Heart failure in dystrophin-deficient (mdx) mice : role of stretch-activated channels and reactive oxygen species

Abstract

Duchenne muscular dystrophy (DMD) is caused by deficiency of the cytoskeletal protein dystrophin. DMD patients develop a dilated cardiomyopathy. The first half of this thesis explores the possibility that dystrophin is involved in the regulation of a stretch-activated channel (SAC). Because cardiac failure only appears late in the progression of DMD. we examined age—related effects in the mdx mouse, an animal model of DMD. Old mdx (9-12 months) mice had raised resting intracellular Ca2+ concentration ([Ca2+]i), while cardiomyocytes from young (9 weeks) and old mdx mice displayed abnormal Ca2+ transients and Ca2+ handling protein expression. Old mdx mice had increased protein expression of TRPCl, a likely candidate protein for SACs, while the SAC inhibitors streptomycin and GsMTx-4 reduced resting [Ca2+], in old mdx mice. These observations suggest that SACs may be involved in the Ca2+ handling abnormalities in these animals. Thus, SACs may play a role in the pathogenesis of the heart failure associated with DMD. The second half of this thesis investigated the effects of the antioxidant N-acetylcysteine (NAC) on myocardial function in young (9 weeks) mdx mice following 6 weeks of treatment. NAC had no effect on wild type mice. Experiments revealed that mdx mice had increased reactive oxygen species levels; NAC-treatment reduced ROS levels in mdx hearts. NACtreatment attenuated abnormalities in mdx cardiomyocyte Ca2+ handling, reversed defects in mdx myofilament function, and prevented myocardial inflammation. de hearts had increased NADPH oxidase activity, a ROS producing enzyme, suggesting it could be a possible source of augmented ROS in mdx mice. Therapies designed to reduce oxidative damage might be beneficial to DMD patients with heart failure.