Objective: 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.
Methods: 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.
Results: 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.
Interpretation: 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.
Copyright © 2011 American Neurological Association.