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How genetics and environment contribute to athletic prowess and compensation for disease deficiencies.


There is ongoing debate about the importance of genes and environment in athletic performance. There are reports in favor of both factors which influence athletic performance. Mutations in nuclear DNA and mitochondrial DNA (mtDNA) result in dysfunctional mitochondrial assembly which ultimately leads to reduced ATP production, leading to mitochondrial myopatbies. Mitochondrial myopathy (MM) patients exhibit a variety of compensatory responses which attempt to reconcile this energy deficiency. The extent and the type of compensatory adaptations are disease-specific. Muscle can be trained to be more efficient by increasing the number of mitochondria present in a muscle cell, called mitochondrial biogenesis, leading to improved performance during exercise. Exercise can induce mitochondrial biogenesis both in healthy subjects and in those with MM, although the long term benefit in those with MM remains unclear. Finally, the role of mitochondria in high altitude athletic performance and in aging is discussed.


Genetic background, environment, and training work together to generate elite athletes. The relative contribution of each factor is of interest to many and poorly understood. Some studies support a genetic basis while others support environment as the main determinant of elite athletic prowess. It is well known that athletes train to improve performance. This improvement in performance is thought to be a result of more efficient generation of energy. Maximal performance is a function of maximal oxygen uptake (VO2max), maximal anaerobic capacity, and effort duration to exhaustion (1). One of the factors limiting VO2max is mitochondrial capacity. Mitochondria are organelles located within the cytoplasm of a cell responsible for converting glucose and fatty acids into energy in the form of adenosine triphosphate (ATP) through the process of oxidative phosphorylation. Mitochondrial DNA (mtDNA) is 16 kilobases, circular, and encodes 13 protein, 22 tRNA and two rRNA genes. There can be many mitochondria in a given cell, and the mitochondrial content of the cell corresponds to the functional energy requirements of a given tissue. Heart muscle, which contracts constantly, has more mitochondria than skeletal muscle which contracts only intermittently.

In patients with mitochondrial disease, muscle function is impaired due to a wide variety of pathogenic mutations in either mtDNA or nuclear DNA. This leads to dysfunctional gene products within the electron transport chain and ultimately compromises ATP production, resulting in reduced work capacity and exercise intolerance. This review focuses on mitochondrial biogenesis in skeletal muscle and describes how this process works both in healthy subjects and in those with mitochondrial disease.

Research Supporting Genetics

"Champions, they are naturally selected. They begin at their own level, and Lance (Armstrong) was at that level, for sure."--Dr. Michele Ferrari, commenting on the first time physiological tests were run on Lance Armstrong (2). Numerous genes have the potential to influence athletic performance. The effect of alpha-actinin 3 (ACTN3) and angiotensin-converting enzyme (ACE) on endurance or sprint athletic performance have been documented. Alpha-actinin 3 (ACTN3) encodes skeletal muscle [alpha]-actinins (3). Differences in ACTN3 genotypes have been found between endurance and sprint athletes (4). A mutation of the ACTN3 gene, the 577X mutation, results in a loss of a-actinin-3 in type II (fast-twitch) muscle fibers, and is less common among sprint and power athletes than controls. This suggests that a-actinin-3 is beneficial for optimal performance (3). In a study of 89 sprint athletes (4), there was an inverse correlation between the frequency of the 577XX and success in sprinting events with none of the top sprinters expressing the wild type gene.

The gene encoding ACE also plays a role in the performance of sprint and endurance athletes (3). The ACE gene has two alleles, "I" and "D". The I allele is more frequently expressed in elite endurance athletes (5-8) while the D allele is linked to elite sprint athletes (9).

Research Supporting Environment

The birthplaces of professional athletes in the United States and Canada were compiled and showed that cities over 500,000 in population are consistently under-represented in terms of producing professional athletes (10). This study suggests that environment plays a role in determining the outcome of an athlete, with smaller cities providing early opportunities for athletic progression that are not matched by larger cities. European children who migrated to the Andes developed higher VO2max and larger lung volume than their lower altitude counterparts (11). Studies attest that environmental variation during upbringing could account for the athleticism of a child, whether through encouragement from family or a coach, positive experiences with peers, early success, or gratification from the sport itself (12-16).

Research Supporting an Interaction Between Genes and Environment

Numerous studies support the interaction of environment, genetics, and training to shape an elite athlete. Performance in sports depends on general well-being, proper training and conditioning, proper nutrition, and genes. Type I (slow-twitch) and type II (fast-twitch) fibers predominantly make up skeletal muscle. Type I fibers use aerobic metabolism, making type I fibers more important in endurance activities whereas type II fibers use anaerobic metabolism, making type II fibers more important for sprint and power athletes. A 1992 study using chronic low-frequency electrical stimulation of animal type II fibers demonstrated that type II fibers have the ability to be converted to type I fibers (17). Therefore, if an individual is lacking type I fibers and wishes to participate in elite endurance activities, training can increase the number of type I fibers which are more beneficial in endurance activity.

The interaction of genes and environment is highlighted by the following studies. A 2003 study found elite Ethiopian athletes to be of a distinct background, both ethnically and environmentally. The study concluded that there are a number of factors other than genetics that may influence the athletic potential of Ethiopian athletic success (18).

The expression of a genetic bias to high physical performance in the common lizard (Lacerta vivipara) strongly depends on its early life environment (19). Endurance in the common lizard at birth from running to exhaustion is highly heritable. Dietary restriction allows the individuals with high endurance to retain their endurance superiority as they age; however, a marked reversal of performance as they age is experienced by lizards that are fully fed.

The world record time in the women's marathon has decreased by more than one hour since the 1960's, supporting the role of training in improving performance. Research suggests that genetics and environment work in concert to establish the potential of an individual to become an elite athlete. Specific genes confer an advantage to endurance or speed, while environment and training can contribute to overall superior athletic performance.

Mitochondrial Biogenesis

The synthesis of new mitochondria requires both nuclear and mtDNA interaction. Mutations in either mtDNA or nuclear DNA leads to the formation of dysfunction proteins, or no protein product, and impaired mitochondrial function (20). Mitochondrial biogenesis can be induced in skeletal muscle in response to endurance training, which has been reported in animal studies to increase mitochondrial content as much as two to threefold, although the typical adaptation to endurance training in humans is approximately a 50% increase. This adaptation leads to enhanced fatigue resistance and improved performance. Systemic treatment with thyroid hormone induces mitochondrial biogenesis in Type 1 skeletal muscle, as well as in the liver and heart (21).

The majority of mitochondrial proteins are nuclear-encoded and synthesized as precursor proteins in the cytosol. These precursor proteins are brought to the mitochondria by chaperones, including heat shock protein 70 (HSP70) and mitochondrial import stimulation factor (MSF). They are then translocated into the mitochondrion by translocase proteins that create pores in the mitochondrial matrix (22, 23). In short, exercise induced mitochondrial biogenesis involves the signaling of nuclear DNA to encode mitochondrial proteins, control of mtDNA gene expression, mitochondrial cell wall opening and closing, and the importation of nuclear gene products into the mitochondrion via import machinery (24).

Mitochondrial diseases predominantly affect muscle and brain, probably because of their high dependence on oxidative metabolism. Muscle can be the only affected tissue or involved as a part of a multi-system disease. Mitochondrial diseases of muscle, called mitochondrial myopathies (MM), involve the respiratory chain and predominantly affect skeletal muscle (25). These diseases involve mutations in either mtDNA or nuclear DNA. The defects decrease energy production and lead to exercise intolerance, cramps, myoglobinuria, weakness in the muscles around the eye leading to droopy eyelids (ptosis), and external ophthalmoplegia (weakness of the eye muscles) (25).

mtDNA shows a higher mutation rate than nuclear DNA due to the absence of protective histones, the proximity of mtDNA to the electron transport chain and reactive oxidative species (ROS) production, and the less developed DNA repair system found within the mitochondria compared to the nucleus (26). Mutant mtDNA molecules randomly segregate in cells, resulting in variable levels of mutant mtDNA in cells of the same tissue, or among tissues, leading to variability in the severity of clinical symptoms in different patients with the same mutation.

mtDNA deletions and duplications, mutations in rRNA genes, and mutations in tRNA genes often affect the expression of many genes, whereas mutations in other genes often affect only the specific protein that the mutated gene encodes.

mtDNA defects are due primarily to large scale (1-10 kilobase) deletions or point mutations. Mitochondrial diseases due to nuclear DNA mutations alter 1) the sequence of the respiratory chain, which affects ATP production (including complexes I, II and coenzyme Q10), 2) the import and assembly of mitochondrial proteins, 3) mtDNA maintenance (20), or 4) the mitochondrial protein import process.

Disorders related to substandard mtDNA maintenance are characterized by mtDNA depletion, multiple mtDNA deletions, or both. They involve mutations in proteins directly regulating mtDNA replication. Mitochondrial DNA depletion syndrome (MDS), characterized by a reduction in mtDNA copy number, has been linked to mutations in the thymidine kinase 2 (TK2) and deoxyguanosine kinase genes (20).

