title: Effects of resveratrol and SIRT1 on PGC-1α activity and mitochondrial biogenesis: a reevaluation.
abstract: It has been reported that feeding mice resveratrol activates AMPK and SIRT1 in skeletal muscle leading to deacetylation and activation of PGC-1α, increased mitochondrial biogenesis, and improved running endurance. This study was done to further evaluate the effects of resveratrol, SIRT1, and PGC-1α deacetylation on mitochondrial biogenesis in muscle. Feeding rats or mice a diet containing 4 g resveratrol/kg diet had no effect on mitochondrial protein levels in muscle. High concentrations of resveratrol lowered ATP concentration and activated AMPK in C₂C₁₂ myotubes, resulting in an increase in mitochondrial proteins. Knockdown of SIRT1, or suppression of SIRT1 activity with a dominant-negative (DN) SIRT1 construct, increased PGC-1α acetylation, PGC-1α coactivator activity, and mitochondrial proteins in C₂C₁₂ cells. Expression of a DN SIRT1 in rat triceps muscle also induced an increase in mitochondrial proteins. Overexpression of SIRT1 decreased PGC-1α acetylation, PGC-1α coactivator activity, and mitochondrial proteins in C₂C₁₂ myotubes. Overexpression of SIRT1 also resulted in a decrease in mitochondrial proteins in rat triceps muscle. We conclude that, contrary to some previous reports, the mechanism by which SIRT1 regulates mitochondrial biogenesis is by inhibiting PGC-1α coactivator activity, resulting in a decrease in mitochondria. We also conclude that feeding rodents resveratrol has no effect on mitochondrial biogenesis in muscle.
authors.affiliation: Division of Geriatrics and Nutritional Sciences, Department of Medicine, Washington University School of Medicine in St. Louis, Missouri, United States of America.
authors.forename: Kazuhiko
authors.initials: K
authors.lastname: Higashida
authors.forename: Sang Hyun
authors.initials: SH
authors.lastname: Kim
authors.forename: Su Ryun
authors.initials: SR
authors.lastname: Jung
authors.forename: Meiko
authors.initials: M
authors.lastname: Asaka
authors.forename: John O
authors.initials: JO
authors.lastname: Holloszy
authors.forename: Dong-Ho
authors.initials: DH
authors.lastname: Han
mesh_terms: D000107:Acetylation / Q000187:drug effects; D000818:Animals; D015153:Blotting, Western; D002460:Cell Line; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D024101:Mitochondrial Proteins / Q000378:metabolism; D018485:Muscle Fibers, Skeletal / Q000187:drug effects / Q000378:metabolism; D018482:Muscle, Skeletal / Q000187:drug effects* / Q000378:metabolism*; D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; D051381:Rats; D017207:Rats, Sprague-Dawley; D000077185:Resveratrol; D056564:Sirtuin 1 / Q000235:genetics / Q000378:metabolism*; D013267:Stilbenes / Q000494:pharmacology*; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism*
chemical_list: D024101:Mitochondrial Proteins; D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; C485290:Ppargc1a protein, mouse; C501429:Ppargc1a protein, rat; D013267:Stilbenes; D014157:Transcription Factors; C470545:Sirt1 protein, mouse; C488368:Sirt1 protein, rat; D056564:Sirtuin 1; D000077185:Resveratrol