title: Enhanced lipid-but not carbohydrate-supported mitochondrial respiration in skeletal muscle of PGC-1α overexpressing mice.
abstract: Skeletal muscle mitochondrial dysfunction has been linked to several disease states as well as the process of aging. A possible factor involved is the peroxisome proliferator-activated receptor (PPAR) γ co-activator 1α (PGC-1α), a major player in the regulation of skeletal muscle mitochondrial metabolism. However, it is currently unknown whether PGC-1α, besides stimulating mitochondrial proliferation, also affects the functional capacity per mitochondrion. Therefore, we here tested whether PGC-1α overexpression, besides increasing mitochondrial content, also leads to intrinsic mitochondrial adaptations. Skeletal muscle mitochondria from 10 male, muscle-specific PGC-1α overexpressing mice (PGC-1αTg) and 8 wild-type (WT) mice were isolated. Equal mitochondrial quantities were then analyzed for their oxidative capacity by high-resolution respirometry, fuelled by a carbohydrate-derived (pyruvate) and a lipid (palmitoyl-CoA plus carnitine) substrate. Additionally, mitochondria were tested for reactive oxygen species (superoxide) production and fatty acid (FA)-induced uncoupling. PGC-1αTg mitochondria were characterized by an improved intrinsic mitochondrial fat oxidative capacity as evidenced by pronounced increase in ADP-stimulated respiration (P < 0.001) and maximal uncoupled respiration (P < 0.001) upon palmitoyl-CoA plus carnitine. Interestingly, intrinsic mitochondrial capacity on a carbohydrate-derived substrate tended to be reduced. Furthermore, the sensitivity to FA-induced uncoupling was diminished in PGC-1αTg mitochondria (P = 0.02) and this was accompanied by a blunted reduction in mitochondrial ROS production upon FAs in PGC-1αTg versus WT mitochondria (P = 0.04). Uncoupling protein 3 (UCP3) levels were markedly reduced in PGC-1αTg mitochondria (P < 0.001). Taken together, in addition to stimulating mitochondrial proliferation in skeletal muscle, we show here that overexpression of PGC-1α leads to intrinsic mitochondrial adaptations that seem restricted to fat metabolism.
authors.affiliation: NUTRIM-School for Nutrition, Toxicology and Metabolism, Department of Human Biology, Maastricht University Medical Center, Maastricht, The Netherlands. j.hoeks@maastrichtuniversity.nl
authors.forename: Joris
authors.initials: J
authors.lastname: Hoeks
authors.forename: Zolt
authors.initials: Z
authors.lastname: Arany
authors.forename: Esther
authors.initials: E
authors.lastname: Phielix
authors.forename: Esther
authors.initials: E
authors.lastname: Moonen-Kornips
authors.forename: Matthijs K C
authors.initials: MK
authors.lastname: Hesselink
authors.forename: Patrick
authors.initials: P
authors.lastname: Schrauwen
mesh_terms: D000818:Animals; D050260:Carbohydrate Metabolism / Q000235:genetics / Q000502:physiology; D019069:Cell Respiration / Q000235:genetics; D004734:Energy Metabolism / Q000235:genetics / Q000502:physiology; D050356:Lipid Metabolism / Q000235:genetics / Q000502:physiology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008817:Mice, Mutant Strains; D008931:Mitochondria, Muscle / Q000235:genetics* / Q000502:physiology; D018482:Muscle, Skeletal / Q000166:cytology / Q000502:physiology*; D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; D015534:Trans-Activators / Q000096:biosynthesis* / Q000235:genetics* / Q000502:physiology; D014157:Transcription Factors
chemical_list: D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; C485290:Ppargc1a protein, mouse; D015534:Trans-Activators; D014157:Transcription Factors