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

Ronald D. Cohn, Christel Van Erp, Jennifer P. Habashi, Arshia A. Soleimani, Erin C. Klein, Matthew T. Lisi, Matthew Gamradt, Colette M. Ap Rhys, Tammy M. Holm, Bart L. Loeys, Francesco Ramirez, Daniel P. Judge, Christopher W. Ward, Harry C. Dietz

Research output: Contribution to journalArticlepeer-review

571 Scopus citations

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. 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 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.

Original languageEnglish
Pages (from-to)204-210
Number of pages7
JournalNature Medicine
Volume13
Issue number2
DOIs
StatePublished - Feb 2007
Externally publishedYes

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