PGC-1α and fasting-induced PDH regulation in mouse skeletal muscle

The purpose of the present study was to examine whether lack of skeletal muscle peroxisome proliferator-activated receptor gamma coactivator 1 alpha (PGC-1 alpha) affects the switch in substrate utilization from a fed to fasted state and the fasting-induced pyruvate dehydrogenase (PDH) regulation in skeletal muscle. Skeletal muscle-specific PGC-1 alpha knockout (MKO) mice and floxed littermate controls were fed or fasted for 24h. Fasting reduced PDHa activity, increased phosphorylation of all four known sites on PDH-E1 alpha and increased pyruvate dehydrogenase kinase (PDK4) and sirtuin 3 (SIRT3) protein levels, but did not alter total acetylation of PDH-E1 alpha. Lack of muscle PGC-1 alpha did not affect the switch from glucose to fat oxidation in the transition from the fed to fasted state, but was associated with lower and higher respiratory exchange ratio (RER) in the fed and fasted state, respectively. PGC-1 alpha MKO mice had lower skeletal muscle PDH-E1 alpha, PDK1, 2, 4, and pyruvate dehydrogenase phosphatase (PDP1) protein content than controls, but this did not prevent the fasting-induced increase in PDH-E1 alpha phosphorylation in PGC-1 alpha MKO mice. However, lack of skeletal muscle PGC-1 alpha reduced SIRT3 protein content, increased total lysine PDH-E1 alpha acetylation in the fed state, and prevented a fasting-induced increase in SIRT3 protein. In conclusion, skeletal muscle PGC-1 alpha is required for fasting-induced upregulation of skeletal muscle SIRT3 and maintaining high fat oxidation in the fasted state, but is dispensable for preserving the capability to switch substrate during the transition from the fed to the fasted state and for fasting-induced PDH regulation in skeletal muscle.