Angiotensin II Type 1 Receptor Blockade Improves TGFb-induced Failure of Muscle Regeneration in the mdx Mouse Model of Duchenne Muscular Dystrophy.

R.D. Cohn, J.P. Habashi, B.L. Loeys, E.C. Klein, M. Gamradt, T.M. Holm, D.P. Judge, H.C. Dietz USA

We have previously shown that increased TGFb activity causes abnormal muscle regeneration and myopathy in fibrillin-1 deficient mice, a model of Marfan syndrome. Systemic antagonism of TGFb via administration of TGFb-neutralizing antibody or the angiotensin II type 1 receptor (AT1) blocker losartan restores abnormal muscle regeneration and prevents subsequent development of myopathic features. Impaired satellite cell performance and muscle repair has also been shown to play a significant role in the disease progression of various forms of muscular dystrophy. Here we demonstrate that myopathic changes in the dystrophin-deficient mdx mouse model of Duchenne muscular dystrophy associates with excessive TGFb signaling, as evidenced by increased phosphorylation of pSmad2/3. Systemic TGFb antagonism via losartan improves the satellite cell response to toxin induced-injury in the mdx mouse. Losartan treated mdx mice have improved steady-state muscle architecture and a near-normal amount of actively regenerating, neonatal myosin positive fibers four days after induced injury. After 18 days, losartan-treated mdx mice show only minimal amount of fibrosis, as demonstrated by vimentin expression, when compared to placebo-treated mice. Moreover, long-term administration of losartan leads to improved functional performance as demonstrated by increased muscle grip strength and decreased muscle fatigue in mdx mice. Together, our data demonstrate that treatment with the FDA approved medication losartan attenuates TGFb-induced failure of muscle regeneration and represents a promising therapeutic strategy for the treatment of Duchenne muscular dystrophy. Given that losartan is widely used to treat hypertension and has an exceptional tolerance profile in all age groups, we propose that a clinical trial using losartan is warranted.