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

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.

Fig. 1

Propagation of NO-cGMP signals in skeletal, smooth, and cardiac muscle. Nitric oxide synthase enzymes (nNOS and eNOS) regulate, and are regulated by, Ca²⁺ fluxes in muscle cells. Ca²⁺/CaM activation of nNOS (or eNOS) leads to synthesis of NO, which in turn binds and activates sGC. cGMP produced by sGC then modulates downstream effector activity (see text) Abbreviations: α-Dg, α-dystroglycan; β-Dg, β-dystroglycan; α-syn, α-syntrophin; AChR, nicotinic acetylcholine receptor; CaM, calmodulin; Cav-1, Caveolin-1; Cav-3, caveolin-3; DHPR, dihyropyridine receptor; IRAG, inositol 1,4,5-triphosphate receptor I-associated cGMP kinase substrate; PKG, protein kinase G (cGK); L-arg, L-arginine; LTCC, L-type calcium channel; MLCP, myosin light chain phosphatase; NO, nitric oxide; PDE, phosphodiesterase; pGD, particulate guanylyl cyclase; PMCA4, plasma membrane calcium ATPase 4; RGS2, regulator of G protein signaling 2; RyR, ryanodine receptor; sGC, soluble guanylyl cyclase; SPN, sarcospan; SR, sarcoplasmic reticulum

Fig. 2

Sildenafil treatment reverses cardiomyopathy in old mdx mice. Twelve-month-old mdx mice exhibit significant left ventricle dysfunction as indicated by a high myocardial performance index compared with wild-type mice (^#p < 0.05). Twelve-month-old mdx mice treated for 3 months with the PDE5 inhibitor sildenafil ad libitum exhibited a significantly reduced (p < 0.05) myocardial performance index comparable to wild-type controls. Sildenafil treatment can reverse established global left ventricle dysfunction in old mdx mice (Adamo et al. 2010)