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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.

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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.

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.

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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.

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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.

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Correspondence to Harry C Dietz.

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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)

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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

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