title: Autonomic, locomotor and cardiac abnormalities in a mouse model of muscular dystrophy: targeting the renin-angiotensin system.
abstract: New Findings What is the topic of this review? This symposium report summarizes autonomic, cardiac and skeletal muscle abnormalities in sarcoglycan-δ-deficient mice (Sgcd-/-), a mouse model of limb girdle muscular dystrophy, with emphasis on the roles of autonomic dysregulation and activation of the renin-angiotensin system at a young age. What advances does it highlight? The contributions of the autonomic nervous system and the renin-angiotensin system to the pathogenesis of muscular dystrophy are highlighted. Results demonstrate that autonomic dysregulation precedes and predicts later development of cardiac dysfunction in Sgcd-/- mice and that treatment of young Sgcd-/- mice with the angiotensin type 1 receptor antagonist losartan or with angiotensin-(1-7) abrogates the autonomic dysregulation, attenuates skeletal muscle pathology and increases spontaneous locomotor activity. 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 in animals and humans. Aberrant autonomic signalling is recognized in a variety of neuromuscular disorders. We hypothesized that activation of the renin-angiotensin system contributes to skeletal muscle and autonomic dysfunction in mice deficient in the sarcoglycan-δ (Sgcd) gene at a young age and that this early autonomic dysfunction contributes to the later development of left ventricular (LV) dysfunction and increased mortality. We demonstrated that young Sgcd-/- mice exhibit histopathological features of skeletal muscle dystrophy, decreased locomotor activity and severe autonomic dysregulation, but normal LV function. Autonomic regulation continued to deteriorate in Sgcd-/- mice with age and was accompanied by LV dysfunction and dilated cardiomyopathy at older ages. Autonomic dysregulation at a young age predicted later development of LV dysfunction and higher mortality in Sgcd-/- mice. Treatment of Sgcd-/- mice with the angiotensin type 1 receptor blocker losartan for 8-9 weeks, beginning at 3 weeks of age, decreased fibrosis and oxidative stress in skeletal muscle, increased locomotor activity and prevented autonomic dysfunction. Chronic infusion of the counter-regulatory peptide angiotensin-(1-7) resulted in similar protection. We conclude that activation of the renin-angiotensin system, 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 signalling from dystrophic skeletal muscle to the brain and contributes to age-related LV dysfunction, dilated cardiomyopathy, arrhythmias and premature death. Therefore, correcting the early autonomic dysregulation and renin-angiotensin system activation may provide a novel therapeutic approach in muscular dystrophy.
authors: * 607 MRC, Internal Medicine, University of Iowa Carver College of Medicine, 501 Newton Road, Iowa City, IA 52242, USA.    rasna-sabharwal@uiowa.edu.
authors: Rasna
authors: R
authors: Sabharwal
authors: Mark W
authors: MW
authors: Chapleau
mesh_terms: D000803:Angiotensin I / Q000494:pharmacology; D047228:Angiotensin II Type 1 Receptor Blockers / Q000494:pharmacology; D000818:Animals; D001341:Autonomic Nervous System / Q000187:drug effects / Q000378:metabolism / Q000503:physiopathology*; D009202:Cardiomyopathies / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology*; D004195:Disease Models, Animal; D005838:Genotype; D006321:Heart / Q000187:drug effects / Q000294:innervation*; D006801:Humans; D018345:Mice, Knockout; D009043:Motor Activity / Q000187:drug effects; D018482:Muscle, Skeletal / Q000187:drug effects / Q000294:innervation* / Q000473:pathology; D049288:Muscular Dystrophies, Limb-Girdle / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology*; D009206:Myocardium / Q000473:pathology; D010446:Peptide Fragments / Q000494:pharmacology; D010641:Phenotype; D012084:Renin-Angiotensin System / Q000187:drug effects; D049031:Sarcoglycans / Q000172:deficiency / Q000235:genetics; D018487:Ventricular Dysfunction, Left / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology*; D016277:Ventricular Function, Left
chemical_list: D047228:Angiotensin II Type 1 Receptor Blockers; D010446:Peptide Fragments; D049031:Sarcoglycans; D000803:Angiotensin I; C118790:angiotensin I (1-7)