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

Abstract

Overexpression of the transcriptional coactivator peroxisome proliferator-activated receptor gamma coactivator 1alpha (PGC-1alpha), like exercise, increases mitochondrial content and inhibits muscle atrophy. To understand these actions, we tested whether PGC-1alpha or its close homolog, PGC-1beta, 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-1alpha or PGC-1beta 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-1beta (like PGC-1alpha) inhibited denervation atrophy, ubiquitin ligase induction, and transcription by NFkappaB. However, increasing muscle PGC-1alpha 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-1alpha and PGC-1beta to inhibit FoxO3 and NFkappaB actions and proteolysis helps explain how exercise prevents muscle atrophy.