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Brief Review

Physical Exercise as an Epigenetic Modulator

Eustress, the “Positive Stress” as an Effector of Gene Expression

Sanchis-Gomar, Fabian1,2; Garcia-Gimenez, Jose Luis2,3; Perez-Quilis, Carme2,3; Gomez-Cabrera, Mari Carmen1,2; Pallardo, Federico V.1,2,3; Lippi, Giuseppe4

Author Information
Journal of Strength and Conditioning Research: December 2012 - Volume 26 - Issue 12 - p 3469-3472
doi: 10.1519/JSC.0b013e31825bb594
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Despite the theoretical recognition that physical exercise positively influences epigenetic mechanisms and improves health, several issues remain unclear concerning the links between physical exercise and epigenetics. Epigenetics pertains to the heritable changes in gene expression or in cellular phenotype independent of modifications in DNA sequence. Thus, individual epigenome governs the activation or silencing of our genes (17). Furthermore, it is through epigenetic marks that the nutrition, stress, toxins, behavior, and stochasticity can control gene expression and imprint on genes that are passed to the next generations (3). During these past years, the main components of epigenetic regulation that include methylation of the DNA, changes in the posttranslational modifications of histones, micro-RNAs expression, and nuclear domains have been established (4,5).

There is also a growing concern about the potentially negative influence of excessive and persistent physical exercise on health. How an individual physically adapts to the prevailing environmental conditions might influence epigenetic mechanisms and modulate gene expression, including favorable physiological effects and the possibility of deleterious implications (30).

The aim of this article is thus to put forward the idea that physical exercise, especially long-term repetitive strenuous exercise, positively affects health, reduces the aging process, and decreases the incidence of cancer through induced stress and epigenetic mechanisms. We propose herein that stress may stimulate genetic adaptations through epigenetic phenomena that, in turn, modulate the link between the environment, human lifestyle factors, and genes.

Stress and Exercise

Georgopoulos et al. demonstrated that athletes who begin competing at an early age, train intensively and perform at a highly competitive level are exposed to extensive physical and psychological stress (8), although the authors concede that this might not necessarily be a negative process. In 1975, Hans Selye published an intriguing model that divided stress into “Eustress” and “Distress.” When stress enhances certain biological functions (such as during strength training), it is considered to be eustress (conventionally known as “good” stress). Conversely, persistent stress that is not resolved through coping or adaptation is considered to be distress. Both kinds of stress induce a wide range of biological responses. Thus, physical activity and human health may be linked through epigenetic mechanisms such as DNA methylation, histone modifications, and micro-RNAs.

Recent data have shown that lifestyle factors, such as nutrition, stress, alcohol consumption, working habits, smoking and physical activity, and human health are linked through epigenetic mechanisms. Zhang et al. further suggested the existence of a positive association between physical activity and global genomic DNA methylation in the cancer-free population (32). This association has also been proposed as a valuable future resource for cancer prevention (31,32). Reduced insulin resistance, increased adiponectin levels, and decreased bioavailable growth hormone–insulin-like growth factor-I and circulating IL-6 are additional benefits that might counteract the development and progression of cancer in physically active individuals (26).

This agrees with the well-known concept that exercise can reduce the growth of primary tumors and the overall risk of distinct forms of cancer (26,31). For instance, the recently discovered antioxidant function of the tumor suppressor protein p53 (18) is strongly induced by exercise (11), as is apolipoprotein(a), which is an antineoplastic, acute-phase, and angiostatin-like protein (16). The p53 expression is controlled by different epigenetic mechanisms, including miRNAs and antisense-RNAs (28). Moreover, obesity, reduced physical activity, and aging increase an individual's susceptibility to chronic pathologies (e.g., type 2 diabetes), whereas epigenetics have been argued to be a molecular link between environmental factors and this type of diabetes (15).

Implications of Epigenetic Regulation in Exercise and Aging

Alegria-Torres et al. stated that lifestyle factors, including physical exercise, might effectively modify epigenetic patterns (2). Epigenetic mechanisms are also involved in the aging process (6,21), and therefore their modulation through physical exercise might open interesting avenues for preventing aging-related diseases (13). It has further been shown that former athletes are more physically active in old age compared with the general population (29). In addition, Ruiz et al. showed that the association between strenuous aerobic exercise and increased life expectancy in elite athletes is not biased by genetic selection (27), which suggests that other underlying mechanisms are involved.

It has been well established that muscle atrophy develops as a consequence of denervation, injury, prolonged immobilization, bed rest, glucocorticoid treatment, sepsis, cancer, and aging (12). Myogenic regulatory factors such as Myogenin, MyoD, Myf5, and MRF4 are associated with muscle growth and muscle atrophy prevention, and these are remarkably induced by exercise (14,25). Interestingly, the control of myogenesis is regulated by epigenetics (24). The expression of the myosin heavy chain, the most abundant protein in skeletal muscle and the major protein responsible for skeletal muscle contraction (22,33), is strongly regulated by posttranslational modifications on histones, and this sets off other epigenetic mechanisms regulating skeletal muscle-related gene expression (23).

