title: Effect of lifelong resveratrol supplementation and exercise training on skeletal muscle oxidative capacity in aging mice; impact of PGC-1α.
abstract: BACKGROUND
  The present study tested the hypothesis that lifelong resveratrol (RSV) supplementation counteracts an age-associated decrease in skeletal muscle oxidative capacity through peroxisome proliferator-activated receptor-γ coactivator (PGC)-1α and that RSV combined with lifelong exercise training (EX) exerts additive effects through PGC-1α in mice.
  
  
  METHODS
  3 month old PGC-1α whole body knockout (KO) and wild type (WT) littermate mice were placed in cages with or without running wheel and fed either standard chow or standard chow with RSV supplementation (4 g/kg food) for 12 months. Young (3 months of age), sedentary mice on standard chow served as young controls. A graded running performance test and a glucose tolerance test were performed 2 and 1 week, respectively, before euthanization where quadriceps and extensor digitorum longus (EDL) muscles were removed.
  
  
  RESULTS
  In PGC-1α KO mice, quadriceps citrate synthase (CS) activity, mitochondrial (mt)DNA content as well as pyruvate dehydrogenase (PDH)-E1α, cytochrome (Cyt) c and vascular endothelial growth factor (VEGF) protein content were 20-75% lower and, EDL capillary-to-fiber (C:F) ratio was 15-30% lower than in WT mice. RSV and/or EX had no effect on the C:F ratio in EDL. CS activity (P=0.063) and mtDNA content (P=0.013) decreased with age in WT mice, and CS activity, mtDNA content, PDH-E1α protein and VEGF protein increased ~1.5-1.8-fold with lifelong EX in WT, but not in PGC-1α KO mice, while RSV alone had no significant effect on these proteins.
  
  
  CONCLUSIONS
  Lifelong EX increased activity/content of oxidative proteins, mtDNA and angiogenic proteins in skeletal muscle through PGC-1α, while RSV supplementation alone had no effect. Combining lifelong EX and RSV supplementation had no additional effect on skeletal muscle oxidative and angiogenic proteins.
authors.affiliation: Centre of Inflammation and Metabolism, August Krogh Centre, Department of Biology, August Krogh Building, University of Copenhagen, Denmark.
authors.forename: Stine
authors.initials: S
authors.lastname: Ringholm
authors.forename: Jesper
authors.initials: J
authors.lastname: Olesen
authors.forename: Jesper Thorhauge
authors.initials: JT
authors.lastname: Pedersen
authors.forename: Christina Tingbjerg
authors.initials: CT
authors.lastname: Brandt
authors.forename: Jens Frey
authors.initials: JF
authors.lastname: Halling
authors.forename: Ylva
authors.initials: Y
authors.lastname: Hellsten
authors.forename: Clara
authors.initials: C
authors.lastname: Prats
authors.forename: Henriette
authors.initials: H
authors.lastname: Pilegaard
mesh_terms: D055372:AMP-Activated Protein Kinases / Q000378:metabolism; D000375:Aging / Q000187:drug effects* / Q000378:metabolism / Q000502:physiology*; D000818:Animals; D002950:Citrate (si)-Synthase / Q000378:metabolism; D004272:DNA, Mitochondrial / Q000235:genetics / Q000378:metabolism; D005260:Female; D051379:Mice; D018345:Mice, Knockout; D009124:Muscle Proteins / Q000378:metabolism; D018482:Muscle, Skeletal / Q000098:blood supply / Q000187:drug effects* / Q000378:metabolism*; D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; D010805:Physical Conditioning, Animal / Q000502:physiology*; D000077185:Resveratrol; D056564:Sirtuin 1 / Q000378:metabolism; D013267:Stilbenes / Q000008:administration & dosage*; D014157:Transcription Factors / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism
chemical_list: D004272:DNA, Mitochondrial; D009124:Muscle Proteins; D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; C485290:Ppargc1a protein, mouse; D013267:Stilbenes; D014157:Transcription Factors; D042461:Vascular Endothelial Growth Factor A; C467480:vascular endothelial growth factor A, mouse; D002950:Citrate (si)-Synthase; D055372:AMP-Activated Protein Kinases; C470545:Sirt1 protein, mouse; D056564:Sirtuin 1; D000077185:Resveratrol
keywords: AMP-activated protein kinase; AMPK; Aging; CD31; COX; CS; Citrate synthase; Cluster of differentiation; Cyt c; Cytochrome c; Cytochrome c oxidase; EDL; Exercise training; Extensor digitorum longus; GAPDH; Glyceraldehyde 3-phosphate dehydrogenase; Mitochondrial DNA; Oxidative capacity; PDH; PGC-1α; Peroxisome proliferator-activated receptor-γ coactivator-1α; Pyruvate dehydrogenase; Resveratrol; SIRT1; Sirtuin 1; VEGF; Vascular endothelial growth factor; mtDNA