Acute Exercise Remodels Promoter Methylation in Human Skeletal Muscle

Abstract

DNA methylation is a covalent biochemical modification controlling chromatin structure and gene expression. Exercise elicits gene expression changes that trigger structural and metabolic adaptations in skeletal muscle. We determined whether DNA methylation plays a role in exercise-induced gene expression. Whole genome methylation was decreased in skeletal muscle biopsies obtained from healthy sedentary men and women after acute exercise. Exercise induced a dose-dependent expression of PGC-1α, PDK4, and PPAR-δ, together with a marked hypomethylation on each respective promoter. Similarly, promoter methylation of PGC-1α, PDK4, and PPAR-δ was markedly decreased in mouse soleus muscles 45 min after ex vivo contraction. In L6 myotubes, caffeine exposure induced gene hypomethylation in parallel with an increase in the respective mRNA content. Collectively, our results provide evidence that acute gene activation is associated with a dynamic change in DNA methylation in skeletal muscle and suggest that DNA hypomethylation is an early event in contraction-induced gene activation.

Effects of short-term high-fat overfeeding on genome-wide DNA methylation in the skeletal muscle of healthy young men

“…All together, the extent to which the observed changes in DNA methylation in this study affect gene expression over time, in a subset of individuals at risk or during certain specific metabolic challenges remain to be determined. The induction of DNA methylation changes after 5 days of HFO supports the growing awareness of DNA methylation as a dynamic signal that is possibly relevant to shortterm day-to-day metabolic adaptations, including acute exercise [26,29,30]. However, our finding of a slow reversibility rate indicates the demethylation process may be somewhat impeded compared with the induction of methylation changes by diet, which could have implications for the preservation or build-up of CpG methylation over time.…”

“…Although this may question the immediate functional relevance of the widespread methylation changes, it remains possible that the methylation changes may influence the expression levels of some genes if HFO is maintained over longer periods of time, as indicated by the slow reversibility of the HFOinduced methylation changes. The methylation changes may also only influence gene expression during specific metabolic challenges or demands, such as in response to acute exercise [25,26], or perhaps in subgroups predisposed to metabolic disease, such as individuals born with low birthweight [16]. To this end, the possibility that the methylation changes induced by HFO actually prevented potentially detrimental effects of HFO on gene expression, representing a homeostatic mechanism, should be mentioned.…”

Are cultured human myotubes far from home?

“…Exercise (Barres, et al, 2012, Nitert, et al, 2012, diet (Jacobsen, et al, 2012) and family history of type 2 diabetes (Nitert, et al, 2012) are all described to influence DNA methylation in human skeletal muscle, traits that may follow the isolated satellite cells into cultured myotubes. Thus, acute exercise was found to induce hypomethylation of promoters of several metabolic genes (Barres, et al, 2012), and a 6-month exercise intervention induced decreased methylation of genes involved in e.g. retinol metabolism, calciumsignaling pathway, starch and sucrose metabolism, and the insulin-signaling pathway (Nitert, et al, 2012).…”

The hitchhiker’s guide to PGC-1α isoform structure and biological functions

“…Access of transcriptional regulators to the appropriate genomic regions can be limited through epigenetic modifications such as DNA methylation [16]. Accordingly, PGC-1α promoter methylation is reduced by physical exercise, a classical inducer of PGC-1α expression in skeletal muscle [17]. Conversely, methylation of the same regions has been found to increase in pathological situations associated with reduced PGC-1α gene expression [18,19].…”