decades in the effort to identify genomic regions, genes, and sequence variants associated with exercise behavior and exercise biology traits. This section reviews advances made over time and key laboratories and investigators involved in these studies. Candidate genes, genome-wide linkage scans, genome-wide association (GWA) studies, and contributions from combinations of transcriptomics and genomics are reviewed. Efforts to identify genetic differences between elite athletes and sedentary controls are also briefly summarized.
Candidate Genes
A candidate gene is a gene that has a theoretical relationship with the behavioral, physiological, or metabolic system regulating the trait of interest. Candidate genes for exercise biology traits have been defined on the basis of advances in exercise physiology studies and animal models and on purely theoretical grounds. Transgenic (overexpression of a gene or genes), knockdown (reduced expression level), and knockout (ablation of a gene or genes) mice have generated a number of candidate genes that were subsequently investigated for potential involvement in human variation. The expression level of a gene has also been used as a candidate phenotype against which DNA variants can be tested for associations. The complete transcriptome, which is the full set of ribonucleic acid (RNA) transcripts in a given cell or tissue, has been used to define new panels of candidate genes for further genomics studies (e.g., 72, 224).
Candidate genes were very prominent in the early phase of exercise genomics. Many of the earlier studies were quite simple in design and were launched primarily because of the availability of whole blood stored in freezers. They were generally case-control or cross-sectional cohort studies with unrelated subjects. In the case of continuous traits (e.g., V\od\O2max), the association with a candidate gene or marker is tested by comparing mean trait values across genotypes or between carriers and noncarriers of a specific allele. In the case-control design, testing for a relation between a trait and a candidate gene marker is based on the comparison of allele and genotype frequencies between two informative groups of subjects, one with the phenotype of interest (e.g., elite power and strength athletes - the "cases") and the other without the phenotype of interest (the "controls").
Special Case of Athletes Versus Controls
Luigi Gedda from the Gregor Mendel Institute of Medical Genetics and Twin Research at the University of Rome was perhaps the pioneer in the effort to understand the importance of genetic differences between athletes and nonathletes (67, 68) (figure 7.7). The initial efforts were based on surveys of Italian twins, specifically on 351 pairs of twins who were engaged in competitive sport. The results of the surveys indicated familial aggregation among athletes and the potential importance of zygosity in concordance of sport selection; participation in markedly different sports occurred in 85% of DZ twins in contrast to only 6% of MZ twins (68). The familial aggregation of athletes was also noted by others, such as Grebe (75, 76) of Germany, Linc and Fleischmann (117) of Czechoslovakia, and Jokl (92, 93), who at the time was in the United States. The work of Gedda and his longtime collaborator, Paolo Parisi, was the most systematic in this regard and focused on genealogical and twin methods. The research of Parisi continues today with the Italian Registry of Twin Athletes (154, 155). A higher prevalence of MZ twins among swimmers has been one of their findings (154). In a large sample of adult British female twins, athlete status (nonathlete vs. local-, county-, or national-level athlete) had a heritability of 0.66 (50).
Luigi Gedda (1902-2000), MD, Mendel Institute of Medical Genetics and Twin Research in Rome, right, and Paolo Parisi (1940 - ), PhD, professor of biology and rector, Italian University Sport and Movement, University of Rome "Foro Italico," left. Gedda was the first to confirm, through classic pedigree studies in the mid-1950s, the common knowledge that elite athletes often cluster in families and to then attempt to quantify the role of genetic factors using the twin concordance model. He studied a large sample of MZ and DZ twin pairs and found considerably higher concordance rates in the former than in the latter with respect to various aspects of sport participation, such as kind of sport practiced and performance level. In later decades, Gedda's longtime associate Paolo Parisi conducted epidemiological and cell genetics research, also through the aid of a special registry of Italian twin athletes, in order to explore the genetic basis of athletic performance. Of particular interest to him is the relation of physical activity to health, aging, and chronic disease. One major line of research of his institute focuses on the role of exercise-induced oxidative stress in genetic regulation processes.
The first documented attempt to identify differences in genetic markers for performance-related phenotypes dates to the late 1960s. A group of geneticists, taking advantage of the 1968 Olympic Games in Mexico, investigated common blood genetic markers in an attempt to discriminate between Olympic athletes and controls (45).
Interestingly, phenylthiocarbamide nontasters were underrepresented among the athletes. The effort to document genetic differences between elite athletes and sedentary controls was continued on the occasion of the 1976 Olympic Games in Montreal (37, 41). A slightly higher frequency of the A1 allele of the ABO blood group was observed in endurance athletes participating in the 1976 Summer Olympic Games than in reference populations (37). However, the other plasma and red blood cell markers (ABO, MNSs, Rhesus, Duffy, Kell, P, LDH, MDH, phosphoglucomutase, adenosine deaminase, adenylate kinase, esterase D, haptoglobin, transferrin, hemoglobin, glucose-6-phosphate dehydrogenase, and acid phosphatase) did not differ between athletes and controls (37, 41, 45). These early attempts were all based on polymorphisms in red blood cell antigens and enzymes. Later, skeletal muscle gene product variants were screened (17, 128) and selected enzyme markers were investigated for their putative effects on a variety of skeletal muscle and cardiorespiratory endurance indicators. Genetic variants of skeletal muscle creatine kinase (CKM) and adenylate kinase 1 (AK1) were screened for using isoelectric focusing in 295 subjects (16). A variant form of both enzymes was identified with an allele frequency of 1% (CKM) and 3.5% (AK1). There was no difference in V\od\O2max between the carriers of the variant alleles and matched controls homozygous for the nonvariant allele (16). None of these studies yielded reliably significant genomic predictors of performance or fitness.
Genomic differences between athletes and untrained controls began to be investigated in a more systematic fashion with the launch of the GENATHLETE study in the laboratory of Claude Bouchard at Laval University in 1993. The main collaborators on GENATHLETE included Louis Perusse, Marcel Boulay, and the late Jean-Aime Simoneau (all from Laval University), Rainer Rauramaa (Kuopio, Finland), and particularly Bernd Wolfahrt (from Germany). The study focused on DNA sequence differences between a panel that has now attained more than 300 elite endurance athletes with a V\od\O2max no lower than 75 ml·kg-1·min-1 and more than 300 sedentary controls with a V\od\O2max no higher than 50 ml·kg-1·min-1. The participants are all white males from Canada, Germany, Finland, and the United States. Single nucleotide polymorphisms (SNPs) in several genes have been investigated to date, but none have provided strong evidence for differences in allele and genotype frequencies between athletes and controls (16, 178, 184, 185, 245-247). However, a common variant and haplotype in the hypoxia inducible factor 1, alpha subunit (HIF1A) gene were found to be more prevalent in athletes compared with controls in a 2010 report based on the GENATHLETE cohort (54), an observation that was defined in an accompanying editorial as an important milestone (194).
Another effort to delineate the differences between athletes and nonathletes is under way in Spain under the leadership of Jonatan Ruiz and Alejandro Lucia. They have used samples of Spanish Caucasian endurance athletes (about 100), power athletes (about 50), and nonathlete controls. A number of differences at candidate genes between athletes and controls, as well as between endurance and power athletes, have been reported (34, 71, 190). Taking advantage of the concept of a total genotype score developed by Williams and Folland (238), Ruiz and colleagues in 2009 attempted to predict world-class endurance athlete status based on the frequency of variant alleles at 7 candidate genes genotyped in 43 Spanish endurance athletes and 123 controls (191).
Yannis Pitsiladis from the faculty of biomedical and life sciences at the University of Glasgow has taken advantage of striking performance differences at the elite level in athletes of various ethnic backgrounds to investigate the potential role of variation in nuclear and mitochondrial DNA (figure 7.8). For instance, distance runners from Kenya and Ethiopia and sprinters from Jamaica won 25% of all track and field medals at the 2008 Olympic Games in Beijing (166). The effort to impute ethnic differences in sport performance to genetic differences is clearly challenging, particularly because only about 10% of human genetic variation can be found between the major ethnic groups. Pitsiladis' laboratory has explored differences in sequence variants in mitochondrial DNA and in Y chromosome markers between Ethiopian athletes, Ethiopian controls, Kenyan athletes, and Kenyan controls. Mitochondrial DNA haplogroups found in Kenya were different from those found in Ethiopia (197). Differences in haplogroup distributions were observed between athletes and controls in Kenya but not in Ethiopia. The full significance of this observation needs to be established. Analyses of Y chromosome haplogroups in endurance athletes from Ethiopia revealed differences between them and samples from the more general Ethiopian population (145). Population stratification was ruled out as the explanation for such differences. One important conclusion reached by Pitsiladis and colleagues is that the clusters of Kenyan and Ethiopian elite runners are distinct from each other from a genetic point of view (166).
Yannis P. Pitsiladis (1967 - ), MMedSci, PhD, FACSM, integrative and systems biology research theme, faculty of biomedical and life sciences, University of Glasgow, Scotland. Pitsiladis is a reader in exercise physiology at the Institute of Biomedical and Life Sciences at the University of Glasgow and founding member (and previous director) of the International Centre for East African Running Science, set up to investigate the physiological, genetic, psychosocial, and economic determinants of the phenomenal success of East African distance runners in international athletics. Recent projects include the study of West African sprinters (including elite sprinters from Jamaica and the United States) and the study of world-class swimmers (e.g., why there are very few black swimmers). He is a visiting professor in medical physiology at Moi University (Eldoret, Kenya), Addis Ababa University (Addis Ababa, Ethiopia), and University of Technology (Kingston, Jamaica). Pitsiladis has a particular research interest in mitochondrial DNA and Y chromosome markers and their potential role in ethnic differences in performance.
Photo courtesy of Yannis P. Pitsiladis.
Two genes have received considerable attention in the exercise genomics literature: angiotensin I-converting enzyme (ACE) and actinin alpha 3 (ACTN3). Both have been strong favorites of exercise scientists over the past decade or so.
ACE Gene
Hugh Montgomery (1962 - ), MB, BS, BSc, FRCP, MD, FRGS, director of University College London Institute for Human Health and Performance; consultant intensivist at Whittington Hospital; and professor of intensive care medicine at University College London. Montgomery obtained his BSc degree in neuropharmacology and in circulatory and respiratory physiology in 1984 before graduating with a medical degree in 1987. He has since trained and accredited in general internal medicine, cardiology, and intensive care medicine. He is now professor of intensive care medicine at University College London, where he also directs the Institute for Human Health and Performance. In the early 1990s, he began using gene - environment interaction as a means to explore human physiology. Working with army recruits, he first identified a role for the angiotensin I-converting enzyme (ACE) I/D polymorphism in the regulation of human cardiac growth. This work was extended to broader measures of performance, including high-altitude mountaineering aptitude. Mechanistically, a role in the regulation of metabolic efficiency was suggested, leading to phase IV studies of ACE inhibition in the treatment of cancer cachexia. Studies of downstream gene variants (e.g., those of the bradykinin B2 receptor gene) have offered further mechanistic insight. Montgomery has a special interest in high-altitude performance: He was science lead for the Caudwell Xtreme Everest Expedition in 2007 and has identified genes under selection pressure in high-altitude populations.
The potential role of ACE sequence differences in human physical performance was first investigated in the 1990s by Hugh Montgomery from the University College London (figure 7.9). He and his coworkers reported in 1997 that 10 wk of physical training in British army recruits induced greater increases in left ventricular mass and septal and posterior wall thickness in the ACE D/D homozygotes than in the I allele carriers (141). A few years later, the same group of investigators confirmed the finding by reporting that the training-induced increase in left ventricular mass in another cohort of army recruits was 2.7 times greater in the D/D genotype compared with the I/I homozygotes (147). The I allele was associated with higher muscular endurance gains after 10 wk of physical training in British army recruits (142).
