Abstract
Physical exercise induces several metabolic adaptations to meet increased energy requirements. Promoter DNA methylation, histone post-translational modifications, or microRNA expression are involved in the gene expression changes implicated in metabolic adaptation after exercise. Epigenetic modifications and many epigenetic enzymes are potentially dependent on changes in the levels of metabolites, such as oxygen, tricarboxylic acid cycle intermediates, 2-oxoglutarate, 2-hydroxyglutarate, and β-hydroxybutyrate, and are therefore susceptible to the changes induced by exercise in a tissue-dependent manner. Most of these changes are regulated by important epigenetic modifiers that control DNA methylation (DNA methyl transferases, and ten–eleven-translocation proteins) and post-translational modifications in histone tails controlled by histone acetyltransferases, histone deacetylases, and histone demethylases (jumonji C proteins, lysine-specific histone demethylase, etc.), among others. Developments in mass spectrometry approaches and the comprehension of the interconnections between epigenetics and metabolism further increase our understanding of underlying epigenetic mechanisms, not only of exercise, but also of disease and aging. In this article, we describe several of these substrates and signaling molecules regulated by exercise that affect some of the most important epigenetic mechanisms, which, in turn, control the gene expression involved in metabolism.
Similar content being viewed by others
References
Vina J, Sanchis-Gomar F, Martinez-Bello V, et al. Exercise acts as a drug; the pharmacological benefits of exercise. Br J Pharmacol. 2012;167(1):1–12.
Blair SN, Kohl HW 3rd, Paffenbarger RS Jr, et al. Physical fitness and all-cause mortality: a prospective study of healthy men and women. JAMA. 1989;262(17):2395–401.
Macera CA, Hootman JM, Sniezek JE. Major public health benefits of physical activity. Arthritis Rheum. 2003;49(1):122–8.
Myers J, Kaykha A, George S, et al. Fitness versus physical activity patterns in predicting mortality in men. Am J Med. 2004;117(12):912–8.
Pedersen BK, Saltin B. Evidence for prescribing exercise as therapy in chronic disease. Scand J Med Sci Sports. 2006;16(Suppl 1):3–63.
Warburton DE, Nicol CW, Bredin SS. Health benefits of physical activity: the evidence. CMAJ. 2006;174(6):801–9.
Allis CD, Jenuwein T, Reinberg D. Epigenetics. New York: Cold Spring Harbor Laboratory Press; 2007. p. 502.
Bird A. Perceptions of epigenetics. Nature. 2007;447(7143):396–8.
Goldberg AD, Allis CD, Bernstein E. Epigenetics: a landscape takes shape. Cell. 2007;128(4):635–8.
Bernstein BE, Meissner A, Lander ES. The mammalian epigenome. Cell. 2007;128(4):669–81.
Jenuwein T, Allis CD. Translating the histone code. Science. 2001;293(5532):1074–80.
Jones PA, Baylin SB. The epigenomics of cancer. Cell. 2007;128(4):683–92.
Irizarry RA, Ladd-Acosta C, Wen B, et al. The human colon cancer methylome shows similar hypo- and hypermethylation at conserved tissue-specific CpG island shores. Nat Genet. 2009;41(2):178–86.
He L, Hannon GJ. MicroRNAs: small RNAs with a big role in gene regulation. Nat Rev Genet. 2004;5(7):522–31.
Lytle JR, Yario TA, Steitz JA. Target mRNAs are repressed as efficiently by microRNA-binding sites in the 5′ UTR as in the 3′ UTR. Proc Natl Acad Sci U S A. 2007;104(23):9667–72.
Vasudevan S, Tong Y, Steitz JA. Switching from repression to activation: microRNAs can up-regulate translation. Science. 2007;318(5858):1931–4.
Strahl BD, Allis CD. The language of covalent histone modifications. Nature. 2000;403(6765):41–5.
Alegria-Torres JA, Baccarelli A, Bollati V. Epigenetics and lifestyle. Epigenomics. 2011;3(3):267–77.
Sanchis-Gomar F, Garcia-Gimenez JL, Perez-Quilis C, et al. Physical exercise as an epigenetic modulator: Eustress, the “positive stress” as an effector of gene expression. J Strength Cond Res. 2012;26(12):3469–72.
Talens RP, Christensen K, Putter H, et al. Epigenetic variation during the adult lifespan: cross-sectional and longitudinal data on monozygotic twin pairs. Aging Cell. 2012;11(4):694–703.
Holloszy JO, Coyle EF. Adaptations of skeletal muscle to endurance exercise and their metabolic consequences. J Appl Physiol. 1984;56(4):831–8.
Barrès R, Yan J, Egan B, et al. Acute exercise remodels promoter methylation in human skeletal muscle. Cell Metab. 2012;15(3):405–11.
Vina J, Gomez-Cabrera MC, Borras C, et al. Mitochondrial biogenesis in exercise and in ageing. Adv Drug Deliv Rev. 2009;61(14):1369–74.
