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.

  • Letter
  • Published:

Angiotensin II type 1 receptor blockade attenuates TGF-β–induced failure of muscle regeneration in multiple myopathic states

A Corrigendum to this article was published on 01 April 2007

This article has been updated

Abstract

Skeletal muscle has the ability to achieve rapid repair in response to injury or disease1. Many individuals with Marfan syndrome (MFS), caused by a deficiency of extracellular fibrillin-1, exhibit myopathy and often are unable to increase muscle mass despite physical exercise. Evidence suggests that selected manifestations of MFS reflect excessive signaling by transforming growth factor (TGF)-β (refs. 2,3). TGF-β is a known inhibitor of terminal differentiation of cultured myoblasts; however, the functional contribution of TGF-β signaling to disease pathogenesis in various inherited myopathic states in vivo remains unknown4,5. Here we show that increased TGF-β activity leads to failed muscle regeneration in fibrillin-1–deficient mice. Systemic antagonism of TGF-β through administration of TGF-β–neutralizing antibody or the angiotensin II type 1 receptor blocker losartan normalizes muscle architecture, repair and function in vivo. Moreover, we show TGF-β–induced failure of muscle regeneration and a similar therapeutic response in a dystrophin-deficient mouse model of Duchenne muscular dystrophy. NOTE: In the version of this article initially published, the same panels were inadvertently used to show negative pSmad2/3 and periostin staining in muscle of Fbn1C1039G/+ mice treated with TGF-β‐neutralizing antibody in both the steady-state (Fig. 1a, right column, second and third rows, respectively) and muscle-regeneration (Fig. 1b, right column, third and fourth rows, respectively) experiments. In reality, these images only relate to the steady-state experiment (Fig. 1a). The intended images for Figure 1b are provided (red, pSmad2/3 staining; green, periostin staining). As both sets of images show negative staining in neutralizing antibody–treated Fbn1C1039G/+ mice, this does not alter any observations or conclusions discussed in the manuscript. The error has been corrected in the HTML and PDF versions of the article.

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

Access options

Rent or buy this article

Prices vary by article type

from$1.95

to$39.95

Prices may be subject to local taxes which are calculated during checkout

Figure 1: Evaluation of steady-state and regenerating skeletal muscles in fibrillin-1 deficient mice.
Figure 2: Losartan antagonizes TGFβ and restores muscle architecture and regeneration in Fbn1C1039G/+ mice.
Figure 3: Increased TGF-β signaling contributes to impaired muscle regeneration in mdx mice.
Figure 4: Losartan decreases angiotensin II-mediated TGF-β signaling and improves muscle function in mdx mice.

Similar content being viewed by others

Change history

  • 27 February 2007

    In the version of this article initially published, the same panels were inadvertently used to show negative pSmad2/3 and periostin staining in muscle of Fbn1C1039G/+ mice treated with TGF-β‐neutralizing antibody in both the steady-state (Fig. 1a, right column, second and third rows, respectively) and muscle-regeneration (Fig. 1b, right column, third and fourth rows, respectively) experiments. In reality, these images only relate to the steady-state experiment (Fig. 1a). The intended images for Figure 1b are provided (red, pSmad2/3 staining; green, periostin staining). As both sets of images show negative staining in neutralizing antibody–treated Fbn1C1039G/+ mice, this does not alter any observations or conclusions discussed in the manuscript. The error has been corrected in the HTML and PDF versions of the article.

References

  1. Charge, S.B. & Rudnicki, M.A. Cellular and molecular regulation of muscle regeneration. Physiol. Rev. 84, 209–238 (2004).

    Article  CAS  Google Scholar 

  2. Ng, C.M. et al. TGF-beta-dependent pathogenesis of mitral valve prolapse in a mouse model of Marfan syndrome. J. Clin. Invest. 114, 1586–1592 (2004).

    Article  CAS  Google Scholar 

  3. Neptune, E.R. et al. Dysregulation of TGF-beta activation contributes to pathogenesis in Marfan syndrome. Nat. Genet. 33, 407–411 (2003).

    Article  CAS  Google Scholar 

  4. Allen, R.E. & Boxhorn, L.K. Inhibition of skeletal muscle satellite cell differentiation by transforming growth factor-beta. J. Cell. Physiol. 133, 567–572 (1987).

    Article  CAS  Google Scholar 

  5. Olson, E.N., Sternberg, E., Hu, J.S., Spizz, G. & Wilcox, C. Regulation of myogenic differentiation by type beta transforming growth factor. J. Cell Biol. 103, 1799–1805 (1986).

