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

Genes Dev. 2011 Dec 15;25(24):2619-30. doi: 10.1101/gad.178434.111. Epub 2011 Dec 1.

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

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cells, Cultured
  • Female
  • Glucose / metabolism*
  • Lactate Dehydrogenases / genetics
  • Lactate Dehydrogenases / metabolism
  • Male
  • Mice
  • Muscle, Skeletal / enzymology
  • Muscle, Skeletal / metabolism*
  • Myogenic Regulatory Factors / metabolism*
  • Oxidation-Reduction
  • PPAR alpha / metabolism
  • PPAR delta / metabolism*
  • Physical Conditioning, Animal
  • Protein Kinases / metabolism*
  • Transcriptional Activation

Substances

  • Myogenic Regulatory Factors
  • PPAR alpha
  • PPAR delta
  • Lactate Dehydrogenases
  • Protein Kinases
  • AMP-activated protein kinase kinase
  • Glucose