Physical Exercise and Epigenetic Modulation: Elucidating Intricate Mechanisms

Physical exercise induces several metabolic adaptations to meet increased energy requirements. Pro- moter DNA methylation, histone post-translational modi- fications, or microRNA expression are involved in the gene expression changes implicated in metabolic adaptation after exercise. Epigenetic modifications and many epige- netic enzymes are potentially dependent on changes in the levels of metabolites, such as oxygen, tricarboxylic acid cycle intermediates, 2-oxoglutarate, 2-hydroxyglutarate, and b-hydroxybutyrate, and are therefore susceptible to the changes induced by exercise in a tissue-dependent manner. Most of these changes are regulated by important epige- netic modifiers that control DNA methylation (DNA methyl transferases, and ten-eleven-translocation proteins) and post-translational modifications in histone tails con- trolled by histone acetyltransferases, histone deacetylases, and histone demethylases (jumonji C proteins, lysine-spe- cific histone demethylase, etc.), among others. Develop- ments 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 regu- lated by exercise that affect some of the most important epigenetic mechanisms, which, in turn, control the gene expression involved in metabolism.