Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

BMP signaling controls muscle mass

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.

This is a preview of subscription content, access via your institution

Relevant articles

Open Access articles citing this article.

Access options

Buy article

Get time limited or full article access on ReadCube.

$32.00

All prices are NET prices.

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.

Accession codes

Primary accessions

Gene Expression Omnibus

References

  1. Sartorelli, V. & Fulco, M. Molecular and cellular determinants of skeletal muscle atrophy and hypertrophy. Sci. STKE 2004, re11 (2004).

    PubMed  Google Scholar 

  2. Sandri, M. Signaling in muscle atrophy and hypertrophy. Physiology (Bethesda) 23, 160–170 (2008).

    CAS  Google Scholar 

  3. Lee, S.J. & McPherron, A.C. Regulation of myostatin activity and muscle growth. Proc. Natl. Acad. Sci. USA 98, 9306–9311 (2001).

    Article  CAS  Google Scholar 

  4. Lee, S.J. et al. Regulation of muscle growth by multiple ligands signaling through activin type II receptors. Proc. Natl. Acad. Sci. USA 102, 18117–18122 (2005).

    Article  CAS  Google Scholar 

  5. Sartori, R. et al. Smad2 and 3 transcription factors control muscle mass in adulthood. Am. J. Physiol. Cell Physiol. 296, C1248–C1257 (2009).

    Article  CAS  Google Scholar 

  6. Trendelenburg, A.U. et al. Myostatin reduces Akt/TORC1/p70S6K signaling, inhibiting myoblast differentiation and myotube size. Am. J. Physiol. Cell Physiol. 296, C1258–C1270 (2009).

    Article  CAS  Google Scholar 

  7. Walsh, D.W., Godson, C., Brazil, D.P. & Martin, F. Extracellular BMP-antagonist regulation in development and disease: tied up in knots. Trends Cell Biol. 20, 244–256 (2010).

    Article  CAS  Google Scholar 

  8. Miyazono, K. & Miyazawa, K. Id: a target of BMP signaling. Sci. STKE 2002, pe40 (2002).

    PubMed  Google Scholar 

  9. Yu, P.B. et al. BMP type I receptor inhibition reduces heterotopic ossification. Nat. Med. 14, 1363–1369 (2008).

    Article  CAS  Google Scholar 

  10. Dennler, S. et al. Direct binding of Smad3 and Smad4 to critical TGF β–inducible elements in the promoter of human plasminogen activator inhibitor–type 1 gene. EMBO J. 17, 3091–3100 (1998).

    Article  CAS  Google Scholar 

  11. Korchynskyi, O. & ten Dijke, P. Identification and functional characterization of distinct critically important bone morphogenetic protein–specific response elements in the Id1 promoter. J. Biol. Chem. 277, 4883–4891 (2002).

    Article  CAS  Google Scholar 

  12. Lecker, S.H., Goldberg, A.L. & Mitch, W.E. Protein degradation by the ubiquitin-proteasome pathway in normal and disease states. J. Am. Soc. Nephrol. 17, 1807–1819 (2006).

    Article  CAS  Google Scholar 

  13. Romanello, V. et al. Mitochondrial fission and remodelling contributes to muscle atrophy. EMBO J. 29, 1774–1785 (2010).

    Article  CAS  Google Scholar 

  14. Zimmerman, L.B., De Jesus-Escobar, J.M. & Harland,, R.M. The Spemann organizer signal noggin binds and inactivates bone morphogenetic protein 4. Cell 86, 599–606 (1996).

    Article  CAS  Google Scholar 

  15. Krause, C., Guzman, A. & Knaus, P. Noggin. Int. J. Biochem. Cell Biol. 43, 478–481 (2011).

    Article  CAS  Google Scholar 

  16. Storm, E.E. et al. Limb alterations in brachypodism mice due to mutations in a new member of the TGF-β superfamily. Nature 368, 639–643 (1994).

    Article  CAS  Google Scholar 

  17. Mammucari, C. et al. FoxO3 controls autophagy in skeletal muscle in vivo. Cell Metab. 6, 458–471 (2007).

    Article  CAS  Google Scholar 

  18. Sacheck, J.M. et al. Rapid disuse and denervation atrophy involve transcriptional changes similar to those of muscle wasting during systemic diseases. FASEB J. 21, 140–155 (2007).

