title: The corepressor NCoR1 antagonizes PGC-1α and estrogen-related receptor α 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 (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.
authors.affiliation: Biozentrum, University of Basel, Basel, Switzerland.
authors.forename: Joaquín
authors.initials: J
authors.lastname: Pérez-Schindler
authors.forename: Serge
authors.initials: S
authors.lastname: Summermatter
authors.forename: Silvia
authors.initials: S
authors.lastname: Salatino
authors.forename: Francesco
authors.initials: F
authors.lastname: Zorzato
authors.forename: Markus
authors.initials: M
authors.lastname: Beer
authors.forename: Piotr J
authors.initials: PJ
authors.lastname: Balwierz
authors.forename: Erik
authors.initials: E
authors.lastname: van Nimwegen
authors.forename: Jérôme N
authors.initials: JN
authors.lastname: Feige
authors.forename: Johan
authors.initials: J
authors.lastname: Auwerx
authors.forename: Christoph
authors.initials: C
authors.lastname: Handschin
mesh_terms: D000818:Animals; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D008822:Mice, Transgenic; D008954:Models, Biological; D009119:Muscle Contraction / Q000235:genetics / Q000502:physiology; D018482:Muscle, Skeletal / Q000378:metabolism / Q000502:physiology*; D056971:Nuclear Receptor Co-Repressor 1 / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D010085:Oxidative Phosphorylation; D010101:Oxygen Consumption; D047494:PPAR delta / Q000378:metabolism; D048068:PPAR-beta / Q000378:metabolism; D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D011960:Receptors, Estrogen / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D015534:Trans-Activators / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D014157:Transcription Factors; D000097983:ERRalpha Estrogen-Related Receptor
chemical_list: D056971:Nuclear Receptor Co-Repressor 1; D047494:PPAR delta; D048068:PPAR-beta; D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; D012333:RNA, Messenger; D011960:Receptors, Estrogen; D015534:Trans-Activators; D014157:Transcription Factors; D000097983:ERRalpha Estrogen-Related Receptor; C539128:Ncor1 protein, mouse; C485290:Ppargc1a protein, mouse