Abstract
Duchenne muscular dystrophy (DMD) is a degenerative disorder affecting skeletal and cardiac muscle for which there is no effective therapy. Angiotension receptor blockade (ARB) has excellent therapeutic potential in DMD based on recent data demonstrating attenuation of skeletal muscle disease progression during 6–9 months of therapy in the mdx mouse model of DMD. Since cardiac-related death is major cause of mortality in DMD, it is important to evaluate the effect of any novel treatment on the heart. Therefore, we evaluated the long-term impact of ARB on both the skeletal muscle and cardiac phenotype of the mdx mouse. Mdx mice received either losartan (0.6 g/L) (n = 8) or standard drinking water (n = 9) for two years, after which echocardiography was performed to assess cardiac function. Skeletal muscle weight, morphology, and function were assessed. Fibrosis was evaluated in the diaphragm and heart by Trichrome stain and by determination of tissue hydroxyproline content. By the study endpoint, 88% of treated mice were alive compared to only 44% of untreated (p = 0.05). No difference in skeletal muscle morphology, function, or fibrosis was noted in losartan-treated animals. Cardiac function was significantly preserved with losartan treatment, with a trend towards reduction in cardiac fibrosis. We saw no impact on the skeletal muscle disease progression, suggesting that other pathways that trigger fibrosis dominate over angiotensin II in skeletal muscle long term, unlike the situation in the heart. Our study suggests that ARB may be an important prophylactic treatment for DMD-associated cardiomyopathy, but will not impact skeletal muscle disease.
Highlights
Duchenne muscular dystrophy (DMD) is a degenerative disorder affecting skeletal and cardiac muscle for which there is no effective therapy [1]
A recent study demonstrated that antagonism of transforming growth factor beta (TGF-b) with losartan, an angiotensin II receptor blocker that is known to significantly reduce TGF-b activity in a number of disease models [7,8], for 6–9 months beginning at 6 weeks of age results in reduced fibrosis in the diaphragm and gastrocnemius muscles and increased forelimb and hindlimb grip strength compared to untreated mdx mice
Male mdx mice were weaned at four weeks and randomized to receive either standard drinking water (n = 9) or drinking water supplemented with losartan (0.6 g/L) (n = 8) for two years [5]
Summary
Duchenne muscular dystrophy (DMD) is a degenerative disorder affecting skeletal and cardiac muscle for which there is no effective therapy [1]. Increased TGF-b signaling has been documented in both the mdx mouse and in the Golden Retriever models of DMD [5,6]. A recent study demonstrated that antagonism of TGF-b with losartan, an angiotensin II receptor blocker that is known to significantly reduce TGF-b activity in a number of disease models [7,8], for 6–9 months beginning at 6 weeks of age results in reduced fibrosis in the diaphragm and gastrocnemius muscles and increased forelimb and hindlimb grip strength compared to untreated mdx mice. To investigate further the therapeutic potential of losartan in DMD, a disease characterized by both skeletal muscle and cardiac dysfunction, we sought to expand on this previous study by evaluating the functional impact of losartan therapy on both skeletal and cardiac muscle of mdx mice after two years of treatment
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