Angiotensin II Type 1 Receptor Blockade Improves TGF-induced Failure of Muscle Regeneration in the mdx Mouse Model of Duchenne Muscular Dystrophy. R.D. Cohn¹, J.P. Habashi², B.L. Loeys¹, E.C. Klein¹, M. Gamradt¹, T.M. Holm¹, D.P. Judge³, H.C. Dietz¹. 1) Institute of Genetic Medicine and HHMI, Johns Hopkins Univ Sch of Med, Baltimore, MD, USA; 2) Division of Pediatric Cardiology, Dept of Pediatrics, Johns Hopkins University Sch of Med; 3) Division of Cardiology, Dept of Medicine, Johns Hopkins University Sch of Med, Baltimore, MD, USA.
   We have previously shown that increased TGF activity causes abnormal muscle regeneration and myopathy in fibrillin-1 deficient mice, a model of Marfan syndrome. Systemic antagonism of TGF via administration of TGF-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 TGF signaling, as evidenced by increased phosphorylation of pSmad2/3. Systemic TGF 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 TGF-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.