The story began in 1990 when it was reported that a 287 bp I/D polymorphism in intron 16 of the ACE gene was associated with plasma ACE activity (183). ACE activity was highest in D/D homozygotes and lowest in I/I homozygotes. More than 50 reports have subsequently dealt with the potential role of the ACE I/D genotype in some aspects of fitness or performance. Overall, the results are heterogeneous and often contradictory. For instance, in postmenopausal women, I/I homozygotes had a higher V\od\O2max than D/D homozygotes (79), whereas the opposite was observed in Chinese males (251). In the HERITAGE Family Study, no associations were found between the ACE I/D polymorphism and maximal and submaximal exercise V\od\O2 and power output phenotypes in healthy, sedentary blacks and whites (41).
This literature was recently reviewed by Montgomery and colleagues (206). In the aggregate, it appears that the ACE I/D polymorphism may contribute to human variation in skeletal and cardiac muscle growth and functional properties as well as in adaptation to hypoxia. However, its contribution to variation in human physical performance remains a matter of debate.
ACTN3 Gene
Kathryn North and colleagues from the Children's Hospital at Westmead in Australia discovered a common variant in the gene for actinin-3, a structural actin binding protein found in skeletal muscle fast-twitch fibers (figure 7.10). The polymorphism (R577X) replaces an arginine residue by a premature stop codon at position 577 and results in ACTN3 deficiency. About 16% of the world population is homozygous for the XX null genotype; the frequency of the null allele is highest in Caucasians and Asians and lowest in Africans (8). The first report on ACTN3 genotype and performance was from North's laboratory in 2003. It indicated that the frequency of the stop codon mutation was lower in sprinters than in controls and endurance athletes (248). Several studies have concluded that the stop codon variant (X577X) was lower in sprint and strength athletes than in nonathletes (55, 57, 153, 189, 192, 248), but other reports have been negative (149, 198, 249). Interestingly, a number of studies based on direct measures of muscle strength and power have also been published and the results are contradictory; that is, the X allele is negatively associated with these muscle phenotypes in some studies whereas the converse is found in others (39, 51, 66, 132, 133, 146, 150, 228). North has reviewed the biology of the ACTN3 polymorphism in recent publications (8, 120). In the aggregate, the data suggest that there is probably a role of the X allele in skeletal muscle function and muscle performance, but the data remain inconclusive at present. More studies with appropriate power and designs, as well as more extensive functional studies, are warranted.
Kathryn North (1960 - ), MD, FRACP, Director, Murdoch Childrens Research Institute, and David Danks Professor of Child Health Research at University of Melbourne, Australia. In the process of studying genes implicated in muscle disease, North and colleagues at the Children's Hospital at Westmead discovered a common variant in the actinin alpha 3 (ACTN3) gene. ACTN3 encodes a structural protein found in fast-twitch skeletal muscle fibers. The ACTN3 gene variant results in complete deficiency of actinin-3 in almost 20% of the general population. North showed that ACTN3 deficiency is rare in sprint athletes, suggesting that this protein plays a crucial role in the function of fast-twitch muscle fibers. North and her team developed a strain of mice engineered to be completely deficient in ACTN3 and showed that the muscle of these knockout mice displays an increase in oxidative metabolism. This metabolic shift could explain why ACTN3 deficiency is detrimental to sprint activities that require fast or glycolytic metabolism. Her analysis of deoxyribonucleic acid (DNA) samples from individuals from around the world suggests that the ACTN3 deficiency provided some benefit to the ancestors of modern Europeans and Asians after their migration out of Africa, resulting in its increase in frequency due to natural selection. The benefit provided by ACTN3 deficiency may have allowed them to adapt to the more hostile environments of Eurasia. North's group plans to use mouse and human studies to determine the effect of ACTN3 deficiency on muscle aging, response to exercise, and the progression of inherited muscle diseases such as the muscular dystrophies.
Other Candidate Genes
A series of studies has dealt with the contributions of other candidate genes to human variation in muscular strength and power. These genes were identified because of their biological relevance to muscle contractile and sarcomeric proteins, myogenesis and muscle regeneration, muscle mass atrophy and sarcopenia, hormonal regulation of muscle mass, energy transfer to sustain muscle contraction, and other properties. The evidence from candidate gene studies of muscle strength and power was recently reviewed by Thomis (220).
An example of such genes is the myostatin (MSTN) gene. Mutations in MSTN leading to inactive or defective gene product have been shown to double or even triple skeletal muscle mass in mice, cows, and sheep. Functional MSTN mutations are very rare in humans. However, a boy appeared extraordinarily muscular at birth and at 4.5 yr of age was described as muscular and very strong (196). It turned out that he was a homozygote for a G/A mutation located five nucleotides downstream of exon 1, which abolishes a normal splice donor site and activates a cryptic splice site further downstream in intron 1, resulting in a truncated, inactive myostatin peptide. A number of polymorphisms in MSTN have been investigated for their associations with muscle hypertrophy or muscle strength and power (40, 60, 107, 199, 231), but the overall findings have been inconsistent.
Another class of candidate genes of great interest for muscular strength and power is that of the insulin-like growth factors and related binding proteins. These molecules play important roles in muscle growth and repair and in muscle response to exercise. Polymorphisms in insulin-like growth factors 1 (IGF1) and 2 (IGF2) have been rather consistently associated with muscle strength and its response to training, as well as other relevant endophenotypes (52, 81, 108, 193, 195).
The laboratories of James Hagberg and Stephen Roth in the department of kinesiology at the University of Maryland in the United States have pioneered a number of candidate gene research avenues since the late 1990s (figure 7.11). Their efforts focused on sequence variants in ACE; nitric oxide synthase 3 (NOS3); angiotensinogen (AGT); ACTN3; angiotensin II receptor, type 1 (AGTR1); tumor necrosis factor (TNF); nuclear factor of kappa light polypeptide gene enhancer in B-cells 1 (NFKB1); activin A receptor, type IIB (ACVR2B); adenosine monophosphate deaminase 1 (AMPD1); vascular endothelial growth factor A (VEGFA); vitamin D receptor (VDR); and MSTN, among others (see 59, 78, 79, 81, 134, 156, 167). Hagberg has a strong interest in exercise blood pressure and other hemodynamic phenotypes and through most of his career has consistently focused on the role of exercise in health-related outcomes and therapeutic applications, with an emphasis on the importance of genetic differences at key genes. Roth, whose primary interest is in muscle size and strength, has contributed a primer on exercise genetics (187) and has a longstanding interest in the role of genetic variation in talent selection for athletic performance. Both have trained a good number of graduate students in exercise genetics and have been longtime contributors to the fitness and performance gene map series that was published in Medicine and Science in Sports and Exercise until 2009.
Stephen M. Roth (1973 - ), PhD, FACSM, associate professor, and James M. Hagberg (1950 - ), PhD, FACSM, professor, department of kinesiology, school of public health, University of Maryland. Hagberg completed his graduate studies at the University of Wisconsin. He has been on the faculty of a number of universities and at the University of Maryland for nearly 20 yr, where he is a distinguished scholar-teacher. He has been funded by the National Institute of Aging for genetics-based investigations and has published numerous papers identifying genetic markers that associate with the degree to which endurance-exercise training improves cardiovascular disease risk factors in older men and women. Stephen M. Roth completed graduate studies in exercise physiology at the University of Maryland in 2000 and postdoctoral training in human genetics at the University of Pittsburgh. In 2003 he was recruited back to the University of Maryland as director of the Functional Genomics Laboratory. He has been funded by the National Institutes of Health to perform a variety of genetics investigations. In addition to several research publications, Roth is author of a textbook titled Genetics Primer for Exercise Science and Health. The department of kinesiology at the University of Maryland was one of the first to develop a research focus in the area of exercise genomics. As a group, they have published more than 60 peer-reviewed publications in the areas of exercise genomics.
When the last version of the fitness and performance gene map was published based on the publications available by the end of 2007, there were 214 autosomal, 7 X chromosome, and 18 mitochondrial gene and other loci entries (31). Most of the entries were related to specific candidate genes and were supported by more than 350 peer-reviewed papers. With the exception of the ACE and ACTN3 common variants, few of the genes had been replicated in multiple studies. Moreover, after almost 25 yr of candidate gene studies in exercise biology, this line of research continues to be plagued by small sample sizes and lack of appropriate statistical power (31, 177). Studies with small sample sizes occasionally report positive findings, especially if they include several traits and perform multiple statistical tests for association. Fortunately, these positive findings are seldom replicated and usually fall into oblivion.
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Early German roots of exercise physiology
In 1719, Friedrich Hoffmann (1660-1742), a physician from Halle, obtained his doctoral degree with experimental investigations about the effects of physical exercise on the human cardiovascular system and on digestion.
Exercise Physiology Research in Germany 1700 to 1910
In 1719, Friedrich Hoffmann (1660-1742), a physician from Halle, obtained his doctoral degree with experimental investigations about the effects of physical exercise on the human cardiovascular system and on digestion. In 1796, the physician Christoph Wilhelm Hufeland (1762-1836) published a textbook about the significance of different types of physical exercise for human health and life expectancy (66).
In the 19th century, the physiologist Emil Dubois-Reymond (1818-1896) studied the role of gymnastics in the human body (21, 22). The physician and chemist Max von Pettenkofer (1818-1901) detected the existence of creatine in the skeletal muscle and described a strengthening of the circulatory system in connection with physical training (111).
The first ergometer in the present-day sense of the word was developed by the German physician Speck in 1883. When using this cranked ergometer, the test person was in the standing position (figure 4.1). The crank friction could be modified by pulling up a screw. Speck determined the resistance with weights hung on the crank. The number of revolutions could be determined by noting the number of turns of twine wound up around the crank axle. The exhaled air was collected in a double spirometer and the postexperimental air composition was determined, thus enabling conclusions to be drawn about the individual performance reaction (2, 125).
In 1887 the Viennese physician Friedrich Gaertner (1847-1917) presented a mechanically braked ergometer, based on Speck's equipment that could measure the work performed in kilogram-meter. This device, called the ergostat, later went into standard production (112).
The first heyday of exercise physiology began with the veterinarian Nathan Zuntz (1847-1920) in Berlin (figure 4.2), who developed the first motor-driven treadmill in 1889 (figure 4.3). His work is described in chapter 1 (142).
Of substantial significance in the application of aspects of exercise physiology in medicine were Adolf Theophil Ferdinand Hueppe (1852-1938) and Ferdinand August Schmidt (1852-1929). In 1899 Hueppe wrote a fundamental work titled A Textbook of Hygiene that covered the whole of the exercise physiology discipline of those days. This was followed by the work titled Hygiene of Physical Exercises, published in 1911. In 1893 Schmidt published the book Physical Exercise According to the Exercise Value, which deals with an overview of suitable physical exercises for different ages (122, 123).
From 1904 to 1906 Kuelbs examined the influence of physical training on the internal organs, particularly the heart. He took two dogs from the same litter and trained one of them 5 times/wk for about 2 h on a treadmill, which he had taken over from Zuntz; the other dog had a normal, everyday life. After 1 yr both animals were killed and all internal organs were measured and examined. Although both dogs had more or less the same body weight, the heart of the dog trained on the treadmill was approximately 33% larger than that of the untrained dog. Similar differences were also manifest in the weights of the liver, kidneys, adrenal glands, spleen, and lungs (77).
