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The Corepressor NCoR1 Antagonizes PGC-1α and Estrogen-Related Receptor α in the Regulation of Skeletal Muscle Function and Oxidative Metabolism

Pérez-Schindler, Joaquín and Summermatter, Serge and Salatino, Silvia and Zorzato, Francesco and Beer, Markus and Balwierz, Piotr J. and van Nimwegen, Erik and Feige, Jérôme N. and Auwerx, Johan and Handschin, Christoph. (2012) The Corepressor NCoR1 Antagonizes PGC-1α and Estrogen-Related Receptor α in the Regulation of Skeletal Muscle Function and Oxidative Metabolism. Molecular and cellular biology, Vol. 32, H. 24. pp. 4913-4924.

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Official URL: http://edoc.unibas.ch/dok/A6056053

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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.
Faculties and Departments:05 Faculty of Science > Departement Biozentrum > Computational & Systems Biology > Bioinformatics (van Nimwegen)
05 Faculty of Science > Departement Biozentrum > Growth & Development > Growth & Development (Handschin)
03 Faculty of Medicine > Departement Biomedizin > Associated Research Groups > Pharmakologie (Handschin)
UniBasel Contributors:van Nimwegen, Erik and Handschin, Christoph
Item Type:Article, refereed
Article Subtype:Research Article
Bibsysno:Link to catalogue
Publisher:American Society for Microbiology
ISSN:1098-5549
Note:Publication type according to Uni Basel Research Database: Journal article
Language:English
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Last Modified:31 Dec 2015 10:51
Deposited On:01 Feb 2013 08:41

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