Biology Reference
In-Depth Information
Evaluation of the Therapeutic Utility
of Phosphodiesterase 5A Inhibition in the mdx
Mouse Model of Duchenne Muscular Dystrophy
Justin M. Percival, Candace M. Adamo, Joseph A. Beavo,
and Stanley C. Froehner
Contents
1 Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 324
2 nNOS Signaling in Skeletal Muscle . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 325
3 nNOS Signaling in Cardiac Muscle . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 328
4 Skeletal Muscle Pathogenesis in Duchenne Muscular Dystrophy . . . . . . . . . . . . . . . . . . . . . . . . 329
5 Cardiac Muscle Pathogenesis in Duchenne Muscular Dystrophy . . . . . . . . . . . . . . . . . . . . . . . . . 331
6 Vascular Dysfunction Contributes to the Pathogenesis
ofDMD ...................................................................................333
7 Augmentation of Nitric Oxide Signaling in mdx Mice . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 335
8 Use of PDE5A Inhibitors to Amplify cGMP Signaling in mdx Mice . . . . . . . . . . . . . . . . . . . . . 336
9 Conclusion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 339
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 340
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 (nNOS m ). Disruption of nNOS m signaling
results in muscle fatigue and unopposed sympathetic vasoconstriction during exer-
cise, thereby increasing contraction-induced damage in dystrophin-deficient mus-
cles. The loss of normal nNOS m 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 nNOS m
signaling in dystrophic skeletal and cardiac muscle by inhibiting phosphodiesterase
5A (PDE5A) have shown promising results. This review addresses nNOS signaling
J.M. Percival ( * ) and S.C. Froehner
Department of Physiology and Biophysics, University of Washington, 357290, 98195-7290
Seattle, WA, USA
e-mail: justinp2@u.washington.edu
C.M. Adamo and J.A. Beavo
Department of Pharmacology, University of Washington, 357290, 98195-7290 Seattle, WA, USA
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