Peroxisome Proliferator-activated Receptor γ Coactivator 1α or 1β Overexpression Inhibits Muscle Protein Degradation, Induction of Ubiquitin Ligases, and Disuse Atrophy

Overexpression of the transcriptional coactivator peroxisome proliferator-activated receptor gamma coactivator 1 alpha (PGC-1 alpha), like exercise, increases mitochondrial content and inhibits muscle atrophy. To understand these actions, we tested whether PGC-1 alpha or its close homolog, PGC-1 alpha, influences muscle protein turnover. In myotubes, overexpression of either coactivator increased protein content by decreasing overall protein degradation without altering protein synthesis rates. Elevated PGC-1 alpha or PGC-1 alpha also prevented the acceleration of proteolysis induced by starvation or FoxO transcription factors and prevented the induction of autophagy and atrophy-specific ubiquitin ligases by a constitutively active FoxO3. In mouse muscles, overexpression of PGC-1 alpha (like PGC-1 alpha) inhibited denervation atrophy, ubiquitin ligase induction, and transcription by NF kappa B. However, increasing muscle PGC-1 alpha levels pharmacologically by treatment of mice with 5-aminoimidazole-4-carboxamide 1-beta-D-ribofuranoside failed to block loss of muscle mass or induction of ubiquitin ligases upon denervation atrophy, although it prevented loss of mitochondria. This capacity of PGC-1 alpha and PGC-1 alpha to inhibit FoxO3 and NF kappa B actions and proteolysis helps explain how exercise prevents muscle atrophy.