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Am J Physiol Heart Circ Physiol (June 15, 2007). doi:10.1152/ajpheart.00489.2007
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Submitted on April 24, 2007
Accepted on June 12, 2007

THE ROLE OF REACTIVE OXYGEN SPECIES IN THE HEARTS OF DYSTROPHIN-DEFICIENT (MDX) MICE

Iwan A Williams1 and David G. Allen2*

1 Sydney, New South Wales, Australia; Department of Physiology and Bosch Institute, University of Sydney, Sydney, Australia
2 Department of Physiology and Bosch Institute, University of Sydney, Sydney, Australia

* To whom correspondence should be addressed. E-mail: davida{at}physiol.usyd.edu.au.

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 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, Ca2+ handling, and the cardiac inflammatory response. Treated mice received 1% NAC in their drinking water for 6 weeks. NAC had no effect on wild-type (WT) mice. Immunohistochemistry experiments revealed that mdx mice had increased di-hydroethidine (DHE) staining, an indicator of superoxide production; NAC-treatment reduced DHE staining in mdx hearts. NAC-treatment attenuated abnormalities in mdx cardiomyocyte Ca2+ handling. Mdx cardiomyocytes had decreased fractional shortening and decreased Ca2+-sensitivity; NAC-treatment returned mdx fractional shortening to WT values, but did not affect the Ca2+-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 ROS 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.




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