    Article  CAS  Google Scholar 

  6. Dietz, H.C. et al. Marfan syndrome caused by a recurrent de novo missense mutation in the fibrillin gene. Nature 352, 337–339 (1991).

    Article  CAS  Google Scholar 

  7. Habashi, J.P. et al. Losartan, an AT1 antagonist, prevents aortic aneurysm in a mouse model of Marfan syndrome. Science 312, 117–121 (2006).

    Article  CAS  Google Scholar 

  8. Heldin, C.H., Miyazono, K. & ten Dijke, P. TGF-beta signalling from cell membrane to nucleus through SMAD proteins. Nature 390, 465–471 (1997).

    Article  CAS  Google Scholar 

  9. Li, Y. et al. Transforming growth factor-beta1 induces the differentiation of myogenic cells into fibrotic cells in injured skeletal muscle: a key event in muscle fibrogenesis. Am. J. Pathol. 164, 1007–1019 (2004).

    Article  CAS  Google Scholar 

  10. Sato, K. et al. Improvement of muscle healing through enhancement of muscle regeneration and prevention of fibrosis. Muscle Nerve 28, 365–372 (2003).

    Article  CAS  Google Scholar 

  11. Gosselin, L.E. et al. Localization and early time course of TGF-beta 1 mRNA expression in dystrophic muscle. Muscle Nerve 30, 645–653 (2004).

    Article  CAS  Google Scholar 

  12. Judge, D.P. et al. Evidence for a critical contribution of haploinsufficiency in the complex pathogenesis of Marfan syndrome. J. Clin. Invest. 114, 172–181 (2004).

    Article  CAS  Google Scholar 

  13. Goetsch, S.C., Hawke, T.J., Gallardo, T.D., Richardson, J.A. & Garry, D.J. Transcriptional profiling and regulation of the extracellular matrix during muscle regeneration. Physiol. Genomics 14, 261–271 (2003).

    Article  CAS  Google Scholar 

  14. Reimann, J., Irintchev, A. & Wernig, A. Regenerative capacity and the number of satellite cells in soleus muscles of normal and mdx mice. Neuromuscul. Disord. 10, 276–282 (2000).

    Article  CAS  Google Scholar 

  15. Jin, Y. et al. Expression of MyoD and myogenin in dystrophic mice, mdx and dy, during regeneration. Acta Neuropathol. (Berl.) 99, 619–627 (2000).

    Article  CAS  Google Scholar 

  16. Lavoie, P. et al. Neutralization of transforming growth factor-beta attenuates hypertension and prevents renal injury in uremic rats. J. Hypertens. 23, 1895–1903 (2005).

    Article  CAS  Google Scholar 

  17. Lim, D.S. et al. Angiotensin II blockade reverses myocardial fibrosis in a transgenic mouse model of human hypertrophic cardiomyopathy. Circulation 103, 789–791 (2001).

    Article  CAS  Google Scholar 

  18. Yamazaki, M. et al. Expression of transforming growth factor-beta 1 and its relation to endomysial fibrosis in progressive muscular dystrophy. Am. J. Pathol. 144, 221–226 (1994).

    CAS  PubMed  PubMed Central  Google Scholar 

  19. Cohn, R.D. et al. Disruption of DAG1 in differentiated skeletal muscle reveals a role for dystroglycan in muscle regeneration. Cell 110, 639–648 (2002).

    Article  CAS  Google Scholar 

  20. Lee, S.J. Regulation of muscle mass by myostatin. Annu. Rev. Cell Dev. Biol. 20, 61–86 (2004).

    Article  CAS  Google Scholar 

  21. Zhu, X., Topouzis, S., Liang, L.F. & Stotish, R.L. Myostatin signaling through Smad2, Smad3 and Smad4 is regulated by the inhibitory Smad7 by a negative feedback mechanism. Cytokine 26, 262–272 (2004).

    Article  CAS  Google Scholar 

  22. Wagner, K.R., McPherron, A.C., Winik, N. & Lee, S.J. Loss of myostatin attenuates severity of muscular dystrophy in mdx mice. Ann. Neurol. 52, 832–836 (2002).

    Article  CAS  Google Scholar 

  23. Bogdanovich, S. et al. Functional improvement of dystrophic muscle by myostatin blockade. Nature 420, 418–421 (2002).

