title: Sodium nitrate alleviates functional muscle ischaemia in patients with Becker muscular dystrophy.
abstract: 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 (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, 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 nNOSμ, 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.
authors.affiliation: Heart Institute, Cedars-Sinai Medical Center, Los Angeles, CA, USA.
authors.forename: Michael D
authors.initials: MD
authors.lastname: Nelson
authors.affiliation: Heart Institute, Cedars-Sinai Medical Center, Los Angeles, CA, USA.
authors.forename: Ryan
authors.initials: R
authors.lastname: Rosenberry
authors.affiliation: NSCT Diagnostic & Advisory Service for Rare Neuromuscular Diseases, Institute of Genetic Medicine, Newcastle upon Tyne, UK.
authors.forename: Rita
authors.initials: R
authors.lastname: Barresi
authors.affiliation: Department of Neurology, Cedars-Sinai Medical Center, Los Angeles, CA, USA.
authors.forename: Evgeny I
authors.initials: EI
authors.lastname: Tsimerinov
authors.affiliation: Heart Institute, Cedars-Sinai Medical Center, Los Angeles, CA, USA.
authors.forename: Florian
authors.initials: F
authors.lastname: Rader
authors.affiliation: Heart Institute, Cedars-Sinai Medical Center, Los Angeles, CA, USA.
authors.forename: Xiu
authors.initials: X
authors.lastname: Tang
authors.affiliation: Heart Institute, Cedars-Sinai Medical Center, Los Angeles, CA, USA.
authors.forename: O'Neil
authors.initials: O
authors.lastname: Mason
authors.affiliation: Heart Institute, Cedars-Sinai Medical Center, Los Angeles, CA, USA.
authors.forename: Avery
authors.initials: A
authors.lastname: Schwartz
authors.affiliation: Duke Institute of Molecular Physiology, Duke University Medical Centre, Durham, NC, USA.
authors.forename: Thomas
authors.initials: T
authors.lastname: Stabler
authors.affiliation: Heart Institute, Cedars-Sinai Medical Center, Los Angeles, CA, USA.
authors.forename: Sarah
authors.initials: S
authors.lastname: Shidban
authors.affiliation: Heart Institute, Cedars-Sinai Medical Center, Los Angeles, CA, USA.
authors.forename: Neigena
authors.initials: N
authors.lastname: Mobaligh
authors.affiliation: Heart Institute, Cedars-Sinai Medical Center, Los Angeles, CA, USA.
authors.forename: Shomari
authors.initials: S
authors.lastname: Hogan
authors.affiliation: Department of Biomathematics, University of California Los Angeles, Los Angeles, CA, USA.
authors.forename: Robert
authors.initials: R
authors.lastname: Elashoff
authors.affiliation: Clinical Exercise Science Program, Institute of Sport, Exercise and Active Living (ISEAL), Victoria University, Melbourne, VIC, Australia.
authors.forename: Jason D
authors.initials: JD
authors.lastname: Allen
authors.affiliation: Heart Institute, Cedars-Sinai Medical Center, Los Angeles, CA, USA.
authors.forename: Ronald G
authors.initials: RG
authors.lastname: Victor
mesh_terms: D000284:Administration, Oral; D000293:Adolescent; D000328:Adult; D006801:Humans; D007511:Ischemia / Q000188:drug therapy*; D008297:Male; D008875:Middle Aged; D018482:Muscle, Skeletal / Q000098:blood supply*; D020388:Muscular Dystrophy, Duchenne / Q000188:drug therapy* / Q000378:metabolism; D009566:Nitrates / Q000008:administration & dosage / Q000627:therapeutic use*; D009569:Nitric Oxide / Q000378:metabolism; D052248:Nitric Oxide Synthase Type I / Q000235:genetics / Q000378:metabolism; D010100:Oxygen / Q000378:metabolism; D013565:Sympatholytics / Q000008:administration & dosage / Q000627:therapeutic use*; D014661:Vasoconstriction
chemical_list: D009566:Nitrates; D013565:Sympatholytics; D009569:Nitric Oxide; C031618:sodium nitrate; D052248:Nitric Oxide Synthase Type I; D010100:Oxygen