Statins, the most effective medications to lower lipids, are widely used, with over 100 million people worldwide taking the agents (27). The most common side effect of these agents is myopathy in skeletal muscle, with symptoms that are generally mild but rarely can be life threatening due to rhabdomyolysis. The only treatment is to stop the statin. Preliminary evidence suggests that the myopathy is due, at least in part, to apoptosis of the myofibers mediated by mitochondria.

Effects of Exercise in Patients with MM

Aerobic training improves mitochondrial biogenesis in patients with MM (28), although mtDNA mutation levels increased relative to wild-type mtDNA, so the long term effects are less clear. The proteins involved in biogenesis, oxidative stress, and apoptosis in subjects with MM and healthy controls were evaluated before and after endurance training (29). Before training, subjects with myopathies had a greater mitochondrial content, along with higher expression of the biogenesis regulator peroxisome proliferator-activated receptor-gamma coactivator-lalpha (PGC-1 alpha). Levels of the apoptotic proteins AIF and Bcl-2 were also higher in myopathy patients. Endurance training increased mitochondrial content in both groups. Thus, before training, patients with MM exhibited an adaptive response of nuclear proteins indicative of a compensatory increase in mitochondrial content, though muscle from patients with MM may be exposed to greater levels of oxidative stress during the course of training. Further investigation is required to evaluate the long-term benefits of endurance training as a therapeutic intervention for mitochondrial myopathy patients.

Aging Effects

As humans age, there is an accumulation of mtDNA mutations and a decrease in mitochondrial enzyme activity in muscle (30). It is hypothesized that the increase in mtDNA mutations with aging, due to prolonged exposure to ROS, leads to a decrease in the oxidative capacity of a given tissue. Mitochondrial dysfunction associated with aging appears to be localized, since aged muscle shows focal accumulation of deleted mtDNA associated with ragged red fibers and deficient oxidative phosphorylation (30). Thus, aging appears to represent a slow progressive form of mitochondrial disease with disruptions in mitochondrial biogenesis pathways that are less severe than in traditional mitochondrial disorders (20).

The mitochondrion plays an important role in apoptosis through the release of cytochrome c, the formation of an apoptosome, and subsequent activation of caspases (27), as well as through caspase independent mechanisms. The loss of muscle with aging, referred to as sarcopenia of aging, is estimated to be present in 25% of people less than 70 and 40% of those 80 years and older (31). Histologically, sarcopenia appears as a decrease in muscle fiber size, with preferential loss of type II fibers (32). Increasing evidence suggests that accelerated apoptosis of skeletal muscle fibers is a primary cause of sarcopenia of aging, and apoptosis is induced in aged and other cells which demonstrate an increase in mtDNA mutations.

Effects of Altitude on Muscle Structure and Performance

Both hypoxia and exercise are thought to affect mitochondrial biogenesis. Sherpas, a population of people who live in the Nepalese Himalayas, have long tradition of high altitude climbing and resistance to stress. Elite Caucasian are known to have marked muscle ultrastructural changes (33), including increased capillary density and decreased mitochondrial volume density. The increased capillary density per unit muscle is thought to increase delivery of oxygen to the muscle. A study was conducted to compare the ultrastructural characteristics of muscle from Sherpa and elite Caucasian high altitude mountain climbers (34). Both Sherpas and Caucasian mountain climbers had increased capillary to muscle density, as well as a decreased mitochondrial volume, resulting in a higher maximal oxygen consumption to mitochondrial volume ratio, suggesting more efficiently functioning mitochondria (34).


There is evidence for both genetic and environmental influences on athletic performance. Thus, certain individuals may be born with the potential for superior performance, but this potential requires an environment conducive to success as well as individual effort through training to achieve optimal performance. Mitochondria play an essential role in generating energy for normal activity and in athletic performance. Mutations in mitochondrial and nuclear genes can lead to myopathies, the presentation of which varies among individuals with the same disease. Aging is a slow form of mitochondrial disease, associated with mitochondrial mutations which develop over time in the presence of ROS within the mitochondrion. Exercise can improve performance both in aging individuals and in those with myopathies, although it does not reverse the mitochondrial defects present. Human studies assessing the long term effects of exercise is patients with MM are few. Further research is required to determine the optimal form of exercise to reverse myopathic degeneration.


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By Edward R. Sauter, MD

Department of Surgery, University of Missouri, Columbia, MO

Correspondence should be addressed to Edward R. Sauter, MD, PhD Department of Surgery, University of Missouri-Columbia, One Hospital Drive, Rm N510, Columbia, MO 65212. Telephone: 573-882-4471; Fax: 573-884-5386; Email:
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Author:Sauter, Edward R.
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Date:Jan 1, 2008
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