| First Author | Pérez-Schindler J | Year | 2012 |
| Journal | Mol Cell Biol | Volume | 32 |
| Issue | 24 | Pages | 4913-24 |
| PubMed ID | 23028049 | Mgi Jnum | J:192729 |
| Mgi Id | MGI:5466419 | Doi | 10.1128/MCB.00877-12 |
| Citation | Perez-Schindler J, et al. (2012) The corepressor NCoR1 antagonizes PGC-1alpha and estrogen-related receptor alpha in the regulation of skeletal muscle function and oxidative metabolism. Mol Cell Biol 32(24):4913-24 |
| abstractText | 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 (PPARgamma) coactivator 1alpha (PGC-1alpha) overexpression on oxidative metabolism in muscle. Importantly, PPARbeta/delta and estrogen-related receptor alpha (ERRalpha) were identified as common targets of NCoR1 and PGC-1alpha 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-1alpha-mediated coactivation of ERRalpha. 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. |
