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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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.
The authors declare no competing financial interests.
Evidence for myopathy in fibrillin-1 deficient mouse and human skeletal muscles. (PDF 577 kb)
Morphometric analyses of satellite cells in Fbn1C1039G/+ mice. (PDF 276 kb)
Losartan treatment decreases thrombospondin-1 and periostin expression and improves in vivo muscle function of fibrillin-1 deficient mice. (PDF 97 kb)
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)
Physiologic and morphometric analyses of explanted EDL muscles (PDF 26 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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