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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-1alpha (PGC-1alpha)-dependent mechanism. Whole body PGC-1alpha-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 approximately 10-40% relative to saline in white muscles of WT but not of PGC-1alpha-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-1alpha-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-1alpha. The hexokinase II (HKII) mRNA and protein response was similar in muscles of WT and PGC-1alpha-KO mice after single and repeated AICAR treatments, respectively, confirming that HKII is regulated independently of PGC-1alpha in response to AICAR. In conclusion, here we provide genetic evidence for a role of PGC-1alpha in AMPK-mediated regulation of mitochondrial and glucose membrane transport protein expression in skeletal muscle.

Original publication

DOI

10.1152/ajpendo.00648.2009

Type

Journal article

Journal

Am J Physiol Endocrinol Metab

Publication Date

09/2010

Volume

299

Pages

E456 - E465

Keywords

Adenylate Kinase, Aminoimidazole Carboxamide, Animals, Antigens, CD36, Blood Glucose, Blotting, Western, Electron Transport Complex IV, Enzyme Activation, Female, Glucose Transporter Type 4, Glycogen, Male, Mice, Mice, Knockout, Muscle, Skeletal, Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha, Phosphorylation, RNA, Messenger, Reverse Transcriptase Polymerase Chain Reaction, Ribonucleotides, Trans-Activators, Transcription Factors