title: 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.
authors.affiliation: McKusick-Nathans Institute of Genetic Medicine, Baltimore, Maryland 21205, USA.
authors.forename: Ronald D
authors.initials: RD
authors.lastname: Cohn
authors.forename: Christel
authors.initials: C
authors.lastname: van Erp
authors.forename: Jennifer P
authors.initials: JP
authors.lastname: Habashi
authors.forename: Arshia A
authors.initials: AA
authors.lastname: Soleimani
authors.forename: Erin C
authors.initials: EC
authors.lastname: Klein
authors.forename: Matthew T
authors.initials: MT
authors.lastname: Lisi
authors.forename: Matthew
authors.initials: M
authors.lastname: Gamradt
authors.forename: Colette M
authors.initials: CM
authors.lastname: ap Rhys
authors.forename: Tammy M
authors.initials: TM
authors.lastname: Holm
authors.forename: Bart L
authors.initials: BL
authors.lastname: Loeys
authors.forename: Francesco
authors.initials: F
authors.lastname: Ramirez
authors.forename: Daniel P
authors.initials: DP
authors.lastname: Judge
authors.forename: Christopher W
authors.initials: CW
authors.lastname: Ward
authors.forename: Harry C
authors.initials: HC
authors.lastname: Dietz
mesh_terms: D000704:Analysis of Variance; D047228:Angiotensin II Type 1 Receptor Blockers / Q000494:pharmacology / Q000627:therapeutic use; D000818:Animals; D000906:Antibodies / Q000494:pharmacology / Q000627:therapeutic use; D000071838:Fibrillin-1; D000071837:Fibrillins; D005455:Fluorescent Antibody Technique; D006651:Histocytochemistry; D019808:Losartan / Q000494:pharmacology / Q000627:therapeutic use*; D008382:Marfan Syndrome / Q000188:drug therapy*; D051379:Mice; D008840:Microfilament Proteins / Q000235:genetics; D018482:Muscle, Skeletal / Q000502:physiology*; D020388:Muscular Dystrophy, Duchenne / Q000188:drug therapy*; D009154:Mutation / Q000235:genetics; D012038:Regeneration / Q000187:drug effects* / Q000502:physiology; D015398:Signal Transduction / Q000187:drug effects*; D016212:Transforming Growth Factor beta / Q000378:metabolism*; D054392:Adipokines
chemical_list: D047228:Angiotensin II Type 1 Receptor Blockers; D000906:Antibodies; D000071838:Fibrillin-1; D000071837:Fibrillins; D019808:Losartan; D008840:Microfilament Proteins; D016212:Transforming Growth Factor beta; C000605724:Fbn1 protein, mouse; D054392:Adipokines