    Article  CAS  Google Scholar 

  19. Sandri, M. et al. Foxo transcription factors induce the atrophy-related ubiquitin ligase atrogin-1 and cause skeletal muscle atrophy. Cell 117, 399–412 (2004).

    Article  CAS  Google Scholar 

  20. Bodine, S.C. et al. Identification of ubiquitin ligases required for skeletal muscle atrophy. Science 294, 1704–1708 (2001).

    Article  CAS  Google Scholar 

  21. Gomes, A.V. et al. Upregulation of proteasome activity in muscle RING finger 1–null mice following denervation. FASEB J. 26, 2986–2999 (2012).

    Article  CAS  Google Scholar 

  22. Lipkowitz, S. & Weissman, A.M. RINGs of good and evil: RING finger ubiquitin ligases at the crossroads of tumour suppression and oncogenesis. Nat. Rev. Cancer 11, 629–643 (2011).

    Article  CAS  Google Scholar 

  23. Hirner, S. et al. MuRF1-dependent regulation of systemic carbohydrate metabolism as revealed from transgenic mouse studies. J. Mol. Biol. 379, 666–677 (2008).

    Article  CAS  Google Scholar 

  24. Winbanks, C.E. et al. The Bone Morphogenetic Protein (BMP) axis is a positive regulator of skeletal muscle mass. J. Cell Biol. (in the press).

  25. Le Goff, C. et al. Mutations at a single codon in Mad homology 2 domain of SMAD4 cause Myhre syndrome. Nat. Genet. 44, 85–88 (2012).

    Article  CAS  Google Scholar 

  26. Bardeesy, N. et al. Smad4 is dispensable for normal pancreas development yet critical in progression and tumor biology of pancreas cancer. Genes Dev. 20, 3130–3146 (2006).

    Article  CAS  Google Scholar 

  27. Bothe, G.W., Haspel, J.A., Smith, C.L., Wiener, H.H. & Burden, S.J. Selective expression of Cre recombinase in skeletal muscle fibers. Genesis 26, 165–166 (2000).

    Article  CAS  Google Scholar 

  28. McPherron, A.C., Lawler, A.M. & Lee, S.J. Regulation of skeletal muscle mass in mice by a new TGF-β superfamily member. Nature 387, 83–90 (1997).

    Article  CAS  Google Scholar 

  29. Akiyama, S. et al. Constitutively active BMP type I receptors transduce BMP-2 signals without the ligand in C2C12 myoblasts. Exp. Cell Res. 235, 362–369 (1997).

    Article  CAS  Google Scholar 

  30. Raffaello, A. et al. JunB transcription factor maintains skeletal muscle mass and promotes hypertrophy. J. Cell Biol. 191, 101–113 (2010).

    Article  CAS  Google Scholar 

  31. Carlson, M.E., Hsu, M. & Conboy, I.M. Imbalance between pSmad3 and Notch induces CDK inhibitors in old muscle stem cells. Nature 454, 528–532 (2008).

    Article  CAS  Google Scholar 

  32. Blaauw, B. et al. Akt activation prevents the force drop induced by eccentric contractions in dystrophin-deficient skeletal muscle. Hum. Mol. Genet. 17, 3686–3696 (2008).

    Article  CAS  Google Scholar 

  33. Blaauw, B. et al. Inducible activation of Akt increases skeletal muscle mass and force without satellite cell activation. FASEB J. 23, 3896–3905 (2009).

    Article  CAS  Google Scholar 

  34. Mouisel, E., Vignaud, A., Hourde, C., Butler-Browne, G. & Ferry, A. Muscle weakness and atrophy are associated with decreased regenerative capacity and changes in mTOR signaling in skeletal muscles of venerable (18–24-month-old) dystrophic mdx mice. Muscle Nerve 41, 809–818 (2010).

    Article  CAS  Google Scholar 

Download references

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.

Author information

Authors and Affiliations

Authors

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.

Ethics declarations

Competing interests

The authors declare no competing financial interests.

Supplementary information

Supplementary Text and Figures

Supplementary Figures 1–22 and Supplementary Tables 1–6 (PDF 10683 kb)

Rights and permissions

Reprints and Permissions

About this article

Cite this article

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

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/ng.2772

This article is cited by

Search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing