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

Nat Med. 2007 Feb;13(2):204-10. doi: 10.1038/nm1536. Epub 2007 Jan 21.


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.

Publication types

  • Comparative Study
  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Analysis of Variance
  • Angiotensin II Type 1 Receptor Blockers / pharmacology
  • Angiotensin II Type 1 Receptor Blockers / therapeutic use
  • Animals
  • Antibodies / pharmacology
  • Antibodies / therapeutic use
  • Fibrillin-1
  • Fibrillins
  • Fluorescent Antibody Technique
  • Histocytochemistry
  • Losartan / pharmacology
  • Losartan / therapeutic use*
  • Marfan Syndrome / drug therapy*
  • Mice
  • Microfilament Proteins / genetics
  • Muscle, Skeletal / physiology*
  • Muscular Dystrophy, Duchenne / drug therapy*
  • Mutation / genetics
  • Regeneration / drug effects*
  • Regeneration / physiology
  • Signal Transduction / drug effects*
  • Transforming Growth Factor beta / metabolism*


  • Angiotensin II Type 1 Receptor Blockers
  • Antibodies
  • Fbn1 protein, mouse
  • Fibrillin-1
  • Fibrillins
  • Microfilament Proteins
  • Transforming Growth Factor beta
  • Losartan