PGC1α−1 Nucleosome Position and Splice Variant Expression and Cardiovascular Disease Risk in Overweight and Obese Individuals

Abstract

PGC1α, a transcriptional coactivator, interacts with PPARs and others to regulate skeletal muscle metabolism.PGC1αundergoes splicing to produce several mRNA variants, with theNTPGC1αvariant having a similar biological function to the full lengthPGC1α(FLPGC1α). CVD is associated with obesity and T2D and a lower percentage of type 1 oxidative fibers and impaired mitochondrial function in skeletal muscle, characteristics determined byPGC1αexpression.PGC1αexpression is epigenetically regulated in skeletal muscle to determine mitochondrial adaptations, and epigenetic modifications may regulate mRNA splicing. We report in this paper that skeletal musclePGC1α  −1 nucleosome (−1N) position is associated with splice variantNTPGC1αbut notFLPGC1αexpression. Division of participants based on the −1N position revealed that those individuals with a −1N phased further upstream from the transcriptional start site (UP) expressed lower levels ofNTPGC1αthan those with the −1N more proximal to TSS (DN). UP showed an increase in body fat percentage and serum total and LDL cholesterol. These findings suggest that the −1N may be a potential epigenetic regulator ofNTPGC1αsplice variant expression, and −1N position andNTPGC1αvariant expression in skeletal muscle are linked to CVD risk. This trial is registered with clinicaltrials.gov, identifierNCT00458133.