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Autonomic, locomotor and cardiac abnormalities in a mouse model of muscular dystrophy: targeting the renin-angiotensin system
Journal article   Open access

Autonomic, locomotor and cardiac abnormalities in a mouse model of muscular dystrophy: targeting the renin-angiotensin system

Rasna Sabharwal and Mark W Chapleau
Experimental physiology, Vol.99(4), pp.627-631
04/2014
DOI: 10.1113/expphysiol.2013.074336
PMCID: PMC4322680
PMID: 24334334
url
http://doi.org/10.1113/expphysiol.2013.074336View
Open Access

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.
 Ventricular Function, Left Humans Muscular Dystrophies, Limb-Girdle - drug therapy Motor Activity - drug effects Muscle, Skeletal - innervation Peptide Fragments - pharmacology Angiotensin II Type 1 Receptor Blockers - pharmacology Autonomic Nervous System - physiopathology Cardiomyopathies - genetics Cardiomyopathies - physiopathology Ventricular Dysfunction, Left - genetics Muscular Dystrophies, Limb-Girdle - genetics Muscle, Skeletal - drug effects Ventricular Dysfunction, Left - pathology Angiotensin I - pharmacology Autonomic Nervous System - metabolism Muscular Dystrophies, Limb-Girdle - pathology Disease Models, Animal Heart - innervation Cardiomyopathies - drug therapy Autonomic Nervous System - drug effects Muscular Dystrophies, Limb-Girdle - physiopathology Cardiomyopathies - pathology Genotype Myocardium - pathology Sarcoglycans - deficiency Ventricular Dysfunction, Left - physiopathology Mice, Knockout Ventricular Dysfunction, Left - metabolism Phenotype Animals Muscular Dystrophies, Limb-Girdle - metabolism Sarcoglycans - genetics Ventricular Dysfunction, Left - drug therapy Cardiomyopathies - metabolism Heart - drug effects Renin-Angiotensin System - drug effects Muscle, Skeletal - pathology

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