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

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) ? co-activator 1a (PGC-1a), a major player in the regulation of skeletal muscle mitochondrial metabolism. However, it is currently unknown whether PGC-1a, besides stimulating mitochondrial proliferation, also affects the functional capacity per mitochondrion. Therefore, we here tested whether PGC-1a overexpression, besides increasing mitochondrial content, also leads to intrinsic mitochondrial adaptations. Skeletal muscle mitochondria from 10 male, muscle-specific PGC-1a overexpressing mice (PGC-1aTg) 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-1aTg 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-1aTg mitochondria (P=0.02) and this was accompanied by a blunted reduction in mitochondrial ROS production upon FAs in PGC-1aTg versus WT mitochondria (P=0.04). Uncoupling protein 3 (UCP3) levels were markedly reduced in PGC-1aTg mitochondria (P<0.001). Taken together, in addition to stimulating mitochondrial proliferation in skeletal muscle, we show here that overexpression of PGC-1a leads to intrinsic mitochondrial adaptations that seem restricted to fat metabolism. J. Cell. Physiol. 227: 10261033, 2012. (C) 2011 Wiley Periodicals, Inc.