Lamininα2‐deficient congenital muscular dystrophy type 1A (MDC1A) is a cureless disease associated with severe disability and shortened lifespan. Previous studies have shown reduced fibrosis and restored skeletal muscle remodeling following treatment with losartan, an angiotensin II type I receptor blocker. We therefore evaluated the effect of losartan treatment in the dy^2J/dy^2J mouse model of MDC1A.

Homozygous dy^2J/dy^2J and control mice were treated with losartan or placebo for 12 weeks from 6 weeks of age. Outcome measures included hindlimb and forelimb muscle strength by Grip Strength Meter and quantitative muscle fibrosis parameters. Losartan's effects on transforming growth factor β (TGF‐β) and mitogen‐activated protein kinase (MAPK) signaling pathways were evaluated with Western blotting, immunofluorescence, and cytokine measurements.

Losartan treatment was associated with significant impressive improvement in muscle strength and amelioration of fibrosis. Administration of losartan inhibited TGF‐β signaling pathway, resulting in decreased serum TGF‐β1 level and reduced downstream phosphorylated (P) Smad2/3 proteins. Moreover, losartan activated Smad7 protein, a key negative regulator of TGF‐β signaling. In addition, losartan treatment inhibited the MAPK cascade as shown by decreased expression of P‐p38 MAPK, P‐c‐jun‐N‐terminal kinase, and P‐extracellular signal‐regulated kinases 1 and 2 in the treated mice.

Losartan, a commonly prescribed US Food and Drug Administration‐approved medication for hypertension, demonstrated clinical improvement and amelioration of fibrosis in the dy^2J/dy^2J mouse model of MDC1A via TGF‐β and MAPK signaling pathways. The results of this study support pursuing a clinical trial of losartan treatment in children with MDC1A. ANN NEUROL 2012;