Angiotensin II type 1 receptor blockade attenuates TGF-beta-induced failure of muscle regeneration in multiple myopathic states.
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.
Cohn
Ronald D
RD
McKusick-Nathans Institute of Genetic Medicine, Baltimore, Maryland 21205, USA.
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
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
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