title: Skeletal muscle-specific expression of PGC-1α-b, an exercise-responsive isoform, increases exercise capacity and peak oxygen uptake.
abstract: BACKGROUND
  Maximal oxygen uptake (VO(2max)) predicts mortality and is associated with endurance performance. Trained subjects have a high VO(2max) due to a high cardiac output and high metabolic capacity of skeletal muscles. Peroxisome proliferator-activated receptor γ coactivator 1α (PGC-1α), a nuclear receptor coactivator, promotes mitochondrial biogenesis, a fiber-type switch to oxidative fibers, and angiogenesis in skeletal muscle. Because exercise training increases PGC-1α in skeletal muscle, PGC-1α-mediated changes may contribute to the improvement of exercise capacity and VO(2max). There are three isoforms of PGC-1α mRNA. PGC-1α-b protein, whose amino terminus is different from PGC-1α-a protein, is a predominant PGC-1α isoform in response to exercise. We investigated whether alterations of skeletal muscle metabolism by overexpression of PGC-1α-b in skeletal muscle, but not heart, would increase VO(2max) and exercise capacity.
  
  
  RESULTS
  Transgenic mice showed overexpression of PGC-1α-b protein in skeletal muscle but not in heart. Overexpression of PGC-1α-b promoted mitochondrial biogenesis 4-fold, increased the expression of fatty acid transporters, enhanced angiogenesis in skeletal muscle 1.4 to 2.7-fold, and promoted exercise capacity (expressed by maximum speed) by 35% and peak oxygen uptake by 20%. Across a broad range of either the absolute exercise intensity, or the same relative exercise intensities, lipid oxidation was always higher in the transgenic mice than wild-type littermates, suggesting that lipid is the predominant fuel source for exercise in the transgenic mice. However, muscle glycogen usage during exercise was absent in the transgenic mice.
  
  
  CONCLUSIONS
  Increased mitochondrial biogenesis, capillaries, and fatty acid transporters in skeletal muscles may contribute to improved exercise capacity via an increase in fatty acid utilization. Increases in PGC-1α-b protein or function might be a useful strategy for sedentary subjects to perform exercise efficiently, which would lead to prevention of life-style related diseases and increased lifespan.
authors.affiliation: Department of Nutritional Science, National Institute of Health and Nutrition, Tokyo, Japan.
authors.forename: Miki
authors.initials: M
authors.lastname: Tadaishi
authors.forename: Shinji
authors.initials: S
authors.lastname: Miura
authors.forename: Yuko
authors.initials: Y
authors.lastname: Kai
authors.forename: Yutaka
authors.initials: Y
authors.lastname: Kano
authors.forename: Yuichi
authors.initials: Y
authors.lastname: Oishi
authors.forename: Osamu
authors.initials: O
authors.lastname: Ezaki
mesh_terms: D000818:Animals; D001823:Body Composition / Q000502:physiology; D050260:Carbohydrate Metabolism; D005215:Fasting / Q000502:physiology; D005786:Gene Expression Regulation; D006003:Glycogen / Q000378:metabolism; D006801:Humans; D019344:Lactic Acid / Q000097:blood; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D008928:Mitochondria / Q000378:metabolism; D018482:Muscle, Skeletal / Q000378:metabolism*; D009206:Myocardium / Q000378:metabolism; D009928:Organ Specificity; D053141:Organelle Size; D010101:Oxygen Consumption; D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; D010805:Physical Conditioning, Animal; D020033:Protein Isoforms / Q000378:metabolism; D015534:Trans-Activators / Q000378:metabolism*; D014157:Transcription Factors
chemical_list: D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; C485290:Ppargc1a protein, mouse; D020033:Protein Isoforms; D015534:Trans-Activators; D014157:Transcription Factors; D019344:Lactic Acid; D006003:Glycogen