    Article  CAS  Google Scholar 

  24. Tkatchenko, A.V. et al. Identification of altered gene expression in skeletal muscles from Duchenne muscular dystrophy patients. Neuromuscul. Disord. 11, 269–277 (2001).

    Article  CAS  Google Scholar 

  25. Zhou, Y., Poczatek, M.H., Berecek, K.H. & Murphy-Ullrich, J.E. Thrombospondin 1 mediates angiotensin II induction of TGF-beta activation by cardiac and renal cells under both high and low glucose conditions. Biochem. Biophys. Res. Commun. 339, 633–641 (2006).

    Article  CAS  Google Scholar 

  26. Delafontaine, P. & Akao, M. Angiotensin II as candidate of cardiac cachexia. Curr. Opin. Clin. Nutr. Metab. Care 9, 220–224 (2006).

    Article  CAS  Google Scholar 

  27. Assereto, S. et al. Pharmacological rescue of the dystrophin-glycoprotein complex in Duchenne and Becker skeletal muscle explants by proteasome inhibitor treatment. Am. J. Physiol. Cell Physiol. 290, C577–C582 (2006).

    Article  CAS  Google Scholar 

  28. Briguet, A., Courdier-Fruh, I., Foster, M., Meier, T. & Magyar, J.P. Histological parameters for the quantitative assessment of muscular dystrophy in the mdx-mouse. Neuromuscul. Disord. 14, 675–682 (2004).

    Article  Google Scholar 

  29. Pereira, L. et al. Targetting of the gene encoding fibrillin-1 recapitulates the vascular aspect of Marfan syndrome. Nat. Genet. 17, 218–222 (1997).

    Article  CAS  Google Scholar 

  30. Horsley, V., Jansen, K.M., Mills, S.T. & Pavlath, G.K. IL-4 acts as a myoblast recruitment factor during mammalian muscle growth. Cell 113, 483–494 (2003).

    Article  CAS  Google Scholar 

Download references

Acknowledgements

We would like to thank K. Wagner and S.-J. Lee for providing muscle samples of mdx Mstn−/− mice. We would like to thank P. Sponseller for providing human muscle samples. H.C. Dietz is an Investigator of the Howard Hughes Medical Institute and is also supported by the US National Institutes of Health, the Smilow Center for Marfan Syndrome Research, the Dana and Albert “Cubby” Broccoli Center for Aortic Diseases and the National Marfan Foundation.

Author information

Authors and Affiliations

Authors

Contributions

R.D.C. conducted most of the experiments and wrote the manuscript; C.E. participated in the analysis of the ex vivo muscle data; J.P.H. participated in the development and execution of treatment protocols for both fibrillin-1–deficient and mdx mice; A.A.S. participated in immunofluorescent analyses; E.C.K., M.G. and T.M.H. maintained the mouse colonies and contributed to tissue harvesting and preparation; M.T.L. and C.M.R. conducted protein expression analyses; B.L.L. contributed to study design and interpretation, F.R. supplied Fbn1mgR/mgR mice and contributed to study design; D.P.J. was extensively involved in analyzing and interpreting all the data; C.W.W. conducted the ex vivo analyses of skeletal muscles; H.C.D. supervised all aspects of this study including study design, execution and interpretation, and manuscript preparation.

Corresponding author

Correspondence to Harry C Dietz.

Ethics declarations

Competing interests

The authors declare no competing financial interests.

Supplementary information

Supplementary Fig. 1

Evidence for myopathy in fibrillin-1 deficient mouse and human skeletal muscles. (PDF 577 kb)

Supplementary Fig. 2

Morphometric analyses of satellite cells in Fbn1C1039G/+ mice. (PDF 276 kb)

Supplementary Fig. 3

Losartan treatment decreases thrombospondin-1 and periostin expression and improves in vivo muscle function of fibrillin-1 deficient mice. (PDF 97 kb)

Supplementary Fig. 4

Losartan treatment does not alter expression of the dystrophin-glycoprotein complex but improves histologic and in vivo functional properties of skeletal muscles of mdx mice. (PDF 666 kb)

Supplementary Table 1

Physiologic and morphometric analyses of explanted EDL muscles (PDF 26 kb)

Supplementary Methods (PDF 15 kb)

Rights and permissions

Reprints and permissions

About this article

Cite this article

Cohn, R., van Erp, C., Habashi, J. et al. Angiotensin II type 1 receptor blockade attenuates TGF-β–induced failure of muscle regeneration in multiple myopathic states. Nat Med 13, 204–210 (2007). https://doi.org/10.1038/nm1536

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/nm1536

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