The deacetylase enzyme SIRT1 is not associated with oxidative capacity in rat heart and skeletal muscle and its overexpression reduces mitochondrial biogenesis.
Deacetylation of PGC-1alpha by SIRT1 is thought to be an important step in increasing PGC-1alpha transcriptional activity, since in muscle cell lines SIRT1 induces PGC-1alpha protein expression and mitochondrial biogenesis. We examined the relationship between SIRT1 protein and activity, PGC-1alpha and markers of mitochondrial density, (a) across a range of metabolically heterogeneous skeletal muscles and the heart, and when mitochondrial biogenesis was stimulated by (b) chronic muscle stimulation (7 days) and (c) AICAR administration (5 days), and finally, (d) we also examined the effects of SIRT1 overexpression on mitochondrial biogenesis and PGC-1alpha. SIRT1 protein and activity were correlated (r = 0.97). There were negative correlations between SIRT1 protein and PGC-1alpha (r = -0.95), COX IV (r = -0.94) and citrate synthase (r = -0.97). Chronic muscle stimulation and AICAR upregulated PGC-1alpha protein (22-159%) and oxidative capacity (COX IV, 20-69%); in each instance SIRT1 protein was downregulated by 20-40%, while SIRT1 intrinsic activity was increased. SIRT1 overexpression in rodent muscle increased SIRT1 protein (+240%) and doubled SIRT1 activity, but PGC-1alpha (-25%), mtTFA (-14%) and COX IV (-10%) proteins were downregulated. Taken altogether these experiments are not consistent with the notion that SIRT1 protein plays an obligatory regulatory role in the process of PGC-1alpha-mediated mitochondrial biogenesis in mammalian muscle.
Gurd
Brendon J
BJ
Department of Human Health and Nutritional Science, University of Guelph, Guelph, Ontario, Canada, N1G 2W1.
Yoshida
Yuko
Y
Lally
James
J
Holloway
Graham P
GP
Bonen
Arend
A
D000620:Aminoimidazole Carboxamide / Q000031:analogs & derivatives / Q000494:pharmacology; D000818:Animals; D015153:Blotting, Western; D002460:Cell Line; D002950:Citrate (si)-Synthase / Q000096:biosynthesis / Q000235:genetics; D004268:DNA-Binding Proteins / Q000096:biosynthesis / Q000235:genetics; D004558:Electric Stimulation; D003576:Electron Transport Complex IV / Q000378:metabolism; D005260:Female; D007004:Hypoglycemic Agents / Q000494:pharmacology; D008929:Mitochondria, Heart / Q000502:physiology*; D008931:Mitochondria, Muscle / Q000502:physiology*; D024101:Mitochondrial Proteins / Q000096:biosynthesis / Q000235:genetics; D018656:Muscle Fibers, Fast-Twitch / Q000378:metabolism; D018657:Muscle Fibers, Slow-Twitch / Q000378:metabolism; D018482:Muscle, Skeletal / Q000378:metabolism*; D009206:Myocardium / Q000378:metabolism*; D010084:Oxidation-Reduction; D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; D016601:RNA-Binding Proteins; D051381:Rats; D017207:Rats, Sprague-Dawley; D012265:Ribonucleotides / Q000494:pharmacology; D056564:Sirtuin 1; D037761:Sirtuins / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology*; D014157:Transcription Factors / Q000096:biosynthesis / Q000235:genetics; D015854:Up-Regulation / Q000235:genetics / Q000502:physiology
D004268:DNA-Binding Proteins; D007004:Hypoglycemic Agents; D024101:Mitochondrial Proteins; D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; C501429:Ppargc1a protein, rat; D016601:RNA-Binding Proteins; D012265:Ribonucleotides; D014157:Transcription Factors; C422562:mitochondrial transcription factor A; D000620:Aminoimidazole Carboxamide; D003576:Electron Transport Complex IV; D002950:Citrate (si)-Synthase; C488368:Sirt1 protein, rat; D056564:Sirtuin 1; D037761:Sirtuins; C031143:AICA ribonucleotide