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Sodium nitrate alleviates functional muscle ischaemia in patients with Becker muscular dystrophy

Lookup NU author(s): Dr Rita Barresi


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Becker muscular dystrophy (BMD) is a progressive X-linked muscle wasting disease for which there is no treatment. BMD is caused by in-frame mutations in the gene encoding dystrophin, a structural cytoskeletal protein that also targets other proteins to the sarcolemma. Among these is neuronal nitric oxide synthase mu (nNOS), which requires specific spectrin-like repeats (SR16/17) in dystrophin's rod domain and the adaptor protein -syntrophin for sarcolemmal targeting. When healthy skeletal muscle is exercised, sarcolemmal nNOS-derived nitric oxide (NO) attenuates -adrenergic vasoconstriction, thus optimizing perfusion. In the mdx mouse model of dystrophinopathy, this protective mechanism (functional sympatholysis) is defective, resulting in functional muscle ischaemia. Treatment with a NO-donating non-steroidal anti-inflammatory drug (NSAID) alleviates this ischaemia and improves the murine dystrophic phenotype. In the present study, we report that, in 13 men with BMD, sympatholysis is defective mainly in patients whose mutations disrupt sarcolemmal targeting of nNOS, with the vasoconstrictor response measured as a decrease in muscle oxygenation (near infrared spectroscopy) to reflex sympathetic activation. Then, in a single-arm, open-label trial in 11 BMD patients and a double-blind, placebo-controlled cross-over trial in six patients, we show that acute treatment with oral sodium nitrate, an inorganic NO donor without a NSIAD moiety, restores sympatholysis and improves post-exercise hyperaemia (Doppler ultrasound). By contrast, sodium nitrate improves neither sympatholysis, nor hyperaemia in healthy controls. Thus, a simple NO donor recapitulates the vasoregulatory actions of sarcolemmal nNOS in BMD patients, and constitutes a putative novel therapy for this disease.

Publication metadata

Author(s): Nelson MD, Rosenberry R, Barresi R, Tsimerinov EI, Rader F, Tang X, Mason O, Schwartz A, Stabler T, Shidban S, Mobaligh N, Hogan S, Elashoff R, Allen JD, Victor RG

Publication type: Article

Publication status: Published

Journal: Journal of Physiology

Year: 2015

Volume: 593

Issue: 23

Pages: 5183-5200

Print publication date: 01/12/2015

Online publication date: 02/11/2015

Acceptance date: 21/09/2015

ISSN (print): 0022-3751

ISSN (electronic): 1469-7793

Publisher: Wiley-Blackwell Publishing, Inc.


DOI: 10.1113/JP271252


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