Enhanced lipid-but not carbohydrate-supported mitochondrial respiration in skeletal muscle of PGC-1 alpha overexpressing mice

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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) gamma co-activator 1alpha (PGC-1alpha), a major player in the regulation of skeletal muscle mitochondrial metabolism. However, it is currently unknown whether PGC-1alpha, besides stimulating mitochondrial proliferation, also affects the functional capacity per mitochondrion. Therefore, we here tested whether PGC-1alpha overexpression, besides increasing mitochondrial content, also leads to intrinsic mitochondrial adaptations. Skeletal muscle mitochondria from 10 male, muscle-specific PGC-1alpha overexpressing mice (PGC-1alphaTg) 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-1alphaTg 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-1alphaTg mitochondria (p = 0.02) and this was accompanied by a blunted reduction in mitochondrial ROS production upon fatty acids in PGC-1alphaTg vs. WT mitochondria (p = 0.04). Uncoupling protein 3 (UCP3) levels were markedly reduced in PGC-1alphaTg mitochondria (p < 0.001). Taken together, in addition to stimulating mitochondrial proliferation in skeletal muscle, we show here that overexpression of PGC-1alpha leads to intrinsic mitochondrial adaptations that seem restricted to fat metabolism. J. Cell. Physiol. (c) 2011 Wiley-Liss, Inc.
Original languageEnglish
Pages (from-to)1026-1033
Number of pages8
JournalJournal of Cellular Physiology
Volume227
Issue number3
DOIs
Publication statusPublished - Mar 2012

Keywords

  • UNCOUPLING PROTEINS UCP2
  • FATTY-ACID
  • OXIDATIVE-PHOSPHORYLATION
  • INSULIN SENSITIVITY
  • ROS PRODUCTION
  • EXPRESSION
  • COPD
  • DYSFUNCTION
  • SUPEROXIDE
  • METABOLISM

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