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

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 (PPAR?) coactivator 1? (PGC-1?) overexpression on oxidative metabolism in muscle. Importantly, PPAR?/? and estrogen-related receptor ? (ERR?) were identified as common targets of NCoR1 and PGC-1? 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-1?-mediated coactivation of ERR?. 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.

SUBMITTER: Perez-Schindler J 

PROVIDER: S-EPMC3510532 | biostudies-literature | 2012 Dec

REPOSITORIES: biostudies-literature