Becker muscular dystrophy (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 (nNOSμ), which requires specific spectrin-like repeats (SR16/17) in dystrophin’s rod domain and the adaptor protein α-syntrophin for sarcolemmal targeting. When healthy skeletal muscle is exercised, sarcolemmal nNOSμ-derived nitric oxide (NO) attenuates α-adrenergic vasoconstriction, thus optimizing perfusion. In the mdx mouse model of dystrophinopathy, this protective mechanism (functional sympatholysis) is defective causing functional muscle ischemia. Treatment with a NO-donating non-steroidal anti-inflammatory drug (NSAID) alleviates this ischemia and improves the murine dystrophic phenotype. Herein, the authors report that in 13 men with BMD, sympatholysis is defective mainly in patients whose mutations disrupt sarcolemmal targeting of nNOSμ; 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 6 patients, they show that acute treatment with oral sodium nitrate-an inorganic NO donor without a NSIAD moiety-restores sympatholysis and improves post-exercise hyperemia (Doppler ultrasound). In contrast, sodium nitrate neither improves sympatholysis nor hyperemia 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.
