3 research outputs found
Sodium nitrate alleviates functional muscle ischaemia in patients with Becker muscular dystrophy
KEY POINTS: Dystrophin deficiency disrupts sarcolemmal targeting of neuronal nitric oxide synathase, resulting in functional muscle ischaemia. Chronic treatment of dystrophic mice with an inorganic nitric oxide (NO) donor alleviates this ischaemia and improves many features of the dystrophic phenotype. The present study translates this preclinical work by showing that a single oral dose of sodium nitrate,which serves as a NO donor when reduced to circulating nitrite by the commensal bacteria in the oral cavity, alleviates functional muscle ischaemia and restores normal blood flow regulation in human patients with dystrophinopathy. The results of the present study further support the mechanistic hypothesis that circulating nitrite serves as an alternative NO donor when reduced by deoxyhaemoglobin and/or deoxymyoglobin in exercising muscle. ABSTRACT: Becker muscular dystrophy (BMD) is a progressive Xâlinked muscle wasting disease for which there is no treatment. BMD is caused by inâframe 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 (nNOSÎŒ), which requires specific spectrinâlike repeats (SR16/17) in dystrophin's rod domain and the adaptor protein αâsyntrophin for sarcolemmal targeting. When healthy skeletal muscle is exercised, sarcolemmal nNOSÎŒâderived nitric oxide (NO) attenuates αâadrenergic 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 NOâdonating nonâsteroidal antiâinflammatory 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 nNOSÎŒ, with the vasoconstrictor response measured as a decrease in muscle oxygenation (near infrared spectroscopy) to reflex sympathetic activation. Then, in a singleâarm, openâlabel trial in 11 BMD patients and a doubleâblind, placeboâcontrolled crossâover 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 postâexercise 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