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BMP signaling controls muscle mass

Nature Genetics volume 45, pages 1309–1318 (2013)Cite this article

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Abstract

Cell size is determined by the balance between protein synthesis and degradation. This equilibrium is affected by hormones, nutrients, energy levels, mechanical stress and cytokines. Mutations that inactivate myostatin lead to excessive muscle growth in animals and humans, but the signals and pathways responsible for this hypertrophy remain largely unknown. Here we show that bone morphogenetic protein (BMP) signaling, acting through Smad1, Smad5 and Smad8 (Smad1/5/8), is the fundamental hypertrophic signal in mice. Inhibition of BMP signaling causes muscle atrophy, abolishes the hypertrophic phenotype of myostatin-deficient mice and strongly exacerbates the effects of denervation and fasting. BMP-Smad1/5/8 signaling negatively regulates a gene (Fbxo30) that encodes a ubiquitin ligase required for muscle loss, which we named muscle ubiquitin ligase of the SCF complex in atrophy-1 (MUSA1). Collectively, these data identify a critical role for the BMP pathway in adult muscle maintenance, growth and atrophy.

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Figure 1: Morphological and functional changes in the muscles of Smad4−/− mice reflect muscle atrophy and weakness.
Figure 2: Smad4−/− mice show exacerbated muscle loss and weakness under catabolic conditions.
Figure 3: BMP signaling is sufficient to induce hypertrophy and to counteract muscle atrophy.
Figure 4: BMP signaling is critical to maintain muscle mass and to prevent muscle atrophy.
Figure 5: Gdf5 (BMP14) is critical to maintain muscle mass and to prevent muscle atrophy.
Figure 6: BMP signaling mediates the hypertrophy of Mstn knockout mice and preserves muscle mass during denervation.
Figure 7: Smad4 recruitment to different promoters derives from the activity of the BMP and myostatin pathways.
Figure 8: BMP signaling negatively regulates the expression of the MUSA1 ubiquitin ligase.

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Acknowledgements

We gratefully acknowledge the critical reading of K. Dyar. We thank S.-J. Lee (Johns Hopkins University School of Medicine) for the kind gift of Mstn−/− mice and S.J. Burden (Skirball Institute, New York University Medical School) for the gift of MLC1f-Cre mice. HA-Skp1, Flag-Cul1 and Flag-Roc1 were kindly provided by S.H. Lecker. We acknowledge C. Beley and G. Precigout for AAV production. This work was supported by Telethon Italy (TCP04009), by the European Research Council (ERC; 282310-MyoPHAGY), by the European Union (MYOAGE, contract 223576 of Framework Programme 7), by the Leducq Foundation and by the Italian Ministry of Education (MiUR; PRIN 2010/2011) to M.S., by Associazione Italiana per la Ricerca sul Cancro (AIRC) Investigator grants to S.P. and S.D. and by a Comitato Promotore Telethon Grant, the AIRC Special Program Molecular Clinical Oncology “5 per Mille,” HSFP, Excellence-IIT and Epigenetics Flagship project CNR-MiUR grants to S.P., by the Association Française contre les Myopathies to H.A., E.S., A.S. and A.F., by the Agence Nationale de la Recherche to H.A. (ANR-12-BSV1-0038) and by the Deutsche Forschungsgemeinschaft and the Université Franco-Allemand (as part of the MyoGrad International Graduate School for Myology GK 1631/1 and CDFA-06-11) to S.S., H.A., A.S. and E.S. E.E. is the recipient of a CARIPARO Foundation PhD fellowship.

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Author notes

  1. Roberta Sartori and Elija Schirwis: These authors contributed equally to this work.

Authors and Affiliations

  1. Dulbecco Telethon Institute at the Venetian Institute of Molecular Medicine, Padova, Italy

    Roberta Sartori, Sergia Bortolanza & Marco Sandri

  2. Department of Biomedical Sciences, University of Padova, Padova, Italy

    Roberta Sartori, Bert Blaauw, Sergia Bortolanza, Elena Enzo, Luana Toniolo, Sirio Dupont, Stefano Piccolo & Marco Sandri

  3. Université Pierre et Marie Curie, Institut de Myologie, UMR Université Pierre et Marie Curie–Association Institut de Myologie (AIM), Unité Mixte 76, INSERM U974, CNRS UMR 7215, Paris, France

    Elija Schirwis, Amalia Stantzou, Etienne Mouisel, Arnaud Ferry & Helge Amthor

  4. UFR (Unité de Formation et de Recherche),

    Elija Schirwis, Amalia Stantzou & Helge Amthor

  5. des Sciences de la Santé, Université de Versailles Saint-Quentin-en-Yvelines, Montigny-le-Bretonneux, France

    Elija Schirwis, Amalia Stantzou & Helge Amthor

  6. Entwicklungsbiologie/Signaltransduktion, Max Delbrück Center for Molecular Medicine, Berlin, Germany

    Elija Schirwis

  7. Department of Cell Biology, Harvard Medical School, Boston, Massachusetts, USA

    Jinghui Zhao & Alfred L Goldberg

  8. Development and Disease Group, Max Planck Institute for Molecular Genetics, Berlin, Germany

    Sigmar Stricker

  9. Service Génétique Médicale, Centre Hospitalier Universitaire Necker–Enfants Malades, Université Paris Descartes, Paris, France

    Helge Amthor

  10. Institute of Neuroscience, Consiglio Nazionale delle Ricerche, Padova, Italy

    Marco Sandri

  11. Department of Medicine, McGill University, Montreal, Quebec, Canada

    Marco Sandri

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  1. Roberta Sartori
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Contributions

R.S. and S.B. performed biochemical analyses, RNA analysis, muscle transfections, mouse treatments, ChIP analysis and cloning. M.S. performed electron microscopy. R.S., S.B. and E.S. performed histology. E.S., A.S., H.A. and E.M. performed AAV infection, morphological and immunohistochemical analysis, protein analysis and RNA analysis. B.B. and L.T. analyzed muscle mechanics. J.Z. performed in vitro ubiquitination assays and analysis. E.E. and E.S. genotyped and maintained mice. S.S. provided Gdf5-mutant mice. A.F. and R.S. performed denervation experiments. R.S., E.S., H.A., M.S., S.D., S.P., E.M., B.B. and A.L.G. were involved in data analysis. R.S., E.S., M.S., H.A., S.D. and S.P. designed the study, analyzed the data and wrote the manuscript. All authors discussed the results and commented on the manuscript.

Corresponding authors

Correspondence to Stefano Piccolo, Helge Amthor or Marco Sandri.

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The authors declare no competing financial interests.

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Sartori, R., Schirwis, E., Blaauw, B. et al. BMP signaling controls muscle mass. Nat Genet 45, 1309–1318 (2013). https://doi.org/10.1038/ng.2772

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