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Over the subsequent decades Arthur Mallwitz (1880-1968) became the most important promoter for German, and later international, sports medicine. He obtained his doctor's degree at Halle University (Saale) in 1908 with what is presumed to be the first ever dissertation in sports medicine. In his dissertation, titled Maximum Performances With Special Consideration of Sports Done at the Olympic Games, Mallwitz considered, above all, the investigations of Hueppe and Schmidt as well as those of Zuntz and his school. In 1910 a comprehensive book about exercise physiology in connection with numerous kinds of sports was edited by Weissbein (141).
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The first ergometer was developed by Speck in 1883. Gaertner produced it in series.
Hollmann W, Strueder HK, Predel HG, Tagarakis CVM. Spiroergometrie. Stuttgart, Schattauer, 2006.
Exercise Physiology Research in Germany 1911 to 1933
German Empire Committee for Scientific Research in Sport and Physical Exercise
The First Congress for Scientific Research in Sport and Physical Exercise took place in Oberhof, Germany, from September 20 to 23, 1912. The congress was conducted by the professor for internal medicine of the University Clinic Berlin Charité, Friedrich Kraus (1858-1936), and was chaired by Schmidt and Hueppe. Approximately 70 doctors participated (93). On September 21, 1912, the German Empire Committee for Scientific Research in Sport and Physical Exercise - the first national medical sport association worldwide - was founded under the chairmanship ofKraus, who was elected president.
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Nathan Zuntz (1847-1920).
Reprinted, by permission, from W. Hollmann and K. Tittel, 2008, History of German sports medicine (Gera: Druckhaus Gera), 15.
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The world's first motorized treadmill, developed by Zuntz and Lehmann in 1889 in Berlin. This apparatus was shown in the international hygiene exhibition in Dresden in 1911.
Hollmann W, Strueder HK, Predel HG, Tagarakis CVM. Spiroergometry. Stuttgart, Schattauer, 2006.
Period From 1913 to 1924
In 1913, Arthur Mallwitz was appointed the first full-time sport physician worldwide by the Prussian State Gymnastics Institute. Mallwitz then took up his office under the official designation of sport physician (94).
At the same time the physician and chemist Otto Meyerhof (1884-1951) recognized the regulating relationship between respiration rate and the suppression of glycolysis in muscles. He demonstrated that the consumption of one molecule of oxygen prevents the formation of two molecules of lactate. Meyerhof's findings supported the assumption that the enzymes fanning lactate also function aerobically but that the lactate formed is resynthesized to carbohydrate at the expense of the energy provided by respiration (98).
Hugo Wilhelm Knipping (1895-1984), physician and internist at Hamburg University, developed a gas metabolism apparatus for examination of humans at rest in 1924 and constructed a dynamo cranked ergometer in 1928. In 1929 he combined an enlarged gas metabolism apparatus for exercise examinations with the crank ergometer and designated the method as spiroergometry (73, 74). It was the genesis of precise and simple clinical exercise diagnostics. Engineering, however, was not able to construct the equipment to satisfy all technical requirements until 1949 (75, 76).
German Medical Association for the Promotion of Physical Exercise (1924-1933)
Because of the political confusion and economic difficulties after the finish of World War I in 1918, approximately 6 yr elapsed before research in sports medicine and thus exercise physiology was renewed in 1924. The founding of the German Physician Association for the Promotion of Physical Exercise in 1924 was the impetus for this.
In 1925 Max Rubner (1854-1932), director of the Robert Koch Institute in Berlin and an internationally recognized metabolism researcher, ascertained that the skeletal musculature in adults amounts to 43% of the total body mass and that the total musculoskeletal system inclusive of bones, heart, and lungs amounts to 61%. The greatest proportion of the musculature was allotted to the legs (56%) and the upper extremities (28%). The head and torso muscles contributed to 16% of the total body mass (120).
Approximately 3,200 kcal could meet the daily energy requirements for physical exercise for a 70 kg person whereas 2,600 calories was sufficient for simple office work. The metabolism of a farm worker during harvesting would require 4,300 kcal. The peak values of the daily calorie consumption for lumberjacks would amount to approximately 6,000 kcal for a 70 kg person. Long-distance racing cyclists, however, could reach a peak daily metabolic rate of 11,000 kcal. Rubner believed that the limiting factor for the uptake of calories in the human body was the intestinal system. A repeat of such great exertion over several days would inevitably lead to loss of body weight (119).
As early as 1925, Herbert Herxheimer (1894-1985) and others precisely described the psychic and physical effects of overtraining, including a decrease in maximal oxygen uptake, reduced appetite, tendency to sweat, shivering, jerky reflexes, and pronounced respiratory arrhythmia with a clear preponderance of the parasympathetic part. Obstipation and painful stomach spasms also could be observed. Herxheimer published all his sports medicine knowledge in his famous book in 1933.
Herxheimer also described the connection between heart size and distance running. He found an increase in the transverse diameters of the heart in the following ascending order: boxing, swimming, middle-distance running, long-distance running, marathon running, and long-distance skiing. Particularly large hearts would work with a large stroke volume. This would result in the corresponding bradycardia at rest. The blood pressure of endurance athletes would be low (39).
Ludwig Aschoff (1866-1942) in Freiburg ascertained that there is one physiological work hypertrophy of the heart muscle as an adaptation to increased muscular activity. The enlargement remains within moderate limits. Sport does not cause a pathological hypertrophy. If a conspicuous general hypertrophy of the heart exists, it is a matter of pathological circumstances (e.g., cardiac valve ailments, hypertony or glomerular-tubular cirrhosis of the kidney). It is impossible for sport to cause a fatality in an individual with a healthy heart. A muscular cardiac insufficiency is to be treated by taking it easy. Puberty is a dangerous period regarding possible functional damage of the heart through sport.
Another significant exercise physiologist of the 1920s was Richard Herbst (1893-1949) in KÃöenigsberg East Prussia. He conducted numerous experimental investigations on the behavior of maximum oxygen absorption in humans of different ages and in different training conditions. He published his findings in 1928, 4 yr after the first description of maximum oxygen uptake by Hill. According to Herbst (1928), endurance-trained subjects had a higher oxygen intake than did untrained subjects. Also, after reaching the maximum oxygen uptake value, ventilation could be increased still further. Herbst used the Douglas bag with the subsequent respiratory gas analysis method for runners and cyclists. Further, he examined running distances between 100 m and marathon using the Douglas bag and gas analysis. The values obtained at that time (e.g., marathon with an energy consumption of 3,050 kcal, 10 m sprint with an energy consumption of 50 kcal) agree with measurements made nowadays. Sustained running loads of more than 3 min were determined from the magnitude of the maximal oxygen uptake. Thus, these parameters were a measure of performance. The lung ventilation volume would still increase further after reaching the maximum oxygen absorption. Cardiac output is represented as the most important factor limiting physical performance (37).
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Harvard Fatigue Laboratory influential in promoting exercise physiology research
Despite its brief history (1927-1947), no physiology laboratory in America is more revered than the Harvard Fatigue Laboratory.
Despite its brief history (1927-1947), no physiology laboratory in America is more revered than the Harvard Fatigue Laboratory. Described as "the first laboratory for the comprehensive study of man" (5), it was perhaps more influential and effective in promoting scientific and collaborative research in exercise physiology (76). This chapter discusses the laboratory's contributions to the study of the acute and chronic effects of exercise and to the effects of altitude and temperature on the exercise response. This chapter includes information from the laboratory's extensive published record as well as from the perspective of the last surviving member of its faculty and staff (figure 3.1) (41).
G. Edgar Folk (1914-) of the University of Iowa in the United States who became a staff member of the Harvard Fatigue Laboratory in 1943. Folk remained at the Harvard Fatigue Laboratory until its closure in 1947. He subsequently spent six yr at Bowdoin College in Maine conducting research and teaching biology to undergraduate students. In 1953, he accepted an appointment in the department of physiology at the University of Iowa. Professor Folk continues to attend APS meetings, write manuscripts, and enjoy life as an elder statesman for physiology.
Harvard University (1920-1927)
In 1920, physiology at Harvard University was represented by four departments: physiology, comparative physiology, applied physiology, and physical chemistry. These departments were collectively known as the laboratories of physiology(53). Three years later, the department of industrial hygiene was transferred from the medical school to the recently established school of public health, facilitated by the efforts of Roger Lee (53). Subsequently, the department of industrial hygiene was renamed the department of applied physiology. At this time, Walter B. Cannon (1871-1945) was chairman of the department of physiology, David Edsall was dean of both the medical school and the school of public health, Lawrence Joseph Henderson (1888-1984) was director of the department of physical chemistry (figure 3.2), Wallace B. Donham was dean of the business school, and A. Laurence Lowell was president of the university (53). Also at this time, Dr. Arlie V. Bock was establishing a laboratory in Massachusetts General Hospital after being a physician in World War I, a Moseley Traveling Fellow in Sir Joseph Barcroft's laboratory for two years learning exercise protocols and blood-equilibration techniques, and after being a participant in Barcroft's high-altitude expedition in Peru (23) (figure 3.2).
David Bruce Dill (1891-1986) received his PhD in chemistry in 1925 from Stanford University and accepted a 2 yr National Research Council fellowship to work in the laboratory of L.J. Henderson to study the physical chemistry of proteins. However, after his arrival at Harvard, he was assigned to a Massachusetts General Hospital laboratory, where the senior staff physician was Dr. John H. Talbott. There he was reassigned to study with Dr. Bock the physiochemical properties of blood (46). When the fellowship was terminated, Dill was appointed as assistant professor of biochemistry in the school of public health, a position he retained until 1936. In addition, from 1927 to 1947, he held a professorship in the department of industrial hygiene at Harvard University (72). Although during his tenure at Harvard Henderson remained as director of the laboratory, it was Dill's leadership, organizational ability, and scientific insights that made the laboratory famous throughout the world. Between 1947 and 1961, Dill served as director of research for the U.S. Army Chemical Research and Development Laboratory. During this interval, he became president of the American Physiological Society (1950-1951) and later (1960-1961) was elected president of the American College of Sports Medicine (45, 74).
Henderson and the Establishment of the Harvard Fatigue Laboratory
Henderson, a recipient of an MD from Harvard in 1902, was professor of biological chemistry from 1919 until 1934 and the Abbot and James Lawrence professor of chemistry from 1934 until his death in 1942 (18) (figure 3.2). Besides chemistry and biology, Henderson had broad interests in sociology, psychology, anthropology, and the philosophy of Vilfredo Pareto, an Italian engineer and socialist (18, 46). He and Elton Mayo (a professor of industrial hygiene who, like Henderson, believed that workers should be studied in the workplace) developed the concept of establishing a laboratory to conduct research on industrial hazards (46). Such a laboratory would study the "group psychology, the social problems, and physiology of fatigue of normal man . . . not only as individual factors in determining physical and mental health, but more especially to determine their interrelatedness and the effect upon work" (46, p. 20).
With leadership from Henderson, the support of advisory and planning committees that included most of the previously mentioned deans and professors, the endorsement of President Lowell, and funding from the Laura Spelman Rockefeller Memorial and the Rockefeller Foundation, the Harvard Fatigue Laboratory was established in 1927 with Lawrence Joseph Henderson as its official director (46). According to Chapman, the term fatigue was selected because all parties believed it was important. However, because they could not agree on a definition, it did not force research activities into a specific departmental shape(19, p. 19). Its home was in the basement of Harvard Business School.
As noted, Dill was designated (although never officially appointed) to organize and direct the research program of the laboratory and quickly assumed the duties and responsibilities of Henderson. Hence, his curriculum vitae in the Mandeville Special Collections Library at the University of California in the United States lists him as the informal director of the laboratory between 1927 and 1946 (72). The Horvaths identified the senior members of the laboratory from 1927 to before World War II as Henderson, Dill, Bock, and Talbott (figure 3.2) (46).
Contributions to Undergraduate and Graduate Student Education
Although the education of undergraduate and graduate students was not a purpose for establishing the laboratory, the laboratory did provide opportunities for undergraduate and graduate students to be introduced to research and become involved with projects that all pertained to physiology and sometimes to exercise physiology. Although the laboratory offered no courses or degrees, it offered opportunities for students to conduct senior theses under the supervision of select faculty members. Twelve undergraduates were involved in activities of the laboratory. Henry Taylor became a renowned exercise physiologist at the University of Minnesota in the United States (figure 3.4). Richard Riley was recognized as an outstanding respiratory physiologist at Johns Hopkins University, and John Pappenheimer and Clifford Barger received acclaim as physiologists on the faculty of Harvard University (46). Sid Robinson and Steven Horvath (figures 3.5 and 3.6) conducted research for their PhD dissertations in the laboratory but received their degrees in biological sciences. Dill served as chairman of Robinson's committee but was unable to do so for Horvath because Horvath had married Dill's daughter (73). G. Edgar Folk Jr. received an MA from Harvard University in 1937 and served as a research associate in the laboratory from 1943 to 1947 (figure 3.1). In 1947, he received a PhD in the biological sciences with John Welch as his advisor (74). Additionally, Pappenheimer, Robinson, and Horvath served along with 13 other staff members as tutors for students in biochemistry (46).
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Advances in studies of genes associated with exercise behavior traits
Several research designs and technologies have been used over the past two decades in the effort to identify genomic regions, genes, and sequence variants associated with exercise behavior and exercise biology traits.
Genomics Studies
Several research designs and technologies have been used over the past two decades in the effort to identify genomic regions, genes, and sequence variants associated with exercise behavior and exercise biology traits. This section reviews advances made over time and key laboratories and investigators involved in these studies. Candidate genes, genome-wide linkage scans, genome-wide association (GWA) studies, and contributions from combinations of transcriptomics and genomics are reviewed. Efforts to identify genetic differences between elite athletes and sedentary controls are also briefly summarized.
Candidate Genes
A candidate gene is a gene that has a theoretical relationship with the behavioral, physiological, or metabolic system regulating the trait of interest. Candidate genes for exercise biology traits have been defined on the basis of advances in exercise physiology studies and animal models and on purely theoretical grounds. Transgenic (overexpression of a gene or genes), knockdown (reduced expression level), and knockout (ablation of a gene or genes) mice have generated a number of candidate genes that were subsequently investigated for potential involvement in human variation. The expression level of a gene has also been used as a candidate phenotype against which DNA variants can be tested for associations. The complete transcriptome, which is the full set of ribonucleic acid (RNA) transcripts in a given cell or tissue, has been used to define new panels of candidate genes for further genomics studies (e.g., 72, 224).
Candidate genes were very prominent in the early phase of exercise genomics. Many of the earlier studies were quite simple in design and were launched primarily because of the availability of whole blood stored in freezers. They were generally case-control or cross-sectional cohort studies with unrelated subjects. In the case of continuous traits (e.g., V\od\O2max), the association with a candidate gene or marker is tested by comparing mean trait values across genotypes or between carriers and noncarriers of a specific allele. In the case-control design, testing for a relation between a trait and a candidate gene marker is based on the comparison of allele and genotype frequencies between two informative groups of subjects, one with the phenotype of interest (e.g., elite power and strength athletes - the "cases") and the other without the phenotype of interest (the "controls").
Special Case of Athletes Versus Controls
Luigi Gedda from the Gregor Mendel Institute of Medical Genetics and Twin Research at the University of Rome was perhaps the pioneer in the effort to understand the importance of genetic differences between athletes and nonathletes (67, 68) (figure 7.7). The initial efforts were based on surveys of Italian twins, specifically on 351 pairs of twins who were engaged in competitive sport. The results of the surveys indicated familial aggregation among athletes and the potential importance of zygosity in concordance of sport selection; participation in markedly different sports occurred in 85% of DZ twins in contrast to only 6% of MZ twins (68). The familial aggregation of athletes was also noted by others, such as Grebe (75, 76) of Germany, Linc and Fleischmann (117) of Czechoslovakia, and Jokl (92, 93), who at the time was in the United States. The work of Gedda and his longtime collaborator, Paolo Parisi, was the most systematic in this regard and focused on genealogical and twin methods. The research of Parisi continues today with the Italian Registry of Twin Athletes (154, 155). A higher prevalence of MZ twins among swimmers has been one of their findings (154). In a large sample of adult British female twins, athlete status (nonathlete vs. local-, county-, or national-level athlete) had a heritability of 0.66 (50).
Luigi Gedda (1902-2000), MD, Mendel Institute of Medical Genetics and Twin Research in Rome, right, and Paolo Parisi (1940 - ), PhD, professor of biology and rector, Italian University Sport and Movement, University of Rome "Foro Italico," left. Gedda was the first to confirm, through classic pedigree studies in the mid-1950s, the common knowledge that elite athletes often cluster in families and to then attempt to quantify the role of genetic factors using the twin concordance model. He studied a large sample of MZ and DZ twin pairs and found considerably higher concordance rates in the former than in the latter with respect to various aspects of sport participation, such as kind of sport practiced and performance level. In later decades, Gedda's longtime associate Paolo Parisi conducted epidemiological and cell genetics research, also through the aid of a special registry of Italian twin athletes, in order to explore the genetic basis of athletic performance. Of particular interest to him is the relation of physical activity to health, aging, and chronic disease. One major line of research of his institute focuses on the role of exercise-induced oxidative stress in genetic regulation processes.
The first documented attempt to identify differences in genetic markers for performance-related phenotypes dates to the late 1960s. A group of geneticists, taking advantage of the 1968 Olympic Games in Mexico, investigated common blood genetic markers in an attempt to discriminate between Olympic athletes and controls (45).
Interestingly, phenylthiocarbamide nontasters were underrepresented among the athletes. The effort to document genetic differences between elite athletes and sedentary controls was continued on the occasion of the 1976 Olympic Games in Montreal (37, 41). A slightly higher frequency of the A1 allele of the ABO blood group was observed in endurance athletes participating in the 1976 Summer Olympic Games than in reference populations (37). However, the other plasma and red blood cell markers (ABO, MNSs, Rhesus, Duffy, Kell, P, LDH, MDH, phosphoglucomutase, adenosine deaminase, adenylate kinase, esterase D, haptoglobin, transferrin, hemoglobin, glucose-6-phosphate dehydrogenase, and acid phosphatase) did not differ between athletes and controls (37, 41, 45). These early attempts were all based on polymorphisms in red blood cell antigens and enzymes. Later, skeletal muscle gene product variants were screened (17, 128) and selected enzyme markers were investigated for their putative effects on a variety of skeletal muscle and cardiorespiratory endurance indicators. Genetic variants of skeletal muscle creatine kinase (CKM) and adenylate kinase 1 (AK1) were screened for using isoelectric focusing in 295 subjects (16). A variant form of both enzymes was identified with an allele frequency of 1% (CKM) and 3.5% (AK1). There was no difference in V\od\O2max between the carriers of the variant alleles and matched controls homozygous for the nonvariant allele (16). None of these studies yielded reliably significant genomic predictors of performance or fitness.
Genomic differences between athletes and untrained controls began to be investigated in a more systematic fashion with the launch of the GENATHLETE study in the laboratory of Claude Bouchard at Laval University in 1993. The main collaborators on GENATHLETE included Louis Perusse, Marcel Boulay, and the late Jean-Aime Simoneau (all from Laval University), Rainer Rauramaa (Kuopio, Finland), and particularly Bernd Wolfahrt (from Germany). The study focused on DNA sequence differences between a panel that has now attained more than 300 elite endurance athletes with a V\od\O2max no lower than 75 ml·kg-1·min-1 and more than 300 sedentary controls with a V\od\O2max no higher than 50 ml·kg-1·min-1. The participants are all white males from Canada, Germany, Finland, and the United States. Single nucleotide polymorphisms (SNPs) in several genes have been investigated to date, but none have provided strong evidence for differences in allele and genotype frequencies between athletes and controls (16, 178, 184, 185, 245-247). However, a common variant and haplotype in the hypoxia inducible factor 1, alpha subunit (HIF1A) gene were found to be more prevalent in athletes compared with controls in a 2010 report based on the GENATHLETE cohort (54), an observation that was defined in an accompanying editorial as an important milestone (194).
Another effort to delineate the differences between athletes and nonathletes is under way in Spain under the leadership of Jonatan Ruiz and Alejandro Lucia. They have used samples of Spanish Caucasian endurance athletes (about 100), power athletes (about 50), and nonathlete controls. A number of differences at candidate genes between athletes and controls, as well as between endurance and power athletes, have been reported (34, 71, 190). Taking advantage of the concept of a total genotype score developed by Williams and Folland (238), Ruiz and colleagues in 2009 attempted to predict world-class endurance athlete status based on the frequency of variant alleles at 7 candidate genes genotyped in 43 Spanish endurance athletes and 123 controls (191).
Yannis Pitsiladis from the faculty of biomedical and life sciences at the University of Glasgow has taken advantage of striking performance differences at the elite level in athletes of various ethnic backgrounds to investigate the potential role of variation in nuclear and mitochondrial DNA (figure 7.8). For instance, distance runners from Kenya and Ethiopia and sprinters from Jamaica won 25% of all track and field medals at the 2008 Olympic Games in Beijing (166). The effort to impute ethnic differences in sport performance to genetic differences is clearly challenging, particularly because only about 10% of human genetic variation can be found between the major ethnic groups. Pitsiladis' laboratory has explored differences in sequence variants in mitochondrial DNA and in Y chromosome markers between Ethiopian athletes, Ethiopian controls, Kenyan athletes, and Kenyan controls. Mitochondrial DNA haplogroups found in Kenya were different from those found in Ethiopia (197). Differences in haplogroup distributions were observed between athletes and controls in Kenya but not in Ethiopia. The full significance of this observation needs to be established. Analyses of Y chromosome haplogroups in endurance athletes from Ethiopia revealed differences between them and samples from the more general Ethiopian population (145). Population stratification was ruled out as the explanation for such differences. One important conclusion reached by Pitsiladis and colleagues is that the clusters of Kenyan and Ethiopian elite runners are distinct from each other from a genetic point of view (166).
Yannis P. Pitsiladis (1967 - ), MMedSci, PhD, FACSM, integrative and systems biology research theme, faculty of biomedical and life sciences, University of Glasgow, Scotland. Pitsiladis is a reader in exercise physiology at the Institute of Biomedical and Life Sciences at the University of Glasgow and founding member (and previous director) of the International Centre for East African Running Science, set up to investigate the physiological, genetic, psychosocial, and economic determinants of the phenomenal success of East African distance runners in international athletics. Recent projects include the study of West African sprinters (including elite sprinters from Jamaica and the United States) and the study of world-class swimmers (e.g., why there are very few black swimmers). He is a visiting professor in medical physiology at Moi University (Eldoret, Kenya), Addis Ababa University (Addis Ababa, Ethiopia), and University of Technology (Kingston, Jamaica). Pitsiladis has a particular research interest in mitochondrial DNA and Y chromosome markers and their potential role in ethnic differences in performance.
Photo courtesy of Yannis P. Pitsiladis.
Two genes have received considerable attention in the exercise genomics literature: angiotensin I-converting enzyme (ACE) and actinin alpha 3 (ACTN3). Both have been strong favorites of exercise scientists over the past decade or so.
ACE Gene
Hugh Montgomery (1962 - ), MB, BS, BSc, FRCP, MD, FRGS, director of University College London Institute for Human Health and Performance; consultant intensivist at Whittington Hospital; and professor of intensive care medicine at University College London. Montgomery obtained his BSc degree in neuropharmacology and in circulatory and respiratory physiology in 1984 before graduating with a medical degree in 1987. He has since trained and accredited in general internal medicine, cardiology, and intensive care medicine. He is now professor of intensive care medicine at University College London, where he also directs the Institute for Human Health and Performance. In the early 1990s, he began using gene - environment interaction as a means to explore human physiology. Working with army recruits, he first identified a role for the angiotensin I-converting enzyme (ACE) I/D polymorphism in the regulation of human cardiac growth. This work was extended to broader measures of performance, including high-altitude mountaineering aptitude. Mechanistically, a role in the regulation of metabolic efficiency was suggested, leading to phase IV studies of ACE inhibition in the treatment of cancer cachexia. Studies of downstream gene variants (e.g., those of the bradykinin B2 receptor gene) have offered further mechanistic insight. Montgomery has a special interest in high-altitude performance: He was science lead for the Caudwell Xtreme Everest Expedition in 2007 and has identified genes under selection pressure in high-altitude populations.
The potential role of ACE sequence differences in human physical performance was first investigated in the 1990s by Hugh Montgomery from the University College London (figure 7.9). He and his coworkers reported in 1997 that 10 wk of physical training in British army recruits induced greater increases in left ventricular mass and septal and posterior wall thickness in the ACE D/D homozygotes than in the I allele carriers (141). A few years later, the same group of investigators confirmed the finding by reporting that the training-induced increase in left ventricular mass in another cohort of army recruits was 2.7 times greater in the D/D genotype compared with the I/I homozygotes (147). The I allele was associated with higher muscular endurance gains after 10 wk of physical training in British army recruits (142).
The story began in 1990 when it was reported that a 287 bp I/D polymorphism in intron 16 of the ACE gene was associated with plasma ACE activity (183). ACE activity was highest in D/D homozygotes and lowest in I/I homozygotes. More than 50 reports have subsequently dealt with the potential role of the ACE I/D genotype in some aspects of fitness or performance. Overall, the results are heterogeneous and often contradictory. For instance, in postmenopausal women, I/I homozygotes had a higher V\od\O2max than D/D homozygotes (79), whereas the opposite was observed in Chinese males (251). In the HERITAGE Family Study, no associations were found between the ACE I/D polymorphism and maximal and submaximal exercise V\od\O2 and power output phenotypes in healthy, sedentary blacks and whites (41).
This literature was recently reviewed by Montgomery and colleagues (206). In the aggregate, it appears that the ACE I/D polymorphism may contribute to human variation in skeletal and cardiac muscle growth and functional properties as well as in adaptation to hypoxia. However, its contribution to variation in human physical performance remains a matter of debate.
ACTN3 Gene
Kathryn North and colleagues from the Children's Hospital at Westmead in Australia discovered a common variant in the gene for actinin-3, a structural actin binding protein found in skeletal muscle fast-twitch fibers (figure 7.10). The polymorphism (R577X) replaces an arginine residue by a premature stop codon at position 577 and results in ACTN3 deficiency. About 16% of the world population is homozygous for the XX null genotype; the frequency of the null allele is highest in Caucasians and Asians and lowest in Africans (8). The first report on ACTN3 genotype and performance was from North's laboratory in 2003. It indicated that the frequency of the stop codon mutation was lower in sprinters than in controls and endurance athletes (248). Several studies have concluded that the stop codon variant (X577X) was lower in sprint and strength athletes than in nonathletes (55, 57, 153, 189, 192, 248), but other reports have been negative (149, 198, 249). Interestingly, a number of studies based on direct measures of muscle strength and power have also been published and the results are contradictory; that is, the X allele is negatively associated with these muscle phenotypes in some studies whereas the converse is found in others (39, 51, 66, 132, 133, 146, 150, 228). North has reviewed the biology of the ACTN3 polymorphism in recent publications (8, 120). In the aggregate, the data suggest that there is probably a role of the X allele in skeletal muscle function and muscle performance, but the data remain inconclusive at present. More studies with appropriate power and designs, as well as more extensive functional studies, are warranted.
Kathryn North (1960 - ), MD, FRACP, Director, Murdoch Childrens Research Institute, and David Danks Professor of Child Health Research at University of Melbourne, Australia. In the process of studying genes implicated in muscle disease, North and colleagues at the Children's Hospital at Westmead discovered a common variant in the actinin alpha 3 (ACTN3) gene. ACTN3 encodes a structural protein found in fast-twitch skeletal muscle fibers. The ACTN3 gene variant results in complete deficiency of actinin-3 in almost 20% of the general population. North showed that ACTN3 deficiency is rare in sprint athletes, suggesting that this protein plays a crucial role in the function of fast-twitch muscle fibers. North and her team developed a strain of mice engineered to be completely deficient in ACTN3 and showed that the muscle of these knockout mice displays an increase in oxidative metabolism. This metabolic shift could explain why ACTN3 deficiency is detrimental to sprint activities that require fast or glycolytic metabolism. Her analysis of deoxyribonucleic acid (DNA) samples from individuals from around the world suggests that the ACTN3 deficiency provided some benefit to the ancestors of modern Europeans and Asians after their migration out of Africa, resulting in its increase in frequency due to natural selection. The benefit provided by ACTN3 deficiency may have allowed them to adapt to the more hostile environments of Eurasia. North's group plans to use mouse and human studies to determine the effect of ACTN3 deficiency on muscle aging, response to exercise, and the progression of inherited muscle diseases such as the muscular dystrophies.
Other Candidate Genes
A series of studies has dealt with the contributions of other candidate genes to human variation in muscular strength and power. These genes were identified because of their biological relevance to muscle contractile and sarcomeric proteins, myogenesis and muscle regeneration, muscle mass atrophy and sarcopenia, hormonal regulation of muscle mass, energy transfer to sustain muscle contraction, and other properties. The evidence from candidate gene studies of muscle strength and power was recently reviewed by Thomis (220).
An example of such genes is the myostatin (MSTN) gene. Mutations in MSTN leading to inactive or defective gene product have been shown to double or even triple skeletal muscle mass in mice, cows, and sheep. Functional MSTN mutations are very rare in humans. However, a boy appeared extraordinarily muscular at birth and at 4.5 yr of age was described as muscular and very strong (196). It turned out that he was a homozygote for a G/A mutation located five nucleotides downstream of exon 1, which abolishes a normal splice donor site and activates a cryptic splice site further downstream in intron 1, resulting in a truncated, inactive myostatin peptide. A number of polymorphisms in MSTN have been investigated for their associations with muscle hypertrophy or muscle strength and power (40, 60, 107, 199, 231), but the overall findings have been inconsistent.
Another class of candidate genes of great interest for muscular strength and power is that of the insulin-like growth factors and related binding proteins. These molecules play important roles in muscle growth and repair and in muscle response to exercise. Polymorphisms in insulin-like growth factors 1 (IGF1) and 2 (IGF2) have been rather consistently associated with muscle strength and its response to training, as well as other relevant endophenotypes (52, 81, 108, 193, 195).
The laboratories of James Hagberg and Stephen Roth in the department of kinesiology at the University of Maryland in the United States have pioneered a number of candidate gene research avenues since the late 1990s (figure 7.11). Their efforts focused on sequence variants in ACE; nitric oxide synthase 3 (NOS3); angiotensinogen (AGT); ACTN3; angiotensin II receptor, type 1 (AGTR1); tumor necrosis factor (TNF); nuclear factor of kappa light polypeptide gene enhancer in B-cells 1 (NFKB1); activin A receptor, type IIB (ACVR2B); adenosine monophosphate deaminase 1 (AMPD1); vascular endothelial growth factor A (VEGFA); vitamin D receptor (VDR); and MSTN, among others (see 59, 78, 79, 81, 134, 156, 167). Hagberg has a strong interest in exercise blood pressure and other hemodynamic phenotypes and through most of his career has consistently focused on the role of exercise in health-related outcomes and therapeutic applications, with an emphasis on the importance of genetic differences at key genes. Roth, whose primary interest is in muscle size and strength, has contributed a primer on exercise genetics (187) and has a longstanding interest in the role of genetic variation in talent selection for athletic performance. Both have trained a good number of graduate students in exercise genetics and have been longtime contributors to the fitness and performance gene map series that was published in Medicine and Science in Sports and Exercise until 2009.
Stephen M. Roth (1973 - ), PhD, FACSM, associate professor, and James M. Hagberg (1950 - ), PhD, FACSM, professor, department of kinesiology, school of public health, University of Maryland. Hagberg completed his graduate studies at the University of Wisconsin. He has been on the faculty of a number of universities and at the University of Maryland for nearly 20 yr, where he is a distinguished scholar-teacher. He has been funded by the National Institute of Aging for genetics-based investigations and has published numerous papers identifying genetic markers that associate with the degree to which endurance-exercise training improves cardiovascular disease risk factors in older men and women. Stephen M. Roth completed graduate studies in exercise physiology at the University of Maryland in 2000 and postdoctoral training in human genetics at the University of Pittsburgh. In 2003 he was recruited back to the University of Maryland as director of the Functional Genomics Laboratory. He has been funded by the National Institutes of Health to perform a variety of genetics investigations. In addition to several research publications, Roth is author of a textbook titled Genetics Primer for Exercise Science and Health. The department of kinesiology at the University of Maryland was one of the first to develop a research focus in the area of exercise genomics. As a group, they have published more than 60 peer-reviewed publications in the areas of exercise genomics.
When the last version of the fitness and performance gene map was published based on the publications available by the end of 2007, there were 214 autosomal, 7 X chromosome, and 18 mitochondrial gene and other loci entries (31). Most of the entries were related to specific candidate genes and were supported by more than 350 peer-reviewed papers. With the exception of the ACE and ACTN3 common variants, few of the genes had been replicated in multiple studies. Moreover, after almost 25 yr of candidate gene studies in exercise biology, this line of research continues to be plagued by small sample sizes and lack of appropriate statistical power (31, 177). Studies with small sample sizes occasionally report positive findings, especially if they include several traits and perform multiple statistical tests for association. Fortunately, these positive findings are seldom replicated and usually fall into oblivion.
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Early German roots of exercise physiology
In 1719, Friedrich Hoffmann (1660-1742), a physician from Halle, obtained his doctoral degree with experimental investigations about the effects of physical exercise on the human cardiovascular system and on digestion.
Exercise Physiology Research in Germany 1700 to 1910
In 1719, Friedrich Hoffmann (1660-1742), a physician from Halle, obtained his doctoral degree with experimental investigations about the effects of physical exercise on the human cardiovascular system and on digestion. In 1796, the physician Christoph Wilhelm Hufeland (1762-1836) published a textbook about the significance of different types of physical exercise for human health and life expectancy (66).
In the 19th century, the physiologist Emil Dubois-Reymond (1818-1896) studied the role of gymnastics in the human body (21, 22). The physician and chemist Max von Pettenkofer (1818-1901) detected the existence of creatine in the skeletal muscle and described a strengthening of the circulatory system in connection with physical training (111).
The first ergometer in the present-day sense of the word was developed by the German physician Speck in 1883. When using this cranked ergometer, the test person was in the standing position (figure 4.1). The crank friction could be modified by pulling up a screw. Speck determined the resistance with weights hung on the crank. The number of revolutions could be determined by noting the number of turns of twine wound up around the crank axle. The exhaled air was collected in a double spirometer and the postexperimental air composition was determined, thus enabling conclusions to be drawn about the individual performance reaction (2, 125).
In 1887 the Viennese physician Friedrich Gaertner (1847-1917) presented a mechanically braked ergometer, based on Speck's equipment that could measure the work performed in kilogram-meter. This device, called the ergostat, later went into standard production (112).
The first heyday of exercise physiology began with the veterinarian Nathan Zuntz (1847-1920) in Berlin (figure 4.2), who developed the first motor-driven treadmill in 1889 (figure 4.3). His work is described in chapter 1 (142).
Of substantial significance in the application of aspects of exercise physiology in medicine were Adolf Theophil Ferdinand Hueppe (1852-1938) and Ferdinand August Schmidt (1852-1929). In 1899 Hueppe wrote a fundamental work titled A Textbook of Hygiene that covered the whole of the exercise physiology discipline of those days. This was followed by the work titled Hygiene of Physical Exercises, published in 1911. In 1893 Schmidt published the book Physical Exercise According to the Exercise Value, which deals with an overview of suitable physical exercises for different ages (122, 123).
From 1904 to 1906 Kuelbs examined the influence of physical training on the internal organs, particularly the heart. He took two dogs from the same litter and trained one of them 5 times/wk for about 2 h on a treadmill, which he had taken over from Zuntz; the other dog had a normal, everyday life. After 1 yr both animals were killed and all internal organs were measured and examined. Although both dogs had more or less the same body weight, the heart of the dog trained on the treadmill was approximately 33% larger than that of the untrained dog. Similar differences were also manifest in the weights of the liver, kidneys, adrenal glands, spleen, and lungs (77).
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Over the subsequent decades Arthur Mallwitz (1880-1968) became the most important promoter for German, and later international, sports medicine. He obtained his doctor's degree at Halle University (Saale) in 1908 with what is presumed to be the first ever dissertation in sports medicine. In his dissertation, titled Maximum Performances With Special Consideration of Sports Done at the Olympic Games, Mallwitz considered, above all, the investigations of Hueppe and Schmidt as well as those of Zuntz and his school. In 1910 a comprehensive book about exercise physiology in connection with numerous kinds of sports was edited by Weissbein (141).
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The first ergometer was developed by Speck in 1883. Gaertner produced it in series.
Hollmann W, Strueder HK, Predel HG, Tagarakis CVM. Spiroergometrie. Stuttgart, Schattauer, 2006.
Exercise Physiology Research in Germany 1911 to 1933
German Empire Committee for Scientific Research in Sport and Physical Exercise
The First Congress for Scientific Research in Sport and Physical Exercise took place in Oberhof, Germany, from September 20 to 23, 1912. The congress was conducted by the professor for internal medicine of the University Clinic Berlin Charité, Friedrich Kraus (1858-1936), and was chaired by Schmidt and Hueppe. Approximately 70 doctors participated (93). On September 21, 1912, the German Empire Committee for Scientific Research in Sport and Physical Exercise - the first national medical sport association worldwide - was founded under the chairmanship ofKraus, who was elected president.
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Nathan Zuntz (1847-1920).
Reprinted, by permission, from W. Hollmann and K. Tittel, 2008, History of German sports medicine (Gera: Druckhaus Gera), 15.
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The world's first motorized treadmill, developed by Zuntz and Lehmann in 1889 in Berlin. This apparatus was shown in the international hygiene exhibition in Dresden in 1911.
Hollmann W, Strueder HK, Predel HG, Tagarakis CVM. Spiroergometry. Stuttgart, Schattauer, 2006.
Period From 1913 to 1924
In 1913, Arthur Mallwitz was appointed the first full-time sport physician worldwide by the Prussian State Gymnastics Institute. Mallwitz then took up his office under the official designation of sport physician (94).
At the same time the physician and chemist Otto Meyerhof (1884-1951) recognized the regulating relationship between respiration rate and the suppression of glycolysis in muscles. He demonstrated that the consumption of one molecule of oxygen prevents the formation of two molecules of lactate. Meyerhof's findings supported the assumption that the enzymes fanning lactate also function aerobically but that the lactate formed is resynthesized to carbohydrate at the expense of the energy provided by respiration (98).
Hugo Wilhelm Knipping (1895-1984), physician and internist at Hamburg University, developed a gas metabolism apparatus for examination of humans at rest in 1924 and constructed a dynamo cranked ergometer in 1928. In 1929 he combined an enlarged gas metabolism apparatus for exercise examinations with the crank ergometer and designated the method as spiroergometry (73, 74). It was the genesis of precise and simple clinical exercise diagnostics. Engineering, however, was not able to construct the equipment to satisfy all technical requirements until 1949 (75, 76).
German Medical Association for the Promotion of Physical Exercise (1924-1933)
Because of the political confusion and economic difficulties after the finish of World War I in 1918, approximately 6 yr elapsed before research in sports medicine and thus exercise physiology was renewed in 1924. The founding of the German Physician Association for the Promotion of Physical Exercise in 1924 was the impetus for this.
In 1925 Max Rubner (1854-1932), director of the Robert Koch Institute in Berlin and an internationally recognized metabolism researcher, ascertained that the skeletal musculature in adults amounts to 43% of the total body mass and that the total musculoskeletal system inclusive of bones, heart, and lungs amounts to 61%. The greatest proportion of the musculature was allotted to the legs (56%) and the upper extremities (28%). The head and torso muscles contributed to 16% of the total body mass (120).
Approximately 3,200 kcal could meet the daily energy requirements for physical exercise for a 70 kg person whereas 2,600 calories was sufficient for simple office work. The metabolism of a farm worker during harvesting would require 4,300 kcal. The peak values of the daily calorie consumption for lumberjacks would amount to approximately 6,000 kcal for a 70 kg person. Long-distance racing cyclists, however, could reach a peak daily metabolic rate of 11,000 kcal. Rubner believed that the limiting factor for the uptake of calories in the human body was the intestinal system. A repeat of such great exertion over several days would inevitably lead to loss of body weight (119).
As early as 1925, Herbert Herxheimer (1894-1985) and others precisely described the psychic and physical effects of overtraining, including a decrease in maximal oxygen uptake, reduced appetite, tendency to sweat, shivering, jerky reflexes, and pronounced respiratory arrhythmia with a clear preponderance of the parasympathetic part. Obstipation and painful stomach spasms also could be observed. Herxheimer published all his sports medicine knowledge in his famous book in 1933.
Herxheimer also described the connection between heart size and distance running. He found an increase in the transverse diameters of the heart in the following ascending order: boxing, swimming, middle-distance running, long-distance running, marathon running, and long-distance skiing. Particularly large hearts would work with a large stroke volume. This would result in the corresponding bradycardia at rest. The blood pressure of endurance athletes would be low (39).
Ludwig Aschoff (1866-1942) in Freiburg ascertained that there is one physiological work hypertrophy of the heart muscle as an adaptation to increased muscular activity. The enlargement remains within moderate limits. Sport does not cause a pathological hypertrophy. If a conspicuous general hypertrophy of the heart exists, it is a matter of pathological circumstances (e.g., cardiac valve ailments, hypertony or glomerular-tubular cirrhosis of the kidney). It is impossible for sport to cause a fatality in an individual with a healthy heart. A muscular cardiac insufficiency is to be treated by taking it easy. Puberty is a dangerous period regarding possible functional damage of the heart through sport.
Another significant exercise physiologist of the 1920s was Richard Herbst (1893-1949) in KÃöenigsberg East Prussia. He conducted numerous experimental investigations on the behavior of maximum oxygen absorption in humans of different ages and in different training conditions. He published his findings in 1928, 4 yr after the first description of maximum oxygen uptake by Hill. According to Herbst (1928), endurance-trained subjects had a higher oxygen intake than did untrained subjects. Also, after reaching the maximum oxygen uptake value, ventilation could be increased still further. Herbst used the Douglas bag with the subsequent respiratory gas analysis method for runners and cyclists. Further, he examined running distances between 100 m and marathon using the Douglas bag and gas analysis. The values obtained at that time (e.g., marathon with an energy consumption of 3,050 kcal, 10 m sprint with an energy consumption of 50 kcal) agree with measurements made nowadays. Sustained running loads of more than 3 min were determined from the magnitude of the maximal oxygen uptake. Thus, these parameters were a measure of performance. The lung ventilation volume would still increase further after reaching the maximum oxygen absorption. Cardiac output is represented as the most important factor limiting physical performance (37).
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Harvard Fatigue Laboratory influential in promoting exercise physiology research
Despite its brief history (1927-1947), no physiology laboratory in America is more revered than the Harvard Fatigue Laboratory.
Despite its brief history (1927-1947), no physiology laboratory in America is more revered than the Harvard Fatigue Laboratory. Described as "the first laboratory for the comprehensive study of man" (5), it was perhaps more influential and effective in promoting scientific and collaborative research in exercise physiology (76). This chapter discusses the laboratory's contributions to the study of the acute and chronic effects of exercise and to the effects of altitude and temperature on the exercise response. This chapter includes information from the laboratory's extensive published record as well as from the perspective of the last surviving member of its faculty and staff (figure 3.1) (41).
G. Edgar Folk (1914-) of the University of Iowa in the United States who became a staff member of the Harvard Fatigue Laboratory in 1943. Folk remained at the Harvard Fatigue Laboratory until its closure in 1947. He subsequently spent six yr at Bowdoin College in Maine conducting research and teaching biology to undergraduate students. In 1953, he accepted an appointment in the department of physiology at the University of Iowa. Professor Folk continues to attend APS meetings, write manuscripts, and enjoy life as an elder statesman for physiology.
Harvard University (1920-1927)
In 1920, physiology at Harvard University was represented by four departments: physiology, comparative physiology, applied physiology, and physical chemistry. These departments were collectively known as the laboratories of physiology(53). Three years later, the department of industrial hygiene was transferred from the medical school to the recently established school of public health, facilitated by the efforts of Roger Lee (53). Subsequently, the department of industrial hygiene was renamed the department of applied physiology. At this time, Walter B. Cannon (1871-1945) was chairman of the department of physiology, David Edsall was dean of both the medical school and the school of public health, Lawrence Joseph Henderson (1888-1984) was director of the department of physical chemistry (figure 3.2), Wallace B. Donham was dean of the business school, and A. Laurence Lowell was president of the university (53). Also at this time, Dr. Arlie V. Bock was establishing a laboratory in Massachusetts General Hospital after being a physician in World War I, a Moseley Traveling Fellow in Sir Joseph Barcroft's laboratory for two years learning exercise protocols and blood-equilibration techniques, and after being a participant in Barcroft's high-altitude expedition in Peru (23) (figure 3.2).
David Bruce Dill (1891-1986) received his PhD in chemistry in 1925 from Stanford University and accepted a 2 yr National Research Council fellowship to work in the laboratory of L.J. Henderson to study the physical chemistry of proteins. However, after his arrival at Harvard, he was assigned to a Massachusetts General Hospital laboratory, where the senior staff physician was Dr. John H. Talbott. There he was reassigned to study with Dr. Bock the physiochemical properties of blood (46). When the fellowship was terminated, Dill was appointed as assistant professor of biochemistry in the school of public health, a position he retained until 1936. In addition, from 1927 to 1947, he held a professorship in the department of industrial hygiene at Harvard University (72). Although during his tenure at Harvard Henderson remained as director of the laboratory, it was Dill's leadership, organizational ability, and scientific insights that made the laboratory famous throughout the world. Between 1947 and 1961, Dill served as director of research for the U.S. Army Chemical Research and Development Laboratory. During this interval, he became president of the American Physiological Society (1950-1951) and later (1960-1961) was elected president of the American College of Sports Medicine (45, 74).
