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

TY - JOUR

T1 - PGC-1α is required for AICAR induced expression of GLUT4 and mitochondrial proteins in mouse skeletal muscle

AU - Leick, Lotte

AU - Fentz, Joachim

AU - Biensø, Rasmus S.

AU - Knudsen, Jakob G.

AU - Jeppesen, Jacob

AU - Kiens, Bente

AU - Wojtaszewski, Jørgen

AU - Pilegaard, Henriette

N1 - CURIS 2010 5200 086

PY - 2010/9

Y1 - 2010/9

N2 - 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-γ coactivator-1α (PGC-1α)-dependent mechanism. Whole body PGC-1α-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 ∼10-40% relative to saline in white muscles of WT but not of PGC-1α-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-1α-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-1α. The hexokinase II (HKII) mRNA and protein response was similar in muscles of WT and PGC-1α-KO mice after single and repeated AICAR treatments, respectively, confirming that HKII is regulated independently of PGC-1α in response to AICAR. In conclusion, here we provide genetic evidence for a role of PGC-1α in AMPK-mediated regulation of mitochondrial and glucose membrane transport protein expression in skeletal muscle.

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

U2 - 10.1152/ajpendo.00648.2009

DO - 10.1152/ajpendo.00648.2009

M3 - Journal article

C2 - 20628026

SN - 0193-1849

VL - 299

SP - E456-E465

JO - American Journal of Physiology: Endocrinology and Metabolism

JF - American Journal of Physiology: Endocrinology and Metabolism

IS - 3

ER -