The corepressor NCoR1 antagonizes PGC-1α and estrogen-related receptor α in the regulation of skeletal muscle function and oxidative metabolism

Mol Cell Biol. 2012 Dec;32(24):4913-24. doi: 10.1128/MCB.00877-12. Epub 2012 Oct 1.

Abstract

Skeletal muscle exhibits a high plasticity and accordingly can quickly adapt to different physiological and pathological stimuli by changing its phenotype largely through diverse epigenetic mechanisms. The nuclear receptor corepressor 1 (NCoR1) has the ability to mediate gene repression; however, its role in regulating biological programs in skeletal muscle is still poorly understood. We therefore studied the mechanistic and functional aspects of NCoR1 function in this tissue. NCoR1 muscle-specific knockout mice exhibited a 7.2% higher peak oxygen consumption (VO(2peak)), a 11% reduction in maximal isometric force, and increased ex vivo fatigue resistance during maximal stimulation. Interestingly, global gene expression analysis revealed a high overlap between the effects of NCoR1 deletion and peroxisome proliferator-activated receptor gamma (PPARγ) coactivator 1α (PGC-1α) overexpression on oxidative metabolism in muscle. Importantly, PPARβ/δ and estrogen-related receptor α (ERRα) were identified as common targets of NCoR1 and PGC-1α with opposing effects on the transcriptional activity of these nuclear receptors. In fact, the repressive effect of NCoR1 on oxidative phosphorylation gene expression specifically antagonizes PGC-1α-mediated coactivation of ERRα. We therefore delineated the molecular mechanism by which a transcriptional network controlled by corepressor and coactivator proteins determines the metabolic properties of skeletal muscle, thus representing a potential therapeutic target for metabolic diseases.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Male
  • Mice
  • Mice, Knockout
  • Mice, Transgenic
  • Models, Biological
  • Muscle Contraction / genetics
  • Muscle Contraction / physiology
  • Muscle, Skeletal / metabolism
  • Muscle, Skeletal / physiology*
  • Nuclear Receptor Co-Repressor 1 / deficiency
  • Nuclear Receptor Co-Repressor 1 / genetics
  • Nuclear Receptor Co-Repressor 1 / metabolism*
  • Oxidative Phosphorylation
  • Oxygen Consumption
  • PPAR delta / metabolism
  • PPAR-beta / metabolism
  • Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha
  • RNA, Messenger / genetics
  • RNA, Messenger / metabolism
  • Receptors, Estrogen / antagonists & inhibitors
  • Receptors, Estrogen / genetics
  • Receptors, Estrogen / metabolism*
  • Trans-Activators / antagonists & inhibitors
  • Trans-Activators / genetics
  • Trans-Activators / metabolism*
  • Transcription Factors

Substances

  • ERRalpha estrogen-related receptor
  • Ncor1 protein, mouse
  • Nuclear Receptor Co-Repressor 1
  • PPAR delta
  • PPAR-beta
  • Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha
  • Ppargc1a protein, mouse
  • RNA, Messenger
  • Receptors, Estrogen
  • Trans-Activators
  • Transcription Factors