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

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)-beta (refs. 2,3). TGF-beta is a known inhibitor of terminal differentiation of cultured myoblasts; however, the functional contribution of TGF-beta signaling to disease pathogenesis in various inherited myopathic states in vivo remains unknown. Here we show that increased TGF-beta activity leads to failed muscle regeneration in fibrillin-1-deficient mice. Systemic antagonism of TGF-beta through administration of TGF-beta-neutralizing antibody or the angiotensin II type 1 receptor blocker losartan normalizes muscle architecture, repair and function in vivo. Moreover, we show TGF-beta-induced failure of muscle regeneration and a similar therapeutic response in a dystrophin-deficient mouse model of Duchenne muscular dystrophy.

SUBMITTER: Cohn RD

PROVIDER: S-EPMC3138130 | biostudies-literature | 2007 Feb

REPOSITORIES: biostudies-literature

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

Cohn Ronald D RD van Erp Christel C Habashi Jennifer P JP Soleimani Arshia A AA Klein Erin C EC Lisi Matthew T MT Gamradt Matthew M ap Rhys Colette M CM Holm Tammy M TM Loeys Bart L BL Ramirez Francesco F Judge Daniel P DP Ward Christopher W CW Dietz Harry C HC

Nature medicine 20070121 2

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)-beta (refs. 2,3). TGF-beta is a known inhibitor of terminal differentiation of cultured myoblasts; howeve ...[more]

PMID: 17237794

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Project description:BACKGROUND AND PURPOSE:Metformin, a small molecule, antihyperglycaemic agent, is a well-known activator of AMP-activated protein kinase (AMPK) and protects against cardiac fibrosis. However, the underlying mechanisms remain elusive. TGF?1 is a key cytokine mediating cardiac fibrosis. Here, we investigated the effects of metformin on TGF?1 production induced by angiotensin II (AngII) and the underlying mechanisms. EXPERIMENTAL APPROACH:Wild-type and AMPK?2-/- C57BL/6 mice were injected s.c. with metformin or saline and infused with AngII (3 mg·kg-1 ·day-1 ) for 7 days. Adult mouse cardiac fibroblasts (CFs) were isolated for in vitro experiments. KEY RESULTS:In CFs, metformin inhibited AngII-induced TGF?1 expression via AMPK activation. Analysis using bioinformatics predicted a potential hepatocyte nuclear factor 4? (HNF4?)-binding site in the promoter region of the Tgfb1 gene. Overexpressing HNF4? increased TGF?1 expression in CFs. HNF4? siRNA attenuated AngII-induced TGF?1 production and cardiac fibrosis in vitro and in vivo. Metformin inhibited the AngII-induced increases in HNF4? protein expression and binding to the Tgfb1 promoter in CFs. In vivo, metformin blocked the AngII-induced increase in cardiac HNF4? protein levels in wild-type mice but not in AMPK?2-/- mice. Consequently, metformin inhibited AngII-induced TGF?1 production and cardiac fibrosis in wild-type mice but not in AMPK?2-/- mice. CONCLUSIONS AND IMPLICATIONS:HNF4? mediates AngII-induced TGF?1 transcription and cardiac fibrosis. Metformin inhibits AngII-induced HNF4? expression via AMPK activation, thus decreasing TGF?1 transcription and cardiac fibrosis. These findings reveal a novel antifibrotic mechanism of action of metformin and identify HNF4? as a new potential therapeutic target for cardiac fibrosis. LINKED ARTICLES:This article is part of a themed section on Spotlight on Small Molecules in Cardiovascular Diseases. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v175.8/issuetoc.

Dataset Information

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

Publications

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

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