Tadalafil alleviates muscle ischemia in patients with becker muscular dystrophy

Elizabeth A. Martin, Rita Barresi, Barry J. Byrne, Evgeny I. Tsimerinov, Bryan L. Scott, Ashley E. Walker, Swaminatha V. Gurudevan, Francine Anene, Robert M. Elashoff, Gail Thomas, Ronald G. Victor

Research output: Contribution to journalArticle

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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 (nNOSμ), which requires certain spectrin-like repeats in dystrophin's rod domain and the adaptor protein α-syntrophin to be targeted to the sarcolemma. When healthy skeletal muscle is subjected to exercise, sarcolemmal nNOSμ-derived NO attenuates local α-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 nNOSμ 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 nNOSμ. 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 nNOSμ 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.

Original languageEnglish (US)
Article number162ra155
JournalScience Translational Medicine
Volume4
Issue number162
DOIs
StatePublished - Nov 28 2012

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Duchenne Muscular Dystrophy
Ischemia
Nitric Oxide Synthase Type I
Muscles
Dystrophin
Sarcolemma
Vasoconstriction
Skeletal Muscle
Exercise
Type 5 Cyclic Nucleotide Phosphodiesterases
Inbred mdx Mouse
Wasting Syndrome
Guanosine Monophosphate
Spectrin
Mutation
Cytoskeletal Proteins
Phosphodiesterase Inhibitors
Tadalafil
Muscle Proteins
Vasoconstrictor Agents

All Science Journal Classification (ASJC) codes

  • Medicine(all)

Cite this

Martin, E. A., Barresi, R., Byrne, B. J., Tsimerinov, E. I., Scott, B. L., Walker, A. E., ... Victor, R. G. (2012). Tadalafil alleviates muscle ischemia in patients with becker muscular dystrophy. Science Translational Medicine, 4(162), [162ra155]. https://doi.org/10.1126/scitranslmed.3004327
Martin, Elizabeth A. ; Barresi, Rita ; Byrne, Barry J. ; Tsimerinov, Evgeny I. ; Scott, Bryan L. ; Walker, Ashley E. ; Gurudevan, Swaminatha V. ; Anene, Francine ; Elashoff, Robert M. ; Thomas, Gail ; Victor, Ronald G. / Tadalafil alleviates muscle ischemia in patients with becker muscular dystrophy. In: Science Translational Medicine. 2012 ; Vol. 4, No. 162.
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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 (nNOSμ), which requires certain spectrin-like repeats in dystrophin's rod domain and the adaptor protein α-syntrophin to be targeted to the sarcolemma. When healthy skeletal muscle is subjected to exercise, sarcolemmal nNOSμ-derived NO attenuates local α-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 nNOSμ 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 nNOSμ. 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 nNOSμ 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.",
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Martin, EA, Barresi, R, Byrne, BJ, Tsimerinov, EI, Scott, BL, Walker, AE, Gurudevan, SV, Anene, F, Elashoff, RM, Thomas, G & Victor, RG 2012, 'Tadalafil alleviates muscle ischemia in patients with becker muscular dystrophy', Science Translational Medicine, vol. 4, no. 162, 162ra155. https://doi.org/10.1126/scitranslmed.3004327

Tadalafil alleviates muscle ischemia in patients with becker muscular dystrophy. / Martin, Elizabeth A.; Barresi, Rita; Byrne, Barry J.; Tsimerinov, Evgeny I.; Scott, Bryan L.; Walker, Ashley E.; Gurudevan, Swaminatha V.; Anene, Francine; Elashoff, Robert M.; Thomas, Gail; Victor, Ronald G.

In: Science Translational Medicine, Vol. 4, No. 162, 162ra155, 28.11.2012.

Research output: Contribution to journalArticle

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AU - Martin, Elizabeth A.

AU - Barresi, Rita

AU - Byrne, Barry J.

AU - Tsimerinov, Evgeny I.

AU - Scott, Bryan L.

AU - Walker, Ashley E.

AU - Gurudevan, Swaminatha V.

AU - Anene, Francine

AU - Elashoff, Robert M.

AU - Thomas, Gail

AU - Victor, Ronald G.

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N2 - 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 (nNOSμ), which requires certain spectrin-like repeats in dystrophin's rod domain and the adaptor protein α-syntrophin to be targeted to the sarcolemma. When healthy skeletal muscle is subjected to exercise, sarcolemmal nNOSμ-derived NO attenuates local α-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 nNOSμ 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 nNOSμ. 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 nNOSμ 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.

AB - 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 (nNOSμ), which requires certain spectrin-like repeats in dystrophin's rod domain and the adaptor protein α-syntrophin to be targeted to the sarcolemma. When healthy skeletal muscle is subjected to exercise, sarcolemmal nNOSμ-derived NO attenuates local α-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 nNOSμ 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 nNOSμ. 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 nNOSμ 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.

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Martin EA, Barresi R, Byrne BJ, Tsimerinov EI, Scott BL, Walker AE et al. Tadalafil alleviates muscle ischemia in patients with becker muscular dystrophy. Science Translational Medicine. 2012 Nov 28;4(162). 162ra155. https://doi.org/10.1126/scitranslmed.3004327