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Chronic oral administration of Ang-(1-7) improves skeletal muscle, autonomic and locomotor phenotypes in muscular dystrophy
Journal article   Open access   Peer reviewed

Chronic oral administration of Ang-(1-7) improves skeletal muscle, autonomic and locomotor phenotypes in muscular dystrophy

Rasna Sabharwal, Michael Z Cicha, Ruben D M Sinisterra, Frederico B De Sousa, Robson A Santos and Mark W Chapleau
Clinical science (1979), Vol.127(2), pp.101-109
07/2014
DOI: 10.1042/CS20130602
PMCID: PMC4318348
PMID: 24502705
url
https://www.ncbi.nlm.nih.gov/pmc/articles/4318348View
Open Access

Abstract

Muscular dystrophies are a group of heterogeneous genetic disorders that cause progressive muscle weakness and wasting, dilated cardiomyopathy and early mortality. There are different types of muscular dystrophies with varying aetiologies but they all have a common hallmark of myofibre degeneration, atrophy and decreased mobility. Mutation in Sgcd (sarcoglycan-δ), a subunit of dystrophin glycoprotein complex, causes LGMD2F (limb girdle muscular dystrophy 2F). Previously, we have reported that Sgcd-deficient (Sgcd-/-) mice exhibit AngII (angiotensin II)-induced autonomic and skeletal muscle dysfunction at a young age, which contributes to onset of dilated cardiomyopathy and mortality at older ages. Two counter-regulatory RAS (renin-angiotensin system) pathways have been identified: deleterious actions of AngII acting on the AT1R (AngII type 1 receptor) compared with the protective actions of Ang-(1-7) [angiotensin-(1-7)] acting on the receptor Mas. We propose that the balance between the AngII/AT1R and Ang-(1-7)/Mas axes is disturbed in Sgcd-/- mice. Control C57BL/6J and Sgcd-/- mice were treated with Ang-(1-7) included in hydroxypropyl β-cyclodextrin (in drinking water) for 8-9 weeks beginning at 3 weeks of age. Ang-(1-7) treatment restored the AngII/AT1R compared with Ang-(1-7)/Mas balance, decreased oxidative stress and fibrosis in skeletal muscle, increased locomotor activity, and prevented autonomic dysfunction without lowering blood pressure in Sgcd-/- mice. Our results suggest that correcting the early autonomic dysregulation by administering Ang-(1-7) or enhancing its endogenous production may provide a novel therapeutic approach in muscular dystrophy.
 Motor Activity - physiology Muscular Dystrophies - metabolism Sarcoglycans - metabolism Administration, Oral Mice, Inbred C57BL Muscular Dystrophies - drug therapy Motor Activity - drug effects Muscle, Skeletal - metabolism Peptide Fragments - pharmacology Fibrosis - metabolism Muscular Dystrophies - genetics Mice, Knockout Phenotype Animals Sarcoglycans - genetics Muscle, Skeletal - drug effects Angiotensin I - pharmacology Mice Muscle, Skeletal - pathology Dystrophin - metabolism

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