It has also recently been reported that the class 2 histone deacetylases 4, 5, 7, and 9 are imperative in skeletal muscle development and, therefore, in exercise adaptation (20). The aging of muscles is a key factor behind the increased frailty in humans and animals (7). Consequently, there is now a huge scientific and social interest in assessing which behaviors might lead to the maintenance of muscle mass in young immobilized subjects or in the elderly. From this perspective, exercise is considered to be one of the most important and effective strategies (13), and the epigenetic mechanisms that are modulated by physical activity may be the origin of the good adaptations that allow healthier aging.

Lifestyle Factors and Epigenetic Mechanisms

Support for the link between exercise and epigenetics has been strengthened by evidence of the strong influence that metabolic pathways exert on the epigenetic programing involved in the development of the fetus. This influence has been shown to reduce chronic disease in later life (9) and may also alter how high-fat maternal diets affect histone deacetylases (1). A crucial issue here is that genes that are epigenetically influenced by nutrition are also strongly targeted by physical exercise and its metabolic processes (10). It is, thus, not surprising that exercise during pregnancy has been advocated to provide better health outcomes, which may derive from a variety of epigenetic events such as the methylation or acetylation of histones or miRNA expression (19).

High-level physical exercise might not be a plausible goal for some sections of the general population (e.g., older people) or some unhealthy individuals (e.g., diabetic patients or obese patients), because in such cases it could generate distress. However, based on the above-described current scientific evidence, we reject the hypothesis that physical exercise might negatively affect health and increase the risk of cancer through epigenetic mechanisms. Thus, eustress should be considered to be an epigenetic modulator that promotes positive epigenetic changes. Consequently, physical exercise and its consequent epigenetic adaptations should be considered to be favorable for health outcomes (Figure 1). This suggestion might also decrease healthcare expenditure on chronic or debilitating pathologies such as cancer, diabetes, and osteoporosis.

Figure 1:
Theoretical relationship between oxidative stress induced by physical activity and epigenetic modulation. Suitable physical exercise induces optimal and recommended levels of oxidative stress “eustress” or “good stress” that may produce an optimal epigenetic regulation that promotes health. On the contrary, high oxidative stress might produce deleterious effects via epigenetic mechanisms. High levels of oxidative stress or “bad stress” (distress) induce epigenetic deregulation producing damaging effects for health. Although, it is still unknown whether physical inactivity levels might modify epigenetic patterns, we consider that any lifestyle change that induces a shift in the eustress area may induce epigenetic deregulation and, therefore, promote harmful effects on health.

Practical Applications

Lifestyle changes that promote physically active behavior and how these changes influence epigenetic regulation should be intensely investigated in future research. A change of attitude toward adopting a healthy lifestyle can change the length and quality of life or minimize the predisposition to become ill. Future research should also focus on how physical activity and exercise can regulate epigenetic mechanisms, thereby increasing the current body of knowledge about how specific genes (e.g., myogenic genes) are regulated by epigenetic phenomena. This should result in improving the prognosis of several aging-related diseases or designing appropriate exercises or lifestyle changes to alter the epigenetic patterns of specific genes. The wide range of currently available technologies allows us to analyze the methylation patterns or posttranslational modification histone maps in genes related to exercise, and this may help us decipher the optimal conditions for maintaining a lifestyle that promotes eustress rather than distress.


