Evaluation of the therapeutic utility of phosphodiesterase 5A inhibition in the mdx mouse model of duchenne muscular dystrophy

Justin Percival, Candace M. Adamo, Joseph A. Beavo, Stanley C. Froehner

Research output: Contribution to journalArticle

21 Scopus citations

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.

Original languageEnglish
Pages (from-to)323-344
Number of pages22
JournalHandbook of Experimental Pharmacology
Volume204
DOIs
StatePublished - Aug 3 2011
Externally publishedYes

Keywords

  • Cardiac muscle
  • Cardiomyopathy
  • cGMP
  • Duchenne Muscular Dystrophy
  • Dystrophin
  • Mdx
  • Neuronal nitric oxide synthase
  • Nitric oxide
  • nNOS
  • PDE5
  • PDE5 inhibitors
  • Sildenafil
  • Skeletal muscle

ASJC Scopus subject areas

  • Pharmacology, Toxicology and Pharmaceutics(all)
  • Biochemistry

Fingerprint Dive into the research topics of 'Evaluation of the therapeutic utility of phosphodiesterase 5A inhibition in the mdx mouse model of duchenne muscular dystrophy'. Together they form a unique fingerprint.

  • Cite this