The Durk Pearson & Sandy Shaw®
Life Extension NewsTM
Volume 16 No. 8 • September 2013

Closing In On Exercise In a Pill? Maybe.
Decreased Methylation in Muscle Genome
Turns On Exercise-Induced Gene Expression

Researchers have identified many of the skeletal muscle genes that are triggered by exercise and contribute importantly to the benefits of exercise. A new paper1 now identifies an important role played by DNA methylation in exercise-induced gene expression. DNA methylation is an important process for determining when genes are expressed (turned on) or silenced (turned off) and much has been learned about natural products that are able to trigger increased DNA methylation (which generally decreases gene expression) or decreased DNA methylation (which generally increases gene expression). With these discoveries, we are moving ever closer to pharmacological control of enhancing genetic expression that would otherwise require exercise as a trigger. Here’s the latest story:

A recent paper1 found that DNA methylation was decreased in skeletal muscle biopsies obtained from healthy sedentary men and women after they performed acute exercise. “Exercise induced a dose-dependent expression of PGC-1alpha [an important regulator of mitochondrial biogenesis], PDK4, and PPAR-delta, together with a marked hypomethylation on each respective promoter. Similarly promoter methylation of PGC-1alpha, PDK4, and PPAR-delta was markedly decreased in mouse soleus muscles 45 minutes after ex vivo contraction.” “Promoter methylation of PGC-1alpha, Tfam, Mef2a, and Cs, but not PDK4, decreased prior to gene expression changes.”1 “Conversely, reactive oxygen species (ROS) production (induced by H2O2 [hydrogen peroxide]) elicitated hypermethylation.” The authors suggest, therefore that “DNA hypomethylation is an early event in [muscle] contraction-induced gene expression.”

In other recent work, EGCG1A and curcumin1B have been identified as natural substances that act as hypomethylating agents, e.g., they decrease DNA methylation. In light of the above study,1 this suggests (we speculate) that taking proper doses of EGCG and/or curcumin shortly before exercise might enhance the hypomethylation induced by muscle contraction, increasing the beneficial effects of exercise. Mild exercise might be able to provide the benefits that would otherwise require more energetic exercise. (The latter has not been demonstrated but we hope to see studies published in the near future testing this hypothesis.)

The authors1 suggest, however, that DNA methylation does not exclusively control exercise-induced gene expression as they have found that ionomycin, AICAR, or ROS production increased mRNA expression without altering promoter methylation. Thus, they propose that DNA methylation “may serve as a selective mechanism to orchestrate the activation of a subset of genes but, clearly, other mechanisms, such as transcription factor activation and recruitment to the chromatin, are likely to be involved.”

Exercise Alters Epigenetic Parameters in Rat Hippocampus

In a second paper on exercise and DNA methylation (an epigenetic process),2 researchers found that exercise can alter DNA methylation in the hippocampus of 3 month and 20 month old Wistar rats. As it is known that exercise can improve cognitive processes, DNA methylation is an interesting link that suggests a possible mechanism for the effect of exercise on cognition.

The authors first point out that epigenetic mechanisms have been shown to affect cognition in earlier studies where histone deacetylase (HDAC) inhibitors improved memory in aged rodents.2 Moreover, exercise has also been shown to ameliorate age-related cognitive decline in rodents. Other studies have reported that exercise modulation of histone deacetylase status in the brain enhanced transcription of genes in the brain related to cognitive function.

The researchers therefore studied the effects of exercise on epigenetic changes as a consequence of aging. They followed the effects of two exercise regimens, a single session of treadmill exercise or chronic treadmill exercise, on changes in DNA methylation in the hippocampus.

The findings included that methylation changes as a result of exercise differed in 3 month old (young) and 20 month-old (aged) male Wistar rat hippocampi. They report decreased DNMT1 (DNA methyltransferase 1) activity in senescent human fibroblasts and suggest that this is correlated with a genome-wide tendency to DNA hypomethylation in multiple vertebrate organs during the aging process.2 Aged hippocampi were found to have lower levels of H3-K9 methylation levels. As the researchers explain, histone methylation can cause either gene activation or gene repression.

The single exercise experiment in young adult rats resulted in significant decrease in both DNMT1 and DNMT3b, two methyltransferases, which could reduce DNA methylation and, consequently, affect gene expression. In contrast, the single exercise test did not have an effect on DNMT1 or DNMT3b levels in the hippocampi of the 20 month-old (aged) rats. Other details reveal considerable complexity to the pattern of epigenetic changes in the hippocampus in conjunction with exercise in young and old rats. It is interesting to note that EGCG inhibits methyltransferases.

It appears quite plausible (but not proven) that DNA methylation changes in the hippocampus as a consequence of exercise may play a role in the improved cognition resulting from exercise but that these effects are different in young vs. old rats. Exercise in a pill? We aren’t there yet, but come back in five years or so.


1. Barres et al. Acute exercise remodels promoter methylation in human skeletal muscle. Cell Metab. 15:405-11 (2012).
1A. Yang et al. Reversal of hypermethylation and reactivation of genes by dietary polyphenolic compounds. Nutr Rev. 66 (Suppl 1):S18-S20 (2008).
1B. Liu et al. Curcumin is a potent DNA hypomethylation agent. Bioorg Med Chem Lett. 19:706-9 (2009).
2. Elsner et al, Exercise induces age-dependent changes on epigenetic parameters in rat hippocampus: a preliminary study. Exp Gerontol. 48:136-9 (2013).

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