NCoR1 is a conserved physiological modulator of muscle mass and oxidative function

Hiroyasu Yamamoto; Evan G. Williams; Laurent Mouchiroud; Carles Cantó; Weiwei Fan; Michael Downes; Christophe Héligon; Grant D. Barish; Béatrice Desvergne; Ronald M. Evans; Kristina Schoonjans; Johan Auwerx

doi:10.1016/j.cell.2011.10.017

NCoR1 is a conserved physiological modulator of muscle mass and oxidative function

Hiroyasu Yamamoto, Evan G. Williams, Laurent Mouchiroud, Carles Cantó, Weiwei Fan, Michael Downes, Christophe Héligon, Grant D. Barish, Béatrice Desvergne, Ronald M. Evans, Kristina Schoonjans, Johan Auwerx^*

^*Corresponding author for this work

Medicine, Endocrinology Division

Research output: Contribution to journal › Article › peer-review

210 Scopus citations

Abstract

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.

Original language	English (US)
Pages (from-to)	827-839
Number of pages	13
Journal	Cell
Volume	147
Issue number	4
DOIs	https://doi.org/10.1016/j.cell.2011.10.017
State	Published - Nov 11 2011

Funding

We acknowledge M. Lazar (University of Pennsylvania, Philadelphia), A. Kralli (Scripps Research Institute, San Diego), J.-S. Annicotte and L. Fajas (Institut de G\u00E9n\u00E9tique Mol\u00E9culaire de Montpellier, France), A. Lusis (University of California, Los Angeles), K. Schughart (Helmholtz Zentrum, Hannover, Germany), R. Williams (University of Tennessee Health Science Center, Memphis), and the Caenorhabditis Genetics Center (CGC) for generous sharing of research reagents and data. We thank N. Messadeq (Institut Clinique de la Souris, Strasbourg, France) for EM analysis and the Center for PhenoGenomics (CPG) at the EPFL for help with mouse phenotyping. This work was supported by the \u00C9cole Polytechnique F\u00E9d\u00E9rale de Lausanne, Swiss National Science Foundation, NIH (DK059820 to J.A., DK062434 to R.M.E., 1K08HL092298 to G.D.B., HD027183 to R.M.E., and DK057978 to R.M.E.), the EU ideas program (ERC-2008-AdG-23118), the Helmsley Charitable Trust, the Glenn Foundation, and the Howard Hughes Medical Institute (HHMI). H.Y. was supported by an FRM fellowship. R.M.E. is an Investigator of the HHMI and the March of Dimes Chair in Molecular and Developmental Biology. J.A. is the Nestle Chair in Energy Metabolism. We thank the members of the Auwerx lab and R. Williams for discussions.

ASJC Scopus subject areas

General Biochemistry, Genetics and Molecular Biology

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@article{439eec8e720f41e699120df31c6415c5,

title = "NCoR1 is a conserved physiological modulator of muscle mass and oxidative function",

abstract = "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.",

author = "Hiroyasu Yamamoto and Williams, {Evan G.} and Laurent Mouchiroud and Carles Cant{\'o} and Weiwei Fan and Michael Downes and Christophe H{\'e}ligon and Barish, {Grant D.} and B{\'e}atrice Desvergne and Evans, {Ronald M.} and Kristina Schoonjans and Johan Auwerx",

note = "Funding Information: We acknowledge M. Lazar (University of Pennsylvania, Philadelphia), A. Kralli (Scripps Research Institute, San Diego), J.-S. Annicotte and L. Fajas (Institut de G{\'e}n{\'e}tique Mol{\'e}culaire de Montpellier, France), A. Lusis (University of California, Los Angeles), K. Schughart (Helmholtz Zentrum, Hannover, Germany), R. Williams (University of Tennessee Health Science Center, Memphis), and the Caenorhabditis Genetics Center (CGC) for generous sharing of research reagents and data. We thank N. Messadeq (Institut Clinique de la Souris, Strasbourg, France) for EM analysis and the Center for PhenoGenomics (CPG) at the EPFL for help with mouse phenotyping. This work was supported by the {\'E}cole Polytechnique F{\'e}d{\'e}rale de Lausanne, Swiss National Science Foundation, NIH (DK059820 to J.A., DK062434 to R.M.E., 1K08HL092298 to G.D.B., HD027183 to R.M.E., and DK057978 to R.M.E.), the EU ideas program (ERC-2008-AdG-23118), the Helmsley Charitable Trust, the Glenn Foundation, and the Howard Hughes Medical Institute (HHMI). H.Y. was supported by an FRM fellowship. R.M.E. is an Investigator of the HHMI and the March of Dimes Chair in Molecular and Developmental Biology. J.A. is the Nestle Chair in Energy Metabolism. We thank the members of the Auwerx lab and R. Williams for discussions. ",

year = "2011",

month = nov,

day = "11",

doi = "10.1016/j.cell.2011.10.017",

language = "English (US)",

volume = "147",

pages = "827--839",

journal = "Cell",

issn = "0092-8674",

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T1 - NCoR1 is a conserved physiological modulator of muscle mass and oxidative function

AU - Yamamoto, Hiroyasu

AU - Williams, Evan G.

AU - Mouchiroud, Laurent

AU - Cantó, Carles

AU - Fan, Weiwei

AU - Downes, Michael

AU - Héligon, Christophe

AU - Barish, Grant D.

AU - Desvergne, Béatrice

AU - Evans, Ronald M.

AU - Schoonjans, Kristina

AU - Auwerx, Johan

N1 - Funding Information: We acknowledge M. Lazar (University of Pennsylvania, Philadelphia), A. Kralli (Scripps Research Institute, San Diego), J.-S. Annicotte and L. Fajas (Institut de Génétique Moléculaire de Montpellier, France), A. Lusis (University of California, Los Angeles), K. Schughart (Helmholtz Zentrum, Hannover, Germany), R. Williams (University of Tennessee Health Science Center, Memphis), and the Caenorhabditis Genetics Center (CGC) for generous sharing of research reagents and data. We thank N. Messadeq (Institut Clinique de la Souris, Strasbourg, France) for EM analysis and the Center for PhenoGenomics (CPG) at the EPFL for help with mouse phenotyping. This work was supported by the École Polytechnique Fédérale de Lausanne, Swiss National Science Foundation, NIH (DK059820 to J.A., DK062434 to R.M.E., 1K08HL092298 to G.D.B., HD027183 to R.M.E., and DK057978 to R.M.E.), the EU ideas program (ERC-2008-AdG-23118), the Helmsley Charitable Trust, the Glenn Foundation, and the Howard Hughes Medical Institute (HHMI). H.Y. was supported by an FRM fellowship. R.M.E. is an Investigator of the HHMI and the March of Dimes Chair in Molecular and Developmental Biology. J.A. is the Nestle Chair in Energy Metabolism. We thank the members of the Auwerx lab and R. Williams for discussions.

PY - 2011/11/11

Y1 - 2011/11/11

N2 - 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.

AB - 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.

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JF - Cell

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ER -

NCoR1 is a conserved physiological modulator of muscle mass and oxidative function

Abstract

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ASJC Scopus subject areas

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