title: The nuclear receptor PPARβ/δ 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 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.
authors.affiliation: Diabetes and Obesity Research Center, Sanford-Burnham Medical Research Institute, Orlando, Florida 32827, USA. dkelly@sanfordburnham.org
authors.forename: Zhenji
authors.initials: Z
authors.lastname: Gan
authors.forename: Eileen M
authors.initials: EM
authors.lastname: Burkart-Hartman
authors.forename: Dong-Ho
authors.initials: DH
authors.lastname: Han
authors.forename: Brian
authors.initials: B
authors.lastname: Finck
authors.forename: Teresa C
authors.initials: TC
authors.lastname: Leone
authors.forename: Emily Y
authors.initials: EY
authors.lastname: Smith
authors.forename: Julio E
authors.initials: JE
authors.lastname: Ayala
authors.forename: John
authors.initials: J
authors.lastname: Holloszy
authors.forename: Daniel P
authors.initials: DP
authors.lastname: Kelly
mesh_terms: D000091162:AMP-Activated Protein Kinase Kinases; D000818:Animals; D002478:Cells, Cultured; D005260:Female; D005947:Glucose / Q000378:metabolism*; D045022:Lactate Dehydrogenases / Q000235:genetics / Q000378:metabolism; D008297:Male; D051379:Mice; D018482:Muscle, Skeletal / Q000201:enzymology / Q000378:metabolism*; D018006:Myogenic Regulatory Factors / Q000378:metabolism*; D010084:Oxidation-Reduction; D047493:PPAR alpha / Q000378:metabolism; D047494:PPAR delta / Q000378:metabolism*; D010805:Physical Conditioning, Animal; D011494:Protein Kinases / Q000378:metabolism*; D015533:Transcriptional Activation
chemical_list: D018006:Myogenic Regulatory Factors; D047493:PPAR alpha; D047494:PPAR delta; D045022:Lactate Dehydrogenases; D011494:Protein Kinases; D000091162:AMP-Activated Protein Kinase Kinases; D005947:Glucose