Functional muscle ischemia in neuronal nitric oxide synthase-deficient skeletal muscle of children with Duchenne muscular dystrophy

Mikael Sander, Bahman Chavoshan, Shannon A. Harris, Susan T. Iannaccone, James T. Stull, Gail D. Thomas, Ronald G. Victor

Research output: Contribution to journalArticle

308 Citations (Scopus)

Abstract

Duchenne muscular dystrophy (DMD) is a fatal disease caused by mutation of the gene encoding the cytoskeletal protein dystrophin. Despite a wealth of recent information about the molecular basis of DMD, effective treatment for this disease does not exist because the mechanism by which dystrophin deficiency produces the clinical phenotype is unknown. In both mouse and human skeletal muscle, dystrophin deficiency results in loss of neuronal nitric oxide synthase, which normally is localized to the sarcolemma as part of the dystrophin-glycoprotein complex. Recent studies in mice suggest that skeletal muscle-derived nitric oxide may play a key role in the regulation of blood flow within exercising skeletal muscle by blunting the vasoconstrictor response to α-adrenergic receptor activation. Here we report that this protective mechanism is defective in children with DMD, because the vasoconstrictor response (measured as a decrease in muscle oxygenation) to reflex sympathetic activation was not blunted during exercise of the dystrophic muscles. In contrast, this protective mechanism is intact in healthy children and those with polymyositis or limb-girdle muscular dystrophy, muscle diseases that do not result in loss of neuronal nitric oxide synthase. This clinical investigation suggests that unopposed sympathetic vasoconstriction in exercising human skeletal muscle may constitute a hereto-fore unappreciated vascular mechanism contributing to the pathogenesis of DMD.

Original languageEnglish (US)
Pages (from-to)13818-13823
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume97
Issue number25
DOIs
StatePublished - Dec 5 2000

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Nitric Oxide Synthase Type I
Dystrophin
Duchenne Muscular Dystrophy
Skeletal Muscle
Ischemia
Muscles
Vasoconstrictor Agents
Limb-Girdle Muscular Dystrophies
Polymyositis
Sarcolemma
Cytoskeletal Proteins
Vasoconstriction
Adrenergic Receptors
Blood Vessels
Reflex
Glycoproteins
Nitric Oxide
Exercise
Phenotype
Mutation

ASJC Scopus subject areas

  • Genetics
  • General

Cite this

Functional muscle ischemia in neuronal nitric oxide synthase-deficient skeletal muscle of children with Duchenne muscular dystrophy. / Sander, Mikael; Chavoshan, Bahman; Harris, Shannon A.; Iannaccone, Susan T.; Stull, James T.; Thomas, Gail D.; Victor, Ronald G.

In: Proceedings of the National Academy of Sciences of the United States of America, Vol. 97, No. 25, 05.12.2000, p. 13818-13823.

Research output: Contribution to journalArticle

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