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

RD Cohn, C Van Erp, JP Habashi, AA Soleimani… - Nature medicine, 2007 - nature.com
RD Cohn, C Van Erp, JP Habashi, AA Soleimani, EC Klein, MT Lisi, M Gamradt…
Nature medicine, 2007nature.com
Skeletal muscle has the ability to achieve rapid repair in response to injury or disease. 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.,). TGF-β is a known inhibitor of terminal
differentiation of cultured myoblasts; however, the functional contribution of TGF-β signaling …
Abstract
Skeletal muscle has the ability to achieve rapid repair in response to injury or disease. 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. ,). 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 unknown,. 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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