N-acetylcysteine treatment in dystrophin-deficient mdx mice reduced superoxide production, attenuated Ca(2+) handling abnormalities, and restored fractional shortening to wild-type levels.
Does N-acetylcysteine improve cardiomyocyte function and reduce cardiac inflammation in dystrophin-deficient mdx mice?
Antioxidant therapy with N-acetylcysteine improves cardiomyocyte function and reduces cardiac inflammation in a mouse model of Duchenne muscular dystrophy, suggesting oxidative damage contributes to DMD-associated heart failure.
Duchenne muscular dystrophy (DMD) is caused by deficiency of the cytoskeletal protein dystrophin. Oxidative stress is thought to contribute to the skeletal muscle damage in DMD; however, little is known about the role of oxidative damage in the pathogenesis of the heart failure that occurs in DMD patients. The dystrophin-deficient (mdx) mouse is an animal model of DMD that also lacks dystrophin. The current study investigates the role of the antioxidant N-acetylcysteine (NAC) on mdx cardiomyocyte function, Ca(2+) handling, and the cardiac inflammatory response. Treated mice received 1% NAC in their drinking water for 6 wk. NAC had no effect on wild-type (WT) mice. Immunohistochemistry experiments revealed that mdx mice had increased dihydroethidine (DHE) staining, an indicator of superoxide production; NAC-treatment reduced DHE staining in mdx hearts. NAC treatment attenuated abnormalities in mdx cardiomyocyte Ca(2+) handling. Mdx cardiomyocytes had decreased fractional shortening and decreased Ca(2+) sensitivity; NAC treatment returned mdx fractional shortening to WT values but did not affect the Ca(2+) sensitivity. Immunohistochemistry experiments revealed that mdx hearts had increased levels of collagen type III and the macrophage-specific protein, CD68; NAC-treatment returned collagen type III and CD68 expression close to WT values. Finally, mdx hearts had increased NADPH oxidase activity, suggesting it could be a possible source of increased reactive oxygen species in mdx mice. 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.
Williams et al. (Sat,) conducted a other in Duchenne muscular dystrophy (DMD) / dystrophin-deficient mdx mice. N-acetylcysteine (NAC) vs. Untreated mdx mice and wild-type (WT) mice was evaluated on Cardiomyocyte function, Ca(2+) handling, and cardiac inflammatory response. N-acetylcysteine treatment in dystrophin-deficient mdx mice reduced superoxide production, attenuated Ca(2+) handling abnormalities, and restored fractional shortening to wild-type levels.