Muscular dystrophies are a heterogeneous group of genetic muscle diseases characterized by muscle weakness and atrophy. Mutations in sarcoglycans and other subunits of the dystrophin-glycoprotein complex cause muscular dystrophy and dilated cardiomyopathy (DCM) in animals and humans [1]. Aberrant autonomic signaling is recognized in several neuromuscular disorders. Antagonists of the renin angiotensin system (RAS) have been shown to attenuate skeletal muscle pathology in mouse models of muscular dystrophy [2]. Furthermore, treatment with an angiotensin converting enzyme inhibitor and β-adrenergic receptor blocker has been shown to reduce symptoms of congestive heart failure in Duchenne muscular dystrophy [3]. Thus, we hypothesized that activation of the RAS contributes to skeletal muscle and autonomic dysfunction in mice deficient in sarcoglycan-δ (Sgcd) at a young age; and this early autonomic dysfunction contributes to later development of left ventricular (LV) dysfunction and increased mortality. We measured cardiac function (echocardiography); blood pressure (BP), heart rate (HR) and locomotor activity (radiotelemetry); spontaneous baroreflex sensitivity (BRS, sequence technique); cardiac sympatho-vagal tone (HR responses to propranolol and atropine, respectively); and survival (Kaplan-Meier) in conscious Sgcd-/- and control mice. We demonstrated that young, 10 wk old Sgcd-/- mice exhibit histopathological features of skeletal muscle dystrophy (fibrosis, centralized nuclei), oxidative stress, decreased locomotor activity and severe autonomic dysregulation, but normal cardiac function [4]. Autonomic function continued to deteriorate in Sgcd-/- mice with age and was accompanied by LV dysfunction and DCM at older ages (>50 wks) [5]. Autonomic dysregulation at a young age predicted later development of LV dysfunction and high mortality in Sgcd-/- mice [5]. Angiotensin II (AngII) acting via type 1 receptors (AT1R) causes oxidative stress, fibrosis, and cardiovascular and autonomic dysfunction, while Ang[1-7] acting via Mas receptors counteracts these deleterious actions [6]. Subgroups of control and Sgcd-/- mice were treated with either the AT1R blocker losartan (10 mg/ml, drinking water) or Ang[1-7] (2.5mg/kg/day, osmotic pump) for 8 wks beginning at 3 wks of age. Both losartan and Ang[1-7] decreased AT1R expression, oxidative stress, and fibrosis in skeletal muscle, increased locomotor activity, and prevented autonomic dysfunction in Sgcd-/- mice without affecting these measures in control mice. Summary: We conclude that activation of RAS, at a young age, contributes to skeletal muscle and autonomic dysfunction in muscular dystrophy. We speculate that the latter is mediated via abnormal sensory nerve and/or cytokine signaling from dystrophic skeletal muscle to brain, and contributes to age-related LV dysfunction, DCM, arrhythmias and premature death. Therefore, correcting the early autonomic dysregulation may provide a novel therapeutic approach in muscular dystrophy.