title: Skeletal Muscle PGC1α -1 Nucleosome Position and -260 nt DNA Methylation Determine Exercise Response and Prevent Ectopic Lipid Accumulation in Men.
abstract: Endurance exercise has been shown to improve lipid oxidation and increase mitochondrial content in skeletal muscle, two features that have shown dependence on increased expression of the peroxisome proliferator-activated receptor-γ coactivator 1α (PGC1α). It is also hypothesized that exercise-related alterations in PGC1α expression occur through epigenetic regulation of nucleosome positioning in association with differential DNA methylation status within the PGC1α 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 -260 nucleotide (nt) region, a known regulatory DNA methylation site, is reduced. This finding is reproduced in vivo in the vastus lateralis from 11 healthy males after a single, long endurance exercise bout in which participants expended 650 kcal. Additionally, we show a significant positive correlation between fold change of PGC1α messenger RNA expression and -1 nucleosome repositioning away from the -260 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 -260 nt methylation status, the -1 nucleosome is repositioned away from the regulatory -260 nt methylation site in high responders, those exhibiting a significant decrease in -260 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 PGC1α promoter to stimulate the therapeutic effects of endurance exercise in skeletal muscle.
authors.affiliation: Department of Kinesiology, University of Texas at El Paso, El Paso, Texas 79968.
authors.forename: Sudip
authors.initials: S
authors.lastname: Bajpeyi
authors.affiliation: Laboratory of Skeletal Muscle Physiology, Pennington Biomedical Research Center, Baton Rouge, Louisiana 70808.|School of Medicine, Louisiana State University Health Sciences Center, New Orleans, Louisiana 70112.
authors.forename: Jeffrey D
authors.initials: JD
authors.lastname: Covington
authors.affiliation: Department of Nutrition Science, Purdue University, West Lafayette, Indiana 47907.
authors.forename: Erin M
authors.initials: EM
authors.lastname: Taylor
authors.affiliation: Rocky Mountain Cancer Rehabilitation Institute, University of Northern Colorado, Greeley, Colorado 80639.
authors.forename: Laura K
authors.initials: LK
authors.lastname: Stewart
authors.affiliation: Pontificia Universidad Católica de Chile, Santiago 8331010, Chile.
authors.forename: Jose E
authors.initials: JE
authors.lastname: Galgani
authors.affiliation: Department of Nutrition Science, Purdue University, West Lafayette, Indiana 47907.
authors.forename: Tara M
authors.initials: TM
authors.lastname: Henagan
mesh_terms: D000273:Adipose Tissue; D000328:Adult; D002478:Cells, Cultured; D002828:Choristoma / Q000235:genetics / Q000378:metabolism; D019175:DNA Methylation; D003924:Diabetes Mellitus, Type 2 / Q000150:complications / Q000235:genetics / Q000378:metabolism; D044127:Epigenesis, Genetic / Q000502:physiology; D015444:Exercise / Q000502:physiology*; D006801:Humans; D050356:Lipid Metabolism / Q000235:genetics; D008297:Male; D018485:Muscle Fibers, Skeletal / Q000378:metabolism; D018482:Muscle, Skeletal / Q000378:metabolism*; D009707:Nucleosomes / Q000378:metabolism*; D009765:Obesity / Q000150:complications / Q000235:genetics / Q000378:metabolism; D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha / Q000235:genetics* / Q000378:metabolism*; D011401:Promoter Regions, Genetic; D055815:Young Adult
chemical_list: D009707:Nucleosomes; C486497:PPARGC1A protein, human; D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha