Skeletal muscle PGC1a 21 nucleosome position and 2260 ntdnamethylationdetermine exercise response and prevent ectopic lipid accumulation in men
Copyright © 2017 Endocrine Society. Endurance exercise has been shown to improve lipid oxidation and increasemitochondrial content in skeletalmuscle, two features that have shown dependence on increased expressionof the peroxisome proliferator-activated receptor-g coactivator 1a (PGC1a). It is also hypothesized that exercise-related alterations in PGC1a expression occur through epigenetic regulation of nucleosome positioning in association with differential DNA methylation status within the PGC1a promoter. In this study, we show that when primary human myotubes from obese patients with type 2 diabetes are exposed to lipolytic stimulus (palmitate, forskolin, inomycin) in vitro, nucleosome occupancy surrounding the 2260 nucleotide (nt) region, a known regulatory DNAmethylation site, is reduced. This finding is reproduced in vivo in the vastus lateralis from11 healthymales after a single, long endurance exercise bout in which participants expended 650 kcal. Additionally, we show a significant positive correlation between fold change of PGC1a messenger RNA expression and 21 nucleosome repositioning away from the 2260 nt methylation site in skeletal muscle tissue following exercise. Finally, we found that when exercise participants are divided into high and low responders based on the 2260 nt methylation status, the21 nucleosome is repositioned away fromthe regulatory2260 ntmethylation site in high responders, those exhibiting a significant decrease in 2260 nt methylation, but not in low responders. Additionally, high but not low responders showed a significant decrease in intramyocellular lipid content after exercise. These findings suggest a potential target for epigenetic modification of the PGC1a promoter to stimulate the therapeutic effects of endurance exercise in skeletal muscle.