PGC-1α is required for AICAR-induced expression of GLUT4 and mitochondrial proteins in mouse skeletal muscle

Leick L, Fentz J, Bienso RS, Knudsen JG, Jeppesen J, Kiens B, Wojtaszewski JF, Pilegaard H. PGC-1 alpha is required for AICAR-induced expression of GLUT4 and mitochondrial proteins in mouse skeletal muscle. Am J Physiol Endocrinol Metab 299: E456-E465, 2010. First published July 13, 2010; doi:10.1152/ajpendo.00648.2009.-We tested the hypothesis that repeated activation of AMP-activated protein kinase (AMPK) induces mitochondrial and glucose membrane transporter mRNA/protein expression via a peroxisome proliferator-activated receptor-gamma coactivator-1 alpha (PGC-1 alpha)-dependent mechanism. Whole body PGC-1 alpha-knockout (KO) and littermate wild-type (WT) mice were given either single or repeated subcutaneous injections of the AMPK activator AICAR or saline. Skeletal muscles were removed either 1 or 4 h after the single AICAR treatment or 24 h after the last injection following repeated AICAR treatment. Repeated AICAR treatment increased GLUT4, cytochrome (cyt) c oxidase I, and (cyt) c protein expression similar to 10-40% relative to saline in white muscles of WT but not of PGC-1 alpha-KO mice, whereas fatty acid translocase/CD36 (FAT/CD36) protein expression was unaffected by AICAR treatment in both genotypes. GLUT4, cyt c, and FAT/CD36 mRNA content increased 30-60% 4 h after a single AICAR injection relative to saline in WT, and FAT/CD36 mRNA content decreased in PGC-1 alpha-KO mice. One hour after a single AICAR treatment, phosphorylation of AMPK and the downstream target acetyl-coenzyme A carboxylase increased in all muscles investigated independent of genotype, indicating normal AICAR-induced AMPK signaling in the absence of PGC-1 alpha. The hexokinase II (HKII) mRNA and protein response was similar in muscles of WT and PGC-1 alpha-KO mice after single and repeated AICAR treatments, respectively, confirming that HKII is regulated independently of PGC-1 alpha in response to AICAR. In conclusion, here we provide genetic evidence for a role of PGC-1 alpha in AMPK-mediated regulation of mitochondrial and glucose membrane transport protein expression in skeletal muscle.