Holloszy JO. Biochemical adaptations in muscle. Effects of exercise on mitochondrial oxygen uptake and respiratory enzyme activity in skeletal muscle. J Biol Chem. 1967;242(9):2278–82.
Bergeron R, Ren JM, Cadman KS, et al. Chronic activation of AMP kinase results in NRF-1 activation and mitochondrial biogenesis. Am J Physiol Endocrinol Metab. 2001;281(6):E1340–6.
Hardie DG. AMP-activated protein kinase: a key system mediating metabolic responses to exercise. Med Sci Sports Exerc. 2004;36(1):28–34.
Hardie DG, Sakamoto K. AMPK: a key sensor of fuel and energy status in skeletal muscle. Physiology (Bethesda). 2006;21:48–60.
Davalos A, Goedeke L, Smibert P, et al. miR-33a/b contribute to the regulation of fatty acid metabolism and insulin signaling. Proc Natl Acad Sci U S A. 2011;108(22):9232–7.
Wang H, Garzon R, Sun H, et al. NF-kappaB-YY1-miR-29 regulatory circuitry in skeletal myogenesis and rhabdomyosarcoma. Cancer Cell. 2008;14(5):369–81.
Alibegovic AC, Sonne MP, Hojbjerre L, et al. Insulin resistance induced by physical inactivity is associated with multiple transcriptional changes in skeletal muscle in young men. Am J Physiol Endocrinol Metab. 2010;299(5):E752–63.
Alibegovic AC, Hojbjerre L, Sonne MP, et al. Impact of 9 days of bed rest on hepatic and peripheral insulin action, insulin secretion, and whole-body lipolysis in healthy young male offspring of patients with type 2 diabetes. Diabetes. 2009;58(12):2749–56.
McKinsey TA, Zhang CL, Olson EN. Control of muscle development by dueling HATs and HDACs. Curr Opin Genet Dev. 2001;11(5):497–504.
McGee SL, Hargreaves M. Histone modifications and exercise adaptations. J Appl Physiol (1985). 2011;110(1):258–63.
Egan B, Carson BP, Garcia-Roves PM, et al. Exercise intensity-dependent regulation of peroxisome proliferator-activated receptor coactivator-1 mRNA abundance is associated with differential activation of upstream signalling kinases in human skeletal muscle. J Physiol. 2010;588(Pt 10):1779–90.
Puthucheary Z, Skipworth JR, Rawal J, et al. The ACE gene and human performance: 12 years on. Sports Med. 2011;41(6):433–48.
Raleigh SM. Epigenetic regulation of the ACE gene might be more relevant to endurance physiology than the I/D polymorphism. J Appl Physiol. (1985). 2012;112(6):1082–3.
Rivière G, Lienhard D, Andrieu T, et al. Epigenetic regulation of somatic angiotensin-converting enzyme by DNA methylation and histone acetylation. Epigenetics. 2011;6(4):478–89.
Gibala MJ, MacLean DA, Graham TE, et al. Tricarboxylic acid cycle intermediate pool size and estimated cycle flux in human muscle during exercise. Am J Physiol. 1998;275(2 Pt 1):E235–42.
O’Hagan KA, Cocchiglia S, Zhdanov AV, et al. PGC-1alpha is coupled to HIF-1alpha-dependent gene expression by increasing mitochondrial oxygen consumption in skeletal muscle cells. Proc Natl Acad Sci U S A. 2009;106(7):2188–93.
Ivan M, Kondo K, Yang H, et al. HIFalpha targeted for VHL-mediated destruction by proline hydroxylation: implications for O2 sensing. Science. 2001;292(5516):464–8.
Bruick RK, McKnight SL. A conserved family of prolyl-4-hydroxylases that modify HIF. Science. 2001;294(5545):1337–40.
Cyr AR, Domann FE. The redox basis of epigenetic modifications: from mechanisms to functional consequences. Antioxid Redox Signal. 2011;15(2):551–89.
Tsukada Y, Fang J, Erdjument-Bromage H, et al. Histone demethylation by a family of JmjC domain-containing proteins. Nature. 2006;439(7078):811–6.
Tahiliani M, Koh KP, Shen Y, et al. Conversion of 5-methylcytosine to 5-hydroxymethylcytosine in mammalian DNA by MLL partner TET1. Science. 2009;324(5929):930–5.
Hirsila M, Koivunen P, Gunzler V, et al. Characterization of the human prolyl 4-hydroxylases that modify the hypoxia-inducible factor. J Biol Chem. 2003;278(33):30772–80.
Kriaucionis S, Heintz N. The nuclear DNA base 5-hydroxymethylcytosine is present in Purkinje neurons and the brain. Science. 2009;324(5929):929–30.
Zhao S, Lin Y, Xu W, et al. Glioma-derived mutations in IDH1 dominantly inhibit IDH1 catalytic activity and induce HIF-1alpha. Science. 2009;324(5924):261–5.
