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Evaluation of the Therapeutic Utility of Phosphodiesterase 5A Inhibition in the mdx Mouse Model of Duchenne Muscular Dystrophy

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Phosphodiesterases as Drug Targets

Part of the book series: Handbook of Experimental Pharmacology ((HEP,volume 204))

Abstract

Duchenne muscular dystrophy (DMD) is a devastating and ultimately fatal disease characterized by progressive muscle wasting and weakness. DMD is caused by the absence of a functional dystrophin protein, which in turn leads to reduced expression and mislocalization of dystrophin-associated proteins including neuronal nitric oxide (NO) synthase mu (nNOSμ). Disruption of nNOSμ signaling results in muscle fatigue and unopposed sympathetic vasoconstriction during exercise, thereby increasing contraction-induced damage in dystrophin-deficient muscles. The loss of normal nNOSμ signaling during exercise is central to the vascular dysfunction proposed over 40 years ago to be an important pathogenic mechanism in DMD. Recent preclinical studies focused on circumventing defective nNOSμ signaling in dystrophic skeletal and cardiac muscle by inhibiting phosphodiesterase 5A (PDE5A) have shown promising results. This review addresses nNOS signaling in normal and dystrophin-deficient muscles and the potential of PDE5A inhibition as a therapeutic approach for the treatment of cardiovascular deficits in DMD.

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Acknowledgments

The authors thanks members of the Froehner lab and Dr Kimberley Craven for helpful discussions and suggestions. Research related to the role of nNOS and PDE5A inhibitors in our laboratories is supported by the Muscular Dystrophy Association (JMP), Charlie’s Fund (SCF and JAB), Parent Project Muscular Dystrophy (JMP and SCF), NIH grants NS33145 (SCF), NS59514 (SCF and JAB), and AR056221 (SCF and JAB).

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Authors and Affiliations

  1. Department of Physiology and Biophysics, University of Washington, 357290, 98195-7290, Seattle, WA, USA

    Justin M. Percival & Stanley C. Froehner

  2. Department of Pharmacology, University of Washington, 357290, 98195-7290, Seattle, WA, USA

    Candace M. Adamo & Joseph A. Beavo

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  1. Justin M. Percival
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  2. Candace M. Adamo
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  3. Joseph A. Beavo
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  4. Stanley C. Froehner
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Correspondence to Justin M. Percival .

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Editors and Affiliations

  1. School of Medicine, Dept. Molecular Physiology & Biophysics, Vanderbilt University, Light Hall 702, Nashville, 37232-0615, Tennessee, USA

    Sharron H. Francis

  2. HSW 1656, Center for Reproductive Sciences, Parnassus Avenue 513, San Francisco, 94143-0556, California, USA

    Marco Conti

  3. Wolfson Building, University of Glasgow, Glasgow, G12 8QQ, United Kingdom

    Miles D. Houslay

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Percival, J.M., Adamo, C.M., Beavo, J.A., Froehner, S.C. (2011). Evaluation of the Therapeutic Utility of Phosphodiesterase 5A Inhibition in the mdx Mouse Model of Duchenne Muscular Dystrophy. In: Francis, S., Conti, M., Houslay, M. (eds) Phosphodiesterases as Drug Targets. Handbook of Experimental Pharmacology, vol 204. Springer, Berlin, Heidelberg. https://doi.org/10.1007/978-3-642-17969-3_14

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