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

Zhenji Gan, Eileen M. Burkart-Hartman, Dong Ho Han, Brian Finck, Teresa C. Leone, Emily Y. Smith, Julio E. Ayala, John Holloszy, Daniel P. Kelly

Research output: Contribution to journalArticlepeer-review

107 Scopus citations


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 (PPARa; muscle creatine kinase [MCK]-PPARα) or PPARβ/δ (MCK-PPARb/d). 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 PPARa, 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.

Original languageEnglish
Pages (from-to)2619-2630
Number of pages12
JournalGenes and Development
Issue number24
StatePublished - Dec 15 2011


  • Exercise
  • Gene regulation
  • Glucose metabolism
  • Muscle
  • Nuclear receptors


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