Henderson and the Establishment of the Harvard Fatigue Laboratory
Henderson, a recipient of an MD from Harvard in 1902, was professor of biological chemistry from 1919 until 1934 and the Abbot and James Lawrence professor of chemistry from 1934 until his death in 1942 (18) (figure 3.2). Besides chemistry and biology, Henderson had broad interests in sociology, psychology, anthropology, and the philosophy of Vilfredo Pareto, an Italian engineer and socialist (18, 46). He and Elton Mayo (a professor of industrial hygiene who, like Henderson, believed that workers should be studied in the workplace) developed the concept of establishing a laboratory to conduct research on industrial hazards (46). Such a laboratory would study the "group psychology, the social problems, and physiology of fatigue of normal man . . . not only as individual factors in determining physical and mental health, but more especially to determine their interrelatedness and the effect upon work" (46, p. 20).
With leadership from Henderson, the support of advisory and planning committees that included most of the previously mentioned deans and professors, the endorsement of President Lowell, and funding from the Laura Spelman Rockefeller Memorial and the Rockefeller Foundation, the Harvard Fatigue Laboratory was established in 1927 with Lawrence Joseph Henderson as its official director (46). According to Chapman, the term fatigue was selected because all parties believed it was important. However, because they could not agree on a definition, it did not force research activities into a specific departmental shape(19, p. 19). Its home was in the basement of Harvard Business School.
As noted, Dill was designated (although never officially appointed) to organize and direct the research program of the laboratory and quickly assumed the duties and responsibilities of Henderson. Hence, his curriculum vitae in the Mandeville Special Collections Library at the University of California in the United States lists him as the informal director of the laboratory between 1927 and 1946 (72). The Horvaths identified the senior members of the laboratory from 1927 to before World War II as Henderson, Dill, Bock, and Talbott (figure 3.2) (46).
Contributions to Undergraduate and Graduate Student Education
Although the education of undergraduate and graduate students was not a purpose for establishing the laboratory, the laboratory did provide opportunities for undergraduate and graduate students to be introduced to research and become involved with projects that all pertained to physiology and sometimes to exercise physiology. Although the laboratory offered no courses or degrees, it offered opportunities for students to conduct senior theses under the supervision of select faculty members. Twelve undergraduates were involved in activities of the laboratory. Henry Taylor became a renowned exercise physiologist at the University of Minnesota in the United States (figure 3.4). Richard Riley was recognized as an outstanding respiratory physiologist at Johns Hopkins University, and John Pappenheimer and Clifford Barger received acclaim as physiologists on the faculty of Harvard University (46). Sid Robinson and Steven Horvath (figures 3.5 and 3.6) conducted research for their PhD dissertations in the laboratory but received their degrees in biological sciences. Dill served as chairman of Robinson's committee but was unable to do so for Horvath because Horvath had married Dill's daughter (73). G. Edgar Folk Jr. received an MA from Harvard University in 1937 and served as a research associate in the laboratory from 1943 to 1947 (figure 3.1). In 1947, he received a PhD in the biological sciences with John Welch as his advisor (74). Additionally, Pappenheimer, Robinson, and Horvath served along with 13 other staff members as tutors for students in biochemistry (46).
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Advances in studies of genes associated with exercise behavior traits
Several research designs and technologies have been used over the past two decades in the effort to identify genomic regions, genes, and sequence variants associated with exercise behavior and exercise biology traits.
Genomics Studies
Several research designs and technologies have been used over the past two decades in the effort to identify genomic regions, genes, and sequence variants associated with exercise behavior and exercise biology traits. This section reviews advances made over time and key laboratories and investigators involved in these studies. Candidate genes, genome-wide linkage scans, genome-wide association (GWA) studies, and contributions from combinations of transcriptomics and genomics are reviewed. Efforts to identify genetic differences between elite athletes and sedentary controls are also briefly summarized.
Candidate Genes
A candidate gene is a gene that has a theoretical relationship with the behavioral, physiological, or metabolic system regulating the trait of interest. Candidate genes for exercise biology traits have been defined on the basis of advances in exercise physiology studies and animal models and on purely theoretical grounds. Transgenic (overexpression of a gene or genes), knockdown (reduced expression level), and knockout (ablation of a gene or genes) mice have generated a number of candidate genes that were subsequently investigated for potential involvement in human variation. The expression level of a gene has also been used as a candidate phenotype against which DNA variants can be tested for associations. The complete transcriptome, which is the full set of ribonucleic acid (RNA) transcripts in a given cell or tissue, has been used to define new panels of candidate genes for further genomics studies (e.g., 72, 224).
Candidate genes were very prominent in the early phase of exercise genomics. Many of the earlier studies were quite simple in design and were launched primarily because of the availability of whole blood stored in freezers. They were generally case-control or cross-sectional cohort studies with unrelated subjects. In the case of continuous traits (e.g., V\od\O2max), the association with a candidate gene or marker is tested by comparing mean trait values across genotypes or between carriers and noncarriers of a specific allele. In the case-control design, testing for a relation between a trait and a candidate gene marker is based on the comparison of allele and genotype frequencies between two informative groups of subjects, one with the phenotype of interest (e.g., elite power and strength athletes - the "cases") and the other without the phenotype of interest (the "controls").
Special Case of Athletes Versus Controls
Luigi Gedda from the Gregor Mendel Institute of Medical Genetics and Twin Research at the University of Rome was perhaps the pioneer in the effort to understand the importance of genetic differences between athletes and nonathletes (67, 68) (figure 7.7). The initial efforts were based on surveys of Italian twins, specifically on 351 pairs of twins who were engaged in competitive sport. The results of the surveys indicated familial aggregation among athletes and the potential importance of zygosity in concordance of sport selection; participation in markedly different sports occurred in 85% of DZ twins in contrast to only 6% of MZ twins (68). The familial aggregation of athletes was also noted by others, such as Grebe (75, 76) of Germany, Linc and Fleischmann (117) of Czechoslovakia, and Jokl (92, 93), who at the time was in the United States. The work of Gedda and his longtime collaborator, Paolo Parisi, was the most systematic in this regard and focused on genealogical and twin methods. The research of Parisi continues today with the Italian Registry of Twin Athletes (154, 155). A higher prevalence of MZ twins among swimmers has been one of their findings (154). In a large sample of adult British female twins, athlete status (nonathlete vs. local-, county-, or national-level athlete) had a heritability of 0.66 (50).
Luigi Gedda (1902-2000), MD, Mendel Institute of Medical Genetics and Twin Research in Rome, right, and Paolo Parisi (1940 - ), PhD, professor of biology and rector, Italian University Sport and Movement, University of Rome "Foro Italico," left. Gedda was the first to confirm, through classic pedigree studies in the mid-1950s, the common knowledge that elite athletes often cluster in families and to then attempt to quantify the role of genetic factors using the twin concordance model. He studied a large sample of MZ and DZ twin pairs and found considerably higher concordance rates in the former than in the latter with respect to various aspects of sport participation, such as kind of sport practiced and performance level. In later decades, Gedda's longtime associate Paolo Parisi conducted epidemiological and cell genetics research, also through the aid of a special registry of Italian twin athletes, in order to explore the genetic basis of athletic performance. Of particular interest to him is the relation of physical activity to health, aging, and chronic disease. One major line of research of his institute focuses on the role of exercise-induced oxidative stress in genetic regulation processes.
The first documented attempt to identify differences in genetic markers for performance-related phenotypes dates to the late 1960s. A group of geneticists, taking advantage of the 1968 Olympic Games in Mexico, investigated common blood genetic markers in an attempt to discriminate between Olympic athletes and controls (45).
Interestingly, phenylthiocarbamide nontasters were underrepresented among the athletes. The effort to document genetic differences between elite athletes and sedentary controls was continued on the occasion of the 1976 Olympic Games in Montreal (37, 41). A slightly higher frequency of the A1 allele of the ABO blood group was observed in endurance athletes participating in the 1976 Summer Olympic Games than in reference populations (37). However, the other plasma and red blood cell markers (ABO, MNSs, Rhesus, Duffy, Kell, P, LDH, MDH, phosphoglucomutase, adenosine deaminase, adenylate kinase, esterase D, haptoglobin, transferrin, hemoglobin, glucose-6-phosphate dehydrogenase, and acid phosphatase) did not differ between athletes and controls (37, 41, 45). These early attempts were all based on polymorphisms in red blood cell antigens and enzymes. Later, skeletal muscle gene product variants were screened (17, 128) and selected enzyme markers were investigated for their putative effects on a variety of skeletal muscle and cardiorespiratory endurance indicators. Genetic variants of skeletal muscle creatine kinase (CKM) and adenylate kinase 1 (AK1) were screened for using isoelectric focusing in 295 subjects (16). A variant form of both enzymes was identified with an allele frequency of 1% (CKM) and 3.5% (AK1). There was no difference in V\od\O2max between the carriers of the variant alleles and matched controls homozygous for the nonvariant allele (16). None of these studies yielded reliably significant genomic predictors of performance or fitness.
Genomic differences between athletes and untrained controls began to be investigated in a more systematic fashion with the launch of the GENATHLETE study in the laboratory of Claude Bouchard at Laval University in 1993. The main collaborators on GENATHLETE included Louis Perusse, Marcel Boulay, and the late Jean-Aime Simoneau (all from Laval University), Rainer Rauramaa (Kuopio, Finland), and particularly Bernd Wolfahrt (from Germany). The study focused on DNA sequence differences between a panel that has now attained more than 300 elite endurance athletes with a V\od\O2max no lower than 75 ml·kg-1·min-1 and more than 300 sedentary controls with a V\od\O2max no higher than 50 ml·kg-1·min-1. The participants are all white males from Canada, Germany, Finland, and the United States. Single nucleotide polymorphisms (SNPs) in several genes have been investigated to date, but none have provided strong evidence for differences in allele and genotype frequencies between athletes and controls (16, 178, 184, 185, 245-247). However, a common variant and haplotype in the hypoxia inducible factor 1, alpha subunit (HIF1A) gene were found to be more prevalent in athletes compared with controls in a 2010 report based on the GENATHLETE cohort (54), an observation that was defined in an accompanying editorial as an important milestone (194).
Another effort to delineate the differences between athletes and nonathletes is under way in Spain under the leadership of Jonatan Ruiz and Alejandro Lucia. They have used samples of Spanish Caucasian endurance athletes (about 100), power athletes (about 50), and nonathlete controls. A number of differences at candidate genes between athletes and controls, as well as between endurance and power athletes, have been reported (34, 71, 190). Taking advantage of the concept of a total genotype score developed by Williams and Folland (238), Ruiz and colleagues in 2009 attempted to predict world-class endurance athlete status based on the frequency of variant alleles at 7 candidate genes genotyped in 43 Spanish endurance athletes and 123 controls (191).
Yannis Pitsiladis from the faculty of biomedical and life sciences at the University of Glasgow has taken advantage of striking performance differences at the elite level in athletes of various ethnic backgrounds to investigate the potential role of variation in nuclear and mitochondrial DNA (figure 7.8). For instance, distance runners from Kenya and Ethiopia and sprinters from Jamaica won 25% of all track and field medals at the 2008 Olympic Games in Beijing (166). The effort to impute ethnic differences in sport performance to genetic differences is clearly challenging, particularly because only about 10% of human genetic variation can be found between the major ethnic groups. Pitsiladis' laboratory has explored differences in sequence variants in mitochondrial DNA and in Y chromosome markers between Ethiopian athletes, Ethiopian controls, Kenyan athletes, and Kenyan controls. Mitochondrial DNA haplogroups found in Kenya were different from those found in Ethiopia (197). Differences in haplogroup distributions were observed between athletes and controls in Kenya but not in Ethiopia. The full significance of this observation needs to be established. Analyses of Y chromosome haplogroups in endurance athletes from Ethiopia revealed differences between them and samples from the more general Ethiopian population (145). Population stratification was ruled out as the explanation for such differences. One important conclusion reached by Pitsiladis and colleagues is that the clusters of Kenyan and Ethiopian elite runners are distinct from each other from a genetic point of view (166).
