title: Sirtuin 1 (SIRT1) deacetylase activity is not required for mitochondrial biogenesis or peroxisome proliferator-activated receptor-gamma coactivator-1alpha (PGC-1alpha) deacetylation following endurance exercise.
abstract: The protein deacetylase, sirtuin 1 (SIRT1), is a proposed master regulator of exercise-induced mitochondrial biogenesis in skeletal muscle, primarily via its ability to deacetylate and activate peroxisome proliferator-activated receptor-γ coactivator-1α (PGC-1α). To investigate regulation of mitochondrial biogenesis by SIRT1 in vivo, we generated mice lacking SIRT1 deacetylase activity in skeletal muscle (mKO). We hypothesized that deacetylation of PGC-1α and mitochondrial biogenesis in sedentary mice and after endurance exercise would be impaired in mKO mice. Skeletal muscle contractile characteristics were determined in extensor digitorum longus muscle ex vivo. Mitochondrial biogenesis was assessed after 20 days of voluntary wheel running by measuring electron transport chain protein content, enzyme activity, and mitochondrial DNA expression. PGC-1α expression, nuclear localization, acetylation, and interacting protein association were determined following an acute bout of treadmill exercise (AEX) using co-immunoprecipitation and immunoblotting. Contrary to our hypothesis, skeletal muscle endurance, electron transport chain activity, and voluntary wheel running-induced mitochondrial biogenesis were not impaired in mKO versus wild-type (WT) mice. Moreover, PGC-1α expression, nuclear translocation, activity, and deacetylation after AEX were similar in mKO versus WT mice. Alternatively, we made the novel observation that deacetylation of PGC-1α after AEX occurs in parallel with reduced nuclear abundance of the acetyltransferase, general control of amino-acid synthesis 5 (GCN5), as well as reduced association between GCN5 and nuclear PGC-1α. These findings demonstrate that SIRT1 deacetylase activity is not required for exercise-induced deacetylation of PGC-1α or mitochondrial biogenesis in skeletal muscle and suggest that changes in GCN5 acetyltransferase activity may be an important regulator of PGC-1α activity after exercise.
authors.affiliation: Department of Neurobiology, Physiology, and Behavior, University of California, Davis, California 95616.
authors.forename: Andrew
authors.initials: A
authors.lastname: Philp
authors.affiliation: Division of Endocrinology and Metabolism, University of California San Diego, La Jolla, California 92093.
authors.forename: Ai
authors.initials: A
authors.lastname: Chen
authors.affiliation: Departments of Orthopaedic Surgery, University of California San Diego, La Jolla, California 92093.
authors.forename: Debin
authors.initials: D
authors.lastname: Lan
authors.affiliation: Bioengineering, University of California San Diego, La Jolla, California 92093.
authors.forename: Gretchen A
authors.initials: GA
authors.lastname: Meyer
authors.affiliation: Pharmacology, University of California San Diego, La Jolla, California 92093.
authors.forename: Anne N
authors.initials: AN
authors.lastname: Murphy
authors.affiliation: Division of Physiology, University of California San Diego, La Jolla, California 92093.
authors.forename: Amy E
authors.initials: AE
authors.lastname: Knapp
authors.affiliation: Division of Exercise Physiology, School of Medicine, West Virginia University, Morgantown, West Virginia 26506.
authors.forename: I Mark
authors.initials: IM
authors.lastname: Olfert
authors.affiliation: Department of Pediatrics and Charles C. Gates Regenerative Medicine and Stem Cell Biology Program, University of Colorado, Aurora, Colorado 80045.
authors.forename: Carrie E
authors.initials: CE
authors.lastname: McCurdy
authors.affiliation: Department of Neurobiology, Physiology, and Behavior, University of California, Davis, California 95616.
authors.forename: George R
authors.initials: GR
authors.lastname: Marcotte
authors.affiliation: Division of Physiology, University of California San Diego, La Jolla, California 92093.
authors.forename: Michael C
authors.initials: MC
authors.lastname: Hogan
authors.affiliation: Department of Neurobiology, Physiology, and Behavior, University of California, Davis, California 95616.
authors.forename: Keith
authors.initials: K
authors.lastname: Baar
authors.affiliation: Departments of Orthopaedic Surgery, University of California San Diego, La Jolla, California 92093. Electronic address: sschenk@ucsd.edu.
authors.forename: Simon
authors.initials: S
authors.lastname: Schenk
mesh_terms: D055372:AMP-Activated Protein Kinases / Q000378:metabolism; D000818:Animals; D002467:Cell Nucleus / Q000378:metabolism; D004247:DNA / Q000378:metabolism; D056545:Group III Histone Deacetylases / Q000737:chemistry*; D051379:Mice; D018345:Mice, Knockout; D008928:Mitochondria / Q000378:metabolism*; D008954:Models, Biological; D018482:Muscle, Skeletal / Q000378:metabolism; D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; D010805:Physical Conditioning, Animal; D056564:Sirtuin 1 / Q000737:chemistry*; D013997:Time Factors; D015534:Trans-Activators / Q000378:metabolism*; D014157:Transcription Factors; D050880:p300-CBP Transcription Factors / Q000378:metabolism*; D000099224:p300-CBP-Associated Factor
chemical_list: D055372:AMP-Activated Protein Kinases; D004247:DNA; D056545:Group III Histone Deacetylases; D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; D056564:Sirtuin 1; D015534:Trans-Activators; D014157:Transcription Factors; D050880:p300-CBP Transcription Factors; D000099224:p300-CBP-Associated Factor; C485290:Ppargc1a protein, mouse