Cervera AM, Bayley JP, Devilee P, et al. Inhibition of succinate dehydrogenase dysregulates histone modification in mammalian cells. Mol Cancer. 2009;8:89.
Gimenez-Roqueplo AP, Favier J, Rustin P, et al. The R22X mutation of the SDHD gene in hereditary paraganglioma abolishes the enzymatic activity of complex II in the mitochondrial respiratory chain and activates the hypoxia pathway. Am J Hum Genet. 2001;69(6):1186–97.
Gimenez-Roqueplo AP, Favier J, Rustin P, et al. Mutations in the SDHB gene are associated with extra-adrenal and/or malignant phaeochromocytomas. Cancer Res. 2003;63(17):5615–21.
Selak MA, Armour SM, MacKenzie ED, et al. Succinate links TCA cycle dysfunction to oncogenesis by inhibiting HIF-alpha prolyl hydroxylase. Cancer Cell. 2005;7(1):77–85.
Brugnara L, Vinaixa M, Murillo S, et al. Metabolomics approach for analyzing the effects of exercise in subjects with type 1 diabetes mellitus. PLoS One. 2012;7(7):e40600.
Xiao M, Yang H, Xu W, et al. Inhibition of alpha-KG-dependent histone and DNA demethylases by fumarate and succinate that are accumulated in mutations of FH and SDH tumor suppressors. Genes Dev. 2012;26(12):1326–38.
Berra E, Ginouves A, Pouyssegur J. The hypoxia-inducible-factor hydroxylases bring fresh air into hypoxia signalling. EMBO Rep. 2006;7(1):41–5.
Gerald D, Berra E, Frapart YM, et al. JunD reduces tumor angiogenesis by protecting cells from oxidative stress. Cell. 2004;118(6):781–94.
Shimazu T, Hirschey MD, Newman J, et al. Suppression of oxidative stress by beta-hydroxybutyrate, an endogenous histone deacetylase inhibitor. Science. 2013;339(6116):211–4.
Zinker BA, Britz K, Brooks GA. Effects of a 36-hour fast on human endurance and substrate utilization. J Appl Physiol. 1990;69(5):1849–55.
Koeslag JH, Noakes TD, Sloan AW. Post-exercise ketosis. J Physiol. 1980;301:79–90.
Gupta R, Nagarajan A, Wajapeyee N. Advances in genome-wide DNA methylation analysis. Biotechniques. 2010;49(4):iii–xi.
Garcia-Gimenez JL, Sanchis-Gomar F, Lippi G, et al. Epigenetic biomarkers: a new perspective in laboratory diagnostics. Clin Chim Acta. 2012;413(19–20):1576–82.
Cocklin RR, Wang M. Identification of methylation and acetylation sites on mouse histone H3 using matrix-assisted laser desorption/ionization time-of-flight and nanoelectrospray ionization tandem mass spectrometry. J Protein Chem. 2003;22(4):327–34.
Koubaa M, Cocuron JC, Thomasset B, et al. Highlighting the tricarboxylic acid cycle: liquid and gas chromatography-mass spectrometry analyses of (13)C-labeled organic acids. Anal Biochem. 2013;436(2):151–9.
Choi J, Grossbach MT, Antoniewicz MR. Measuring complete isotopomer distribution of aspartate using gas chromatography/tandem mass spectrometry. Anal Chem. 2012;84(10):4628–32.
Koubaa M, Mghaieth S, Thomasset B, et al. Gas chromatography-mass spectrometry analysis of 13C labeling in sugars for metabolic flux analysis. Anal Biochem. 2012;425(2):183–8.
O’Grady J, Schwender J, Shachar-Hill Y, et al. Metabolic cartography: experimental quantification of metabolic fluxes from isotopic labelling studies. J Exp Bot. 2012;63(6):2293–308.
Dahl SR, Olsen KM, Strand DH. Determination of gamma-hydroxybutyrate (GHB), beta-hydroxybutyrate (BHB), pregabalin, 1,4-butane-diol (1,4BD) and gamma-butyrolactone (GBL) in whole blood and urine samples by UPLC-MSMS. J Chromatogr B Analyt Technol Biomed Life Sci. 2012;885–886:37–42.
Acknowledgments
No sources of funding were used to help prepare this article. The authors have no potential conflicts of interest that are directly relevant to the content of this article.
Author information
Authors and Affiliations
Corresponding author
Rights and permissions
About this article
Cite this article
Pareja-Galeano, H., Sanchis-Gomar, F. & García-Giménez, J.L. Physical Exercise and Epigenetic Modulation: Elucidating Intricate Mechanisms. Sports Med 44, 429–436 (2014). https://doi.org/10.1007/s40279-013-0138-6
Published:
Issue Date:
DOI: https://doi.org/10.1007/s40279-013-0138-6