The nuclear receptor PPARbeta/delta programs muscle glucose metabolism in cooperation with AMPK and MEF2.

摘要

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 alpha (PPARalpha; muscle creatine kinase [MCK]-PPARalpha) or PPARbeta/delta (MCK-PPARbeta/delta). MCK-PPARbeta/delta mice are known to have enhanced exercise performance, whereas MCK-PPARalpha mice perform at low levels. Transcriptional profiling revealed that the lactate dehydrogenase b (Ldhb)/Ldha gene expression ratio is increased in MCK-PPARbeta/delta muscle, an isoenzyme shift that diverts pyruvate into the mitochondrion for the final steps of glucose oxidation. PPARbeta/delta gain- and loss-of-function studies in skeletal myotubes demonstrated that PPARbeta/delta, but not PPARalpha, 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 PPARbeta/delta ligand-independent manner. MCK-PPARbeta/delta 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-PPARbeta/delta 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.