A role for the transcriptional coactivator PGC-1α in muscle refueling

The transcriptional coactivator peroxisome proliferator-activated receptor gamma coactivator-1 alpha(PGC-1 alpha) has been identified as an inducible regulator of mitochondrial function. Skeletal muscle PGC-1 alpha expression is induced post-exercise. Therefore, we sought to determine its role in the regulation of muscle fuel metabolism. Studies were performed using conditional, muscle-specific, PGC-1 alpha gain-of-function and constitutive, generalized, loss-of-function mice. Forced expression of PGC-1 alpha increased muscle glucose uptake concomitant with augmentation of glycogen stores, a metabolic response similar to post-exercise recovery. Induction of muscle PGC-1 alpha expression prevented muscle glycogen depletion during exercise. Conversely, PGC-1 alpha-deficient animals exhibited reduced rates of muscle glycogen repletion post-exercise. PGC-1 alpha was shown to increase muscle glycogen stores via several mechanisms including stimulation of glucose import, suppression of glycolytic flux, and by down-regulation of the expression of glycogen phosphorylase and its activating kinase, phosphorylase kinase alpha. These findings identify PGC-1 alpha as a critical regulator of skeletal muscle fuel stores.