The nuclear receptor PPAR?/? programs muscle glucose metabolism in cooperation with AMPK and MEF2.

ABSTRACT: To identify new gene regulatory pathways controlling skeletal muscle energy metabolism, comparative studies were conducted on muscle-specific transgenic mouse lines expressing the nuclear receptors peroxisome proliferator-activated receptor ? (PPAR?; muscle creatine kinase [MCK]-PPAR?) or PPAR?/? (MCK-PPAR?/?). MCK-PPAR?/? mice are known to have enhanced exercise performance, whereas MCK-PPAR? mice perform at low levels. Transcriptional profiling revealed that the lactate dehydrogenase b (Ldhb)/Ldha gene expression ratio is increased in MCK-PPAR?/? muscle, an isoenzyme shift that diverts pyruvate into the mitochondrion for the final steps of glucose oxidation. PPAR?/? gain- and loss-of-function studies in skeletal myotubes demonstrated that PPAR?/?, but not PPAR?, interacts with the exercise-inducible kinase AMP-activated protein kinase (AMPK) to synergistically activate Ldhb gene transcription by cooperating with myocyte enhancer factor 2A (MEF2A) in a PPAR?/? ligand-independent manner. MCK-PPAR?/? muscle was shown to have high glycogen stores, increased levels of GLUT4, and augmented capacity for mitochondrial pyruvate oxidation, suggesting a broad reprogramming of glucose utilization pathways. Lastly, exercise studies demonstrated that MCK-PPAR?/? mice persistently oxidized glucose compared with nontransgenic controls, while exhibiting supranormal performance. These results identify a transcriptional regulatory mechanism that increases capacity for muscle glucose utilization in a pattern that resembles the effects of exercise training.

SUBMITTER: Gan Z 

PROVIDER: S-EPMC3248683 | biostudies-literature | 2011 Dec

REPOSITORIES: biostudies-literature