Total Skeletal Muscle PGC-1 Deficiency Uncouples Mitochondrial Derangements from Fiber Type Determination and Insulin Sensitivity

• DOI: 10.1016/j.cmet.2010.11.008
• Publication Date: 2010-12-02T09:51:44Z
• Authors: Christoph Zechner; Ling Lai; Juliet F. Zechner; Tuoyu Geng; Zhen Yan; John W. Rumsey; Deanna Collia; Zhouji Chen; David F. Wozniak; Teresa C. Leone; Daniel P. Kelly
• Keywords: Mice, Knockout; Analysis of Variance; Physiology; Gene Expression Profiling; Cell Biology; Glucose Tolerance Test; Polymerase Chain Reaction; Mitochondria; Mice; Microscopy, Electron; Oxygen Consumption; Physical Conditioning, Animal; Animals; Insulin Resistance; Muscle, Skeletal; Molecular Biology; Transcription Factors

Evidence is emerging that the PGC-1 coactivators serve a critical role in skeletal muscle metabolism, function, and disease. Mice with total PGC-1 deficiency in skeletal muscle (PGC-1α(-/-)β(f/f/MLC-Cre) mice) were generated and characterized. PGC-1α(-/-)β(f/f/MLC-Cre) mice exhibit a dramatic reduction in exercise performance compared to single PGC-1α- or PGC-1β-deficient mice and wild-type controls. The exercise phenotype of the PGC-1α(-/-)β(f/f/MLC-Cre) mice was associated with a marked diminution in muscle oxidative capacity, together with rapid depletion of muscle glycogen stores. In addition, the PGC-1α/β-deficient muscle exhibited mitochondrial structural derangements consistent with fusion/fission and biogenic defects. Surprisingly, the proportion of oxidative muscle fiber types (I, IIa) was not reduced in the PGC-1α(-/-)β(f/f/MLC-Cre) mice. Moreover, insulin sensitivity and glucose tolerance were not altered in the PGC-1α(-/-)β(f/f/MLC-Cre) mice. Taken together, we conclude that PGC-1 coactivators are necessary for the oxidative and mitochondrial programs of skeletal muscle but are dispensable for fundamental fiber type determination and insulin sensitivity.