The nuclear receptor PPARβ/δ programs muscle glucose metabolism in cooperation with AMPK and MEF2

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