1. Aagaard-Tillery KM, Grove K, Bishop J, Ke X, Fu Q, McKnight R, Lane RH. Developmental origins of disease and determinants of chromatin structure: Maternal diet modifies the primate fetal epigenome. J Mol Endocrinol 41: 91–102, 2008.
2. Alegria-Torres JA, Baccarelli A, Bollati V. Epigenetics and lifestyle. Epigenomics 3: 267–277, 2011.
3. Faulk C, Dolinoy DC. Timing is everything: The when and how of environmentally induced changes in the epigenome of animals. Epigenetics 6: 791–797, 2011.
4. Feil R, Fraga MF. Epigenetics and the environment: Emerging patterns and implications. Nat Rev Genet 13: 97–109, 2012.
5. Ferguson-Smith AC. Genomic imprinting: The emergence of an epigenetic paradigm. Nat Rev Genet 12: 565–575, 2011.
6. Fraga MF, Esteller M. Epigenetics and aging: The targets and the marks. Trends Genet 23: 413–418, 2007.
7. Fried LP, Tangen CM, Walston J, Newman AB, Hirsch C, Gottdiener J, Seeman T, Tracy R, Kop WJ, Burke G, McBurnie MA. Frailty in older adults: Evidence for a phenotype. J Gerontol A Biol Sci Med Sci 56: M146–M156, 2001.
8. Georgopoulos NA, Roupas ND, Theodoropoulou A, Tsekouras A, Vagenakis AG, Markou KB. The influence of intensive physical training on growth and pubertal development in athletes. Ann N Y Acad Sci 1205: 39–44, 2010.
9. Hanson M, Godfrey KM, Lillycrop KA, Burdge GC, Gluckman PD. Developmental plasticity and developmental origins of non-communicable disease: Theoretical considerations and epigenetic mechanisms. Prog Biophys Mol Biol 106: 272–280, 2011.
10. Ho E, Dashwood RH. Dietary manipulation of histone structure and function. World Rev Nutr Diet 101: 95–102, 2010.
11. Hoene M, Weigert C. The stress response of the liver to physical exercise. Exerc Immunol Rev 16: 163–183, 2010.
12. Jagoe RT, Goldberg AL. What do we really know about the ubiquitin-proteasome pathway in muscle atrophy? Curr Opin Clin Nutr Metab Care 4: 183–190, 2001.
13. Kaliman P, Parrizas M, Lalanza JF, Camins A, Escorihuela RM, Pallas M. Neurophysiological and epigenetic effects of physical exercise on the aging process. Ageing Res Rev 10: 475–486, 2011.
14. Leiter JR, Peeler J, Anderson JE. Exercise-induced muscle growth is muscle-specific and age-dependent. Muscle Nerve 43: 828–838, 2011.
15. Ling C, Groop L. Epigenetics: A molecular link between environmental factors and type 2 diabetes. Diabetes 58: 2718–2725, 2009.
16. Lippi G, Franchini M, Salvagno GL, Guidi GC. Lipoprotein[a] and cancer: Anti-neoplastic effect besides its cardiovascular potency. Cancer Treat Rev 33: 427–436, 2007.
17. Lu Q, Qiu X, Hu N, Wen H, Su Y, Richardson BC. Epigenetics, disease, and therapeutic interventions. Ageing Res Rev 5: 449–467, 2006.
18. Matheu A, Maraver A, Klatt P, Flores I, Garcia-Cao I, Borras C, Flores JM, Vina J, Blasco MA, Serrano M. Delayed ageing through damage protection by the Arf/p53 pathway. Nature 448: 375–379, 2007.
19. McGee SL, Fairlie E, Garnham AP, Hargreaves M. Exercise-induced histone modifications in human skeletal muscle. J Physiol 587: 5951–5958, 2009.
20. McGee SL, Hargreaves M. Histone modifications and exercise adaptations. J Appl Physiol 110: 258–263, 2011.
21. Oberdoerffer P, Sinclair DA. The role of nuclear architecture in genomic instability and ageing. Nat Rev Mol Cell Biol 8: 692–702, 2007.
22. Pandorf CE, Haddad F, Roy RR, Qin AX, Edgerton VR, Baldwin KM. Dynamics of myosin heavy chain gene regulation in slow skeletal muscle: Role of natural antisense RNA. J Biol Chem 281: 38330–38342, 2006.
23. Pandorf CE, Haddad F, Wright C, Bodell PW, Baldwin KM. Differential epigenetic modifications of histones at the myosin heavy chain genes in fast and slow skeletal muscle fibers and in response to muscle unloading. Am J Physiol Cell Physiol 297: C6–C16, 2009.
24. Perdiguero E, Sousa-Victor P, Ballestar E, Munoz-Canoves P. Epigenetic regulation of myogenesis. Epigenetics 4: 541–550, 2009.
25. Raue U, Slivka D, Jemiolo B, Hollon C, Trappe S. Myogenic gene expression at rest and after a bout of resistance exercise in young (18–30 yr) and old (80–89 yr) women. J Appl Physiol 101: 53–59, 2006.
26. Richman EL, Kenfield SA, Stampfer MJ, Paciorek A, Carroll PR, Chan JM. Physical activity after diagnosis and risk of prostate cancer progression: Data from the cancer of the prostate strategic urologic research endeavor. Cancer Res 71: 3889–3895, 2011.
27. Ruiz JR, Moran M, Arenas J, Lucia A. Strenuous endurance exercise improves life expectancy: It's in our genes. Br J Sports Med 45:159–161, 2011.
28. Saldana-Meyer R, Recillas-Targa F. Transcriptional and epigenetic regulation of the p53 tumor suppressor gene. Epigenetics 1;6, 2011.
29. Sarna S, Sahi T, Koskenvuo M, Kaprio J. Increased life expectancy of world class male athletes. Med Sci Sports Exerc 25: 237–244, 1993.
30. Schwarzenbach H. Impact of physical activity and doping on epigenetic gene regulation. Drug Test Anal, 3:682–687, 2011.
31. Thune I, Brenn T, Lund E, Gaard M. Physical activity and the risk of breast cancer. N Engl J Med 336: 1269–1275, 1997.
32. Zhang FF, Cardarelli R, Carroll J, Zhang S, Fulda KG, Gonzalez K, Vishwanatha JK, Morabia A, Santella RM. Physical activity and global genomic DNA methylation in a cancer-free population. Epigenetics 6: 293–299, 2011.
33. Zwetsloot KA, Laye MJ, Booth FW. Novel epigenetic regulation of skeletal muscle myosin heavy chain genes. Focus on “Differential epigenetic modifications of histones at the myosin heavy chain genes in fast and slow skeletal muscle fibers and in response to muscle unloading.” Am J Physiol Cell Physiol 297: C1–C3, 2009.

DNA methylation; histones; oxidative stress; free radicals; muscle damage

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