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Tadalafil Alleviates Muscle Ischemia in Patients with Becker Muscular Dystrophy

Lookup NU author(s): Dr Rita Barresi

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Abstract

Becker muscular dystrophy (BMD) is a progressive X-linked muscle wasting disease for which there is no treatment. Like Duchenne muscular dystrophy (DMD), BMD is caused by mutations in the gene encoding dystrophin, a structural cytoskeletal protein that also targets other proteins to the muscle sarcolemma. Among these is neuronal nitric oxide synthase (nNOS mu), which requires certain spectrin-like repeats in dystrophin's rod domain and the adaptor protein alpha-syntrophin to be targeted to the sarcolemma. When healthy skeletal muscle is subjected to exercise, sarcolemmal nNOSm-derived NO attenuates local alpha-adrenergic vasoconstriction, thereby optimizing perfusion of muscle. We found previously that this protective mechanism is defective-causing functional muscle ischemia-in dystrophin-deficient muscles of the mdx mouse (a model of DMD) and of children with DMD, in whom nNOSm is mislocalized to the cytosol instead of the sarcolemma. We report that this protective mechanism also is defective in men with BMD in whom the most common dystrophin mutations disrupt sarcolemmal targeting of nNOSm. In these men, the vasoconstrictor response, measured as a decrease in muscle oxygenation, to reflex sympathetic activation is not appropriately attenuated during exercise of the dystrophic muscles. In a randomized placebo-controlled crossover trial, we show that functional muscle ischemia is alleviated and normal blood flow regulation is fully restored in the muscles of men with BMD by boosting NO-cGMP (guanosine 3',5'-monophosphate) signaling with a single dose of the drug tadalafil, a phosphodiesterase 5A inhibitor. These results further support an essential role for sarcolemmal nNOSm in the normal modulation of sympathetic vasoconstriction in exercising human skeletal muscle and implicate the NO-cGMP pathway as a putative new target for treating BMD.


Publication metadata

Author(s): Martin EA, Barresi R, Byrne BJ, Tsimerinov EI, Scott BL, Walker AE, Gurudevan SV, Anene F, Elashoff RM, Thomas GD, Victor RG

Publication type: Article

Publication status: Published

Journal: Science Translational Medicine

Year: 2012

Volume: 4

Issue: 162

Print publication date: 28/11/2012

Acceptance date: 08/11/2012

ISSN (print): 1946-6234

ISSN (electronic): 1946-6242

Publisher: American Association for the Advancement of Science

URL: http://dx.doi.org/10.1126/scitranslmed.3004327

DOI: 10.1126/scitranslmed.3004327


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