May M. Chen

A Role for the Transcriptional Coactivator PGC-1α in Muscle Refueling

The transcriptional coactivator peroxisome proliferator-activated receptor γ coactivator-1α (PGC-1α) has been identified as an inducible regulator of mitochondrial function. Skeletal muscle PGC-1α 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-1α gain-of-function and constitutive, generalized, loss-of-function mice. Forced expression of PGC-1α increased muscle glucose uptake concomitant with augmentation of glycogen stores, a metabolic response similar to post-exercise recovery. Induction of muscle PGC-1α expression prevented muscle glycogen depletion during exercise. Conversely, PGC-1α-deficient animals exhibited reduced rates of muscle glycogen repletion post-exercise. PGC-1α 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 α. These findings identify PGC-1α as a critical regulator of skeletal muscle fuel stores.

A High Fat Diet Impairs Stimulation of Glucose Transport in Muscle FUNCTIONAL EVALUATION OF POTENTIAL MECHANISMS

A high fat diet causes resistance of skeletal muscle glucose transport to insulin and contractions. We tested the hypothesis that fat feeding causes a change in plasma membrane composition that interferes with functioning of glucose transporters and/or insulin receptors. Epitrochlearis muscles of rats fed a high (50% of calories) fat diet for 8 weeks showed ∼50% decreases in insulin- and contraction-stimulated 3-O-methylglucose transport. Similar decreases in stimulated glucose transport activity occurred in muscles of wild-type mice with 4 weeks of fat feeding. In contrast, GLUT1 overexpressing muscles of transgenic mice fed a high fat diet showed no decreases in their high rates of glucose transport, providing evidence against impaired glucose transporter function. Insulin-stimulated system A amino acid transport, insulin receptor (IR) tyrosine kinase activity, and insulin-stimulated IR and IRS-1 tyrosine phosphorylation were all normal in muscles of rats fed the high fat diet for 8 weeks. However, after 30 weeks on the high fat diet, there was a significant reduction in insulin-stimulated tyrosine phosphorylation in muscle. The increases in GLUT4 at the cell surface induced by insulin or muscle contractions, measured with the 3H-labeled 2-N-4-(1-azi-2,2,2-trifluoroethyl)-benzoyl-1,3-bis-(d-mannose-4-yloxy)-2-propylamine photolabel, were 26–36% smaller in muscles of the 8-week high fat-fed rats as compared with control rats. Our findings provide evidence that (a) impairment of muscle glucose transport by 8 weeks of high fat feeding is not due to plasma membrane composition-related reductions in glucose transporter or insulin receptor function, (b) a defect in insulin receptor signaling is a late event, not a primary cause, of the muscle insulin resistance induced by fat feeding, and (c) impaired GLUT4 translocation to the cell surface plays a major role in the decrease in stimulated glucose transport.