Yannis P. Pitsiladis (1967 - ), MMedSci, PhD, FACSM, integrative and systems biology research theme, faculty of biomedical and life sciences, University of Glasgow, Scotland. Pitsiladis is a reader in exercise physiology at the Institute of Biomedical and Life Sciences at the University of Glasgow and founding member (and previous director) of the International Centre for East African Running Science, set up to investigate the physiological, genetic, psychosocial, and economic determinants of the phenomenal success of East African distance runners in international athletics. Recent projects include the study of West African sprinters (including elite sprinters from Jamaica and the United States) and the study of world-class swimmers (e.g., why there are very few black swimmers). He is a visiting professor in medical physiology at Moi University (Eldoret, Kenya), Addis Ababa University (Addis Ababa, Ethiopia), and University of Technology (Kingston, Jamaica). Pitsiladis has a particular research interest in mitochondrial DNA and Y chromosome markers and their potential role in ethnic differences in performance.
Photo courtesy of Yannis P. Pitsiladis.
Two genes have received considerable attention in the exercise genomics literature: angiotensin I-converting enzyme (ACE) and actinin alpha 3 (ACTN3). Both have been strong favorites of exercise scientists over the past decade or so.
ACE Gene
Hugh Montgomery (1962 - ), MB, BS, BSc, FRCP, MD, FRGS, director of University College London Institute for Human Health and Performance; consultant intensivist at Whittington Hospital; and professor of intensive care medicine at University College London. Montgomery obtained his BSc degree in neuropharmacology and in circulatory and respiratory physiology in 1984 before graduating with a medical degree in 1987. He has since trained and accredited in general internal medicine, cardiology, and intensive care medicine. He is now professor of intensive care medicine at University College London, where he also directs the Institute for Human Health and Performance. In the early 1990s, he began using gene - environment interaction as a means to explore human physiology. Working with army recruits, he first identified a role for the angiotensin I-converting enzyme (ACE) I/D polymorphism in the regulation of human cardiac growth. This work was extended to broader measures of performance, including high-altitude mountaineering aptitude. Mechanistically, a role in the regulation of metabolic efficiency was suggested, leading to phase IV studies of ACE inhibition in the treatment of cancer cachexia. Studies of downstream gene variants (e.g., those of the bradykinin B2 receptor gene) have offered further mechanistic insight. Montgomery has a special interest in high-altitude performance: He was science lead for the Caudwell Xtreme Everest Expedition in 2007 and has identified genes under selection pressure in high-altitude populations.
The potential role of ACE sequence differences in human physical performance was first investigated in the 1990s by Hugh Montgomery from the University College London (figure 7.9). He and his coworkers reported in 1997 that 10 wk of physical training in British army recruits induced greater increases in left ventricular mass and septal and posterior wall thickness in the ACE D/D homozygotes than in the I allele carriers (141). A few years later, the same group of investigators confirmed the finding by reporting that the training-induced increase in left ventricular mass in another cohort of army recruits was 2.7 times greater in the D/D genotype compared with the I/I homozygotes (147). The I allele was associated with higher muscular endurance gains after 10 wk of physical training in British army recruits (142).
The story began in 1990 when it was reported that a 287 bp I/D polymorphism in intron 16 of the ACE gene was associated with plasma ACE activity (183). ACE activity was highest in D/D homozygotes and lowest in I/I homozygotes. More than 50 reports have subsequently dealt with the potential role of the ACE I/D genotype in some aspects of fitness or performance. Overall, the results are heterogeneous and often contradictory. For instance, in postmenopausal women, I/I homozygotes had a higher V\od\O2max than D/D homozygotes (79), whereas the opposite was observed in Chinese males (251). In the HERITAGE Family Study, no associations were found between the ACE I/D polymorphism and maximal and submaximal exercise V\od\O2 and power output phenotypes in healthy, sedentary blacks and whites (41).
This literature was recently reviewed by Montgomery and colleagues (206). In the aggregate, it appears that the ACE I/D polymorphism may contribute to human variation in skeletal and cardiac muscle growth and functional properties as well as in adaptation to hypoxia. However, its contribution to variation in human physical performance remains a matter of debate.
ACTN3 Gene
Kathryn North and colleagues from the Children's Hospital at Westmead in Australia discovered a common variant in the gene for actinin-3, a structural actin binding protein found in skeletal muscle fast-twitch fibers (figure 7.10). The polymorphism (R577X) replaces an arginine residue by a premature stop codon at position 577 and results in ACTN3 deficiency. About 16% of the world population is homozygous for the XX null genotype; the frequency of the null allele is highest in Caucasians and Asians and lowest in Africans (8). The first report on ACTN3 genotype and performance was from North's laboratory in 2003. It indicated that the frequency of the stop codon mutation was lower in sprinters than in controls and endurance athletes (248). Several studies have concluded that the stop codon variant (X577X) was lower in sprint and strength athletes than in nonathletes (55, 57, 153, 189, 192, 248), but other reports have been negative (149, 198, 249). Interestingly, a number of studies based on direct measures of muscle strength and power have also been published and the results are contradictory; that is, the X allele is negatively associated with these muscle phenotypes in some studies whereas the converse is found in others (39, 51, 66, 132, 133, 146, 150, 228). North has reviewed the biology of the ACTN3 polymorphism in recent publications (8, 120). In the aggregate, the data suggest that there is probably a role of the X allele in skeletal muscle function and muscle performance, but the data remain inconclusive at present. More studies with appropriate power and designs, as well as more extensive functional studies, are warranted.
Kathryn North (1960 - ), MD, FRACP, Director, Murdoch Childrens Research Institute, and David Danks Professor of Child Health Research at University of Melbourne, Australia. In the process of studying genes implicated in muscle disease, North and colleagues at the Children's Hospital at Westmead discovered a common variant in the actinin alpha 3 (ACTN3) gene. ACTN3 encodes a structural protein found in fast-twitch skeletal muscle fibers. The ACTN3 gene variant results in complete deficiency of actinin-3 in almost 20% of the general population. North showed that ACTN3 deficiency is rare in sprint athletes, suggesting that this protein plays a crucial role in the function of fast-twitch muscle fibers. North and her team developed a strain of mice engineered to be completely deficient in ACTN3 and showed that the muscle of these knockout mice displays an increase in oxidative metabolism. This metabolic shift could explain why ACTN3 deficiency is detrimental to sprint activities that require fast or glycolytic metabolism. Her analysis of deoxyribonucleic acid (DNA) samples from individuals from around the world suggests that the ACTN3 deficiency provided some benefit to the ancestors of modern Europeans and Asians after their migration out of Africa, resulting in its increase in frequency due to natural selection. The benefit provided by ACTN3 deficiency may have allowed them to adapt to the more hostile environments of Eurasia. North's group plans to use mouse and human studies to determine the effect of ACTN3 deficiency on muscle aging, response to exercise, and the progression of inherited muscle diseases such as the muscular dystrophies.
Other Candidate Genes
A series of studies has dealt with the contributions of other candidate genes to human variation in muscular strength and power. These genes were identified because of their biological relevance to muscle contractile and sarcomeric proteins, myogenesis and muscle regeneration, muscle mass atrophy and sarcopenia, hormonal regulation of muscle mass, energy transfer to sustain muscle contraction, and other properties. The evidence from candidate gene studies of muscle strength and power was recently reviewed by Thomis (220).
An example of such genes is the myostatin (MSTN) gene. Mutations in MSTN leading to inactive or defective gene product have been shown to double or even triple skeletal muscle mass in mice, cows, and sheep. Functional MSTN mutations are very rare in humans. However, a boy appeared extraordinarily muscular at birth and at 4.5 yr of age was described as muscular and very strong (196). It turned out that he was a homozygote for a G/A mutation located five nucleotides downstream of exon 1, which abolishes a normal splice donor site and activates a cryptic splice site further downstream in intron 1, resulting in a truncated, inactive myostatin peptide. A number of polymorphisms in MSTN have been investigated for their associations with muscle hypertrophy or muscle strength and power (40, 60, 107, 199, 231), but the overall findings have been inconsistent.
Another class of candidate genes of great interest for muscular strength and power is that of the insulin-like growth factors and related binding proteins. These molecules play important roles in muscle growth and repair and in muscle response to exercise. Polymorphisms in insulin-like growth factors 1 (IGF1) and 2 (IGF2) have been rather consistently associated with muscle strength and its response to training, as well as other relevant endophenotypes (52, 81, 108, 193, 195).
The laboratories of James Hagberg and Stephen Roth in the department of kinesiology at the University of Maryland in the United States have pioneered a number of candidate gene research avenues since the late 1990s (figure 7.11). Their efforts focused on sequence variants in ACE; nitric oxide synthase 3 (NOS3); angiotensinogen (AGT); ACTN3; angiotensin II receptor, type 1 (AGTR1); tumor necrosis factor (TNF); nuclear factor of kappa light polypeptide gene enhancer in B-cells 1 (NFKB1); activin A receptor, type IIB (ACVR2B); adenosine monophosphate deaminase 1 (AMPD1); vascular endothelial growth factor A (VEGFA); vitamin D receptor (VDR); and MSTN, among others (see 59, 78, 79, 81, 134, 156, 167). Hagberg has a strong interest in exercise blood pressure and other hemodynamic phenotypes and through most of his career has consistently focused on the role of exercise in health-related outcomes and therapeutic applications, with an emphasis on the importance of genetic differences at key genes. Roth, whose primary interest is in muscle size and strength, has contributed a primer on exercise genetics (187) and has a longstanding interest in the role of genetic variation in talent selection for athletic performance. Both have trained a good number of graduate students in exercise genetics and have been longtime contributors to the fitness and performance gene map series that was published in Medicine and Science in Sports and Exercise until 2009.
Stephen M. Roth (1973 - ), PhD, FACSM, associate professor, and James M. Hagberg (1950 - ), PhD, FACSM, professor, department of kinesiology, school of public health, University of Maryland. Hagberg completed his graduate studies at the University of Wisconsin. He has been on the faculty of a number of universities and at the University of Maryland for nearly 20 yr, where he is a distinguished scholar-teacher. He has been funded by the National Institute of Aging for genetics-based investigations and has published numerous papers identifying genetic markers that associate with the degree to which endurance-exercise training improves cardiovascular disease risk factors in older men and women. Stephen M. Roth completed graduate studies in exercise physiology at the University of Maryland in 2000 and postdoctoral training in human genetics at the University of Pittsburgh. In 2003 he was recruited back to the University of Maryland as director of the Functional Genomics Laboratory. He has been funded by the National Institutes of Health to perform a variety of genetics investigations. In addition to several research publications, Roth is author of a textbook titled Genetics Primer for Exercise Science and Health. The department of kinesiology at the University of Maryland was one of the first to develop a research focus in the area of exercise genomics. As a group, they have published more than 60 peer-reviewed publications in the areas of exercise genomics.
When the last version of the fitness and performance gene map was published based on the publications available by the end of 2007, there were 214 autosomal, 7 X chromosome, and 18 mitochondrial gene and other loci entries (31). Most of the entries were related to specific candidate genes and were supported by more than 350 peer-reviewed papers. With the exception of the ACE and ACTN3 common variants, few of the genes had been replicated in multiple studies. Moreover, after almost 25 yr of candidate gene studies in exercise biology, this line of research continues to be plagued by small sample sizes and lack of appropriate statistical power (31, 177). Studies with small sample sizes occasionally report positive findings, especially if they include several traits and perform multiple statistical tests for association. Fortunately, these positive findings are seldom replicated and usually fall into oblivion.
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