Epigenetic Modifications of the PGC-1α Promoter during Exercise Induced Expression in Mice

Abstract

The transcriptional coactivator, PGC-1α, is known for its role in mitochondrial biogenesis. Although originally thought to exist as a single protein isoform, recent studies have identified additional promoters which produce multiple mRNA transcripts. One of these promoters (promoter B), approximately 13.7kb upstream of the canonical PGC-1α promoter (promoter A), yields alternative transcripts present at levels much lower than the canonical PGC-1α mRNA transcript. In skeletal muscle, exercise resulted in a substantial, rapid increase of mRNA of these alternative PGC-1α transcripts. Although the β2-adrenergic receptor was identified as a signaling pathway that activates transcription from PGC-1α promoter B, it is not yet known what molecular changes occur to facilitate PGC-1α promoter B activation following exercise. We sought to determine whether epigenetic modifications were involved in this exercise response in mouse skeletal muscle. We found that DNA hydroxymethylation correlated to increased basal mRNA levels from PGC-1α promoter A, but that DNA methylation appeared to play no role in the exercise-induced activation of PGC-1α promoter B. The level of the activating histone mark H3K4me3 increased with exercise 2–4 fold across PGC-1α promoter B, but remained unaltered past the canonical PGC-1α transcriptional start site. Together, these data show that epigenetic modifications partially explain exercise-induced changes in the skeletal muscle mRNA levels of PGC-1α isoforms.

Muscle Contraction Induces Acute Hydroxymethylation of the Exercise-Responsive Gene Nr4a3

“…EPS altered mRNA level of Ccnd1 and Ppard , two genes respectively involved in muscle growth and metabolism and previously shown to be induced by muscle contraction (27, 28). In contrast, our EPS protocol failed to induce Ppargc1a mRNA expression although several studies including one from our group have reported that Ppargc1a expression is increased after a single bout of exercise (4, 25, 28, 29). The lack of response for Ppargc1a gene in our hands is likely due to the nature of the contraction protocol, as previous reports show Ppargc1a gene expression is induced by slow-type tetanic contraction (30).…”

Does skeletal muscle have an ‘epi’‐memory? The role of epigenetics in nutritional programming, metabolic disease, aging and exercise

“…More, recently 120 min of steady‐state exercise (60% Vo 2 peak) reportedly increased methylation in the promoter of fatty acid‐binding protein 3 (FABP3) after 4 h of recovery resulting in the impaired mRNA transcription (Lane et al ., ). Furthermore, suppression of DNA methylation was also associated with increased basal mRNA levels of the PGC‐1α promoter A after exercise but not the PGC‐1α promoter B where this was controlled by the methylation of lysine 4 on histone 3 (H3K4me3) (Lochmann et al ., ). With respect to chronic exercise, 6 months of supervised aerobic exercise 3 × 1 h per week (varied intensity) changed the methylation of several genes associated with metabolism (Nitert et al ., ).…”

Exercise and the Skeletal Muscle Epigenome

“…Interestingly, the same exercise modality at a lower intensity (40% VO 2 max) had no effect on DNA methylation, suggesting that exercise intensity may be a critical factor in influencing DNA methylation. A recent study in mice has replicated some of these findings, showing that exercise reduced PGC1a promoter methylation, which was associated with increased basal transcription of this gene (Lochmann et al 2015). Another study has found that 120 min of cycling in healthy subjects (60% VO 2 max) increased methylation at the promoters of FABP3 and COX4L1, which was associated with decreased expression of these genes (Lane et al 2015).…”