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

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.

• Authors: Rasna Sabharwal, Michael Z Cicha, Ruben D M Sinisterra, Frederico B De Sousa, Robson A Santos, Mark W Chapleau
• Journal: Clinical science (London, England : 1979) (Clin Sci (Lond)) Vol. 127 Issue 2 Pg. 101-9 (Jul 2014) ISSN: 1470-8736 [Electronic] England
• PMID: 24502705 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, U.S. Gov't, Non-P.H.S.)

Chemical References

• Dystrophin
• Peptide Fragments
• Sarcoglycans
• Angiotensin I
• angiotensin I (1-7)

Topics

• Administration, Oral
• Angiotensin I (pharmacology)
• Animals
• Dystrophin (metabolism)
• Fibrosis (metabolism)
• Mice
• Mice, Inbred C57BL
• Mice, Knockout
• Motor Activity (drug effects, physiology)
• Muscle, Skeletal (drug effects, metabolism, pathology)
• Muscular Dystrophies (drug therapy, genetics, metabolism)
• Peptide Fragments (pharmacology)
• Phenotype
• Sarcoglycans (genetics, metabolism)