NCoR1 Is a Conserved Physiological Modulator of Muscle Mass and Oxidative Function

• Published in: Cell Vol. 147; no. 4; pp. 827 - 839
• Main Authors: Yamamoto, Hiroyasu, Williams, Evan G., Mouchiroud, Laurent, Cantó, Carles, Fan, Weiwei, Downes, Michael, Héligon, Christophe, Barish, Grant D., Desvergne, Béatrice, Evans, Ronald M., Schoonjans, Kristina, Auwerx, Johan
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 11.11.2011
• Subjects: aerobiosis; Animals; Caenorhabditis elegans - metabolism; Caenorhabditis elegans Proteins - genetics; Caenorhabditis elegans Proteins - metabolism; exercise; Gene Deletion; gene expression regulation; Gene Knockdown Techniques; Humans; lipid metabolism; Mice; mitochondria; Mitochondria, Muscle - metabolism; Muscle Development; muscle physiology; Muscle, Skeletal - metabolism; muscles; Nuclear Receptor Co-Repressor 1 - genetics; Nuclear Receptor Co-Repressor 1 - metabolism; Physical Conditioning, Animal; PPAR delta - metabolism; PPAR-beta - metabolism; transcription (genetics); transcription factors
• ISSN: 0092-8674; 1097-4172
• DOI: 10.1016/j.cell.2011.10.017

Transcriptional coregulators control the activity of many transcription factors and are thought to have wide-ranging effects on gene expression patterns. We show here that muscle-specific loss of nuclear receptor corepressor 1 (NCoR1) in mice leads to enhanced exercise endurance due to an increase of both muscle mass and of mitochondrial number and activity. The activation of selected transcription factors that control muscle function, such as MEF2, PPARβ/δ, and ERRs, underpins these phenotypic alterations. NCoR1 levels are decreased in conditions that require fat oxidation, resetting transcriptional programs to boost oxidative metabolism. Knockdown of gei-8, the sole C. elegans NCoR homolog, also robustly increased muscle mitochondria and respiration, suggesting conservation of NCoR1 function. Collectively, our data suggest that NCoR1 plays an adaptive role in muscle physiology and that interference with NCoR1 action could be used to improve muscle function. [Display omitted] ► Muscle mass and oxidative capacity increase in muscle-specific NCoR1 −/− mice ► NCoR1 modulates the activity of transcription factors MEF2, PPARβ/δ, and ERRs ► NCoR1 levels are reduced by physiological conditions that favor fat oxidation ► NCoR1 impact on muscle function is conserved in C. elegans Exercise capacity and mitochondrial oxidation are enhanced by the loss of a transcriptional cofactor in muscle cells through modulation of a select set of transcription factors that includes PPARβ/δ.