title: Nuclear SIRT1 activity, but not protein content, regulates mitochondrial biogenesis in rat and human skeletal muscle.
abstract: Silent mating type information regulator 2 homolog 1 (SIRT1)-mediated peroxisome proliferator-activated receptor gamma coactivator-1α (PGC-1α) deacetylation is potentially key for activating mitochondrial biogenesis. Yet, at the whole muscle level, SIRT1 is not associated with mitochondrial biogenesis (Gurd, BJ, Yoshida Y, Lally J, Holloway GP, Bonen A. J Physiol 587: 1817-1828, 2009). Therefore, we examined nuclear SIRT1 protein and activity in muscle with varied mitochondrial content and in response to acute exercise. We also measured these parameters after stimulating mitochondrial biogenesis with chronic muscle contraction and 5-aminoimidazole-4-carboxamide-1-β-d-ribofuranoside (AICAR) administration in rodents and exercise training in humans. In skeletal and heart muscles, nuclear SIRT1 protein was negatively correlated with indices of mitochondrial density (citrate synthase activity, CS; cytochrome oxidase IV, COX IV), but SIRT1 activity was positively correlated with these parameters (r > 0.98). Acute exercise did not alter nuclear SIRT1 protein but did induce a time-dependent increase in nuclear SIRT1 activity. This increase in SIRT1 activity was temporally related to increases in mRNA expression of genes activated by PGC-1α. Both chronic muscle stimulation and AICAR increased mitochondrial biogenesis and muscle PGC-1α, but not nuclear PGC-1α. Concomitantly, muscle and nuclear SIRT1 protein contents were reduced, but nuclear SIRT1 activity was increased. In human muscle, training-induced mitochondrial biogenesis did not alter muscle or nuclear SIRT1 protein content, but it did increase muscle and nuclear PGC-1α and SIRT1 activity. Thus, nuclear SIRT1 activity, but not muscle or nuclear SIRT1 protein content, is associated with contraction-stimulated mitochondrial biogenesis in rat and human muscle, possibly via AMPK activation.
authors.affiliation: School of Kinesiology and Health Studies, Queen's University, Kingston, Canada. gurdb@queensu.ca
authors.forename: Brendon J
authors.initials: BJ
authors.lastname: Gurd
authors.forename: Yuko
authors.initials: Y
authors.lastname: Yoshida
authors.forename: Jay T
authors.initials: JT
authors.lastname: McFarlan
authors.forename: Graham P
authors.initials: GP
authors.lastname: Holloway
authors.forename: Chris D
authors.initials: CD
authors.lastname: Moyes
authors.forename: George J F
authors.initials: GJ
authors.lastname: Heigenhauser
authors.forename: Lawrence
authors.initials: L
authors.lastname: Spriet
authors.forename: Arend
authors.initials: A
authors.lastname: Bonen
mesh_terms: D055372:AMP-Activated Protein Kinases / Q000378:metabolism; D000620:Aminoimidazole Carboxamide / Q000031:analogs & derivatives / Q000494:pharmacology; D000818:Animals; D002467:Cell Nucleus / Q000378:metabolism*; D015444:Exercise / Q000502:physiology; D005260:Female; D006360:Heat-Shock Proteins / Q000378:metabolism; D006801:Humans; D007004:Hypoglycemic Agents / Q000494:pharmacology; D008297:Male; D008931:Mitochondria, Muscle / Q000187:drug effects / Q000502:physiology*; D023421:Models, Animal; D009119:Muscle Contraction / Q000502:physiology; D018482:Muscle, Skeletal / Q000378:metabolism*; D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; D010805:Physical Conditioning, Animal / Q000502:physiology; D016601:RNA-Binding Proteins / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D012265:Ribonucleotides / Q000494:pharmacology; D056564:Sirtuin 1 / Q000378:metabolism*; D014157:Transcription Factors / Q000378:metabolism
chemical_list: D006360:Heat-Shock Proteins; D007004:Hypoglycemic Agents; C486497:PPARGC1A protein, human; D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; C501429:Ppargc1a protein, rat; D016601:RNA-Binding Proteins; D012265:Ribonucleotides; D014157:Transcription Factors; D000620:Aminoimidazole Carboxamide; D055372:AMP-Activated Protein Kinases; C447939:SIRT1 protein, human; C488368:Sirt1 protein, rat; D056564:Sirtuin 1; C031143:AICA ribonucleotide