Enhanced myocardial ERK activation in animal models of Duchenne and Limb Girdle 2F Muscular Dystrophy

Abstract

Duchenne muscular dystrophy (DMD) is caused by deficiency of the protein dystrophin. Oxidative stress is thought to be involved in the pathogenesis of DMD skeletal muscle damage. However, little is known about the role of oxidative damage in the pathogenesis of the heart failure that occurs in DMD patients. The mdx mouse is an animal model of DMD which also lacks dystrophin. The current study investigates the role of the antioxidant, N-acetylcysteine (NAC), on mdx cardiomyocyte function, Ca-handling, and the cardiac inflammatory response. 4 groups of animals (9 weeks old) were studied: wild-type (WT), mdx and WT and mdx mice that received 1% NAC in their drinking water for 6 weeks. NAC had no effect on WT mice. Immunohistochemistry experiments revealed that compared to WT hearts, mdx mice had increased DHE staining, an indictor of superoxide production; NAC treatment reduced DHE staining in mdx hearts. NAC treatment attenuated abnormalities in mdx cardiomyocyte Ca handling. Mdx cardiomyocytes had decreased fractional shortening (FS) and decreased Ca-sensitivity; NAC treatment returned mdx FS to WT values, but did not affect the Ca-sensitivity. Immunohistochemistry experiments revealed that mdx hearts had increased levels of the macrophage specific protein CD68 and of collagen type III; NAC treatment reduced CD68 expression and returned collagen type III expression close to WT values. This study is the first to demonstrate that oxidative damage may be involved in the pathogenesis of the heart failure that occurs in mdx mice. Therapies designed to reduce oxidative damage might be beneficial to DMD patients with heart failure.