Hoeks 2012 J Cell Physiol
|Hoeks J, Arany Z, Phielix E, Moonen-Kornips E, Hesselink MK, Schrauwen P (2012) Enhanced lipid -but not carbohydrate- supported mitochondrial respiration in skeletal muscle of PGC-1α overexpressing mice. J Cell Physiol 227:1026-33.|
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 fatty acids in PGC-1αTg vs. 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.
• Keywords: Skeletal muscle, Mitochondria, Fat metabolism, ROS, Mitochondrial uncoupling
• O2k-Network Lab: NL Maastricht Schrauwen P
Labels: MiParea: Respiration
Stress:Oxidative stress;RONS Organism: Mouse Tissue;cell: Skeletal muscle Preparation: Isolated mitochondria
Coupling state: LEAK, OXPHOS, ET Pathway: F, N HRR: Oxygraph-2k