Journal
FREE RADICAL BIOLOGY AND MEDICINE
Volume 52, Issue 9, Pages 1597-1606Publisher
ELSEVIER SCIENCE INC
DOI: 10.1016/j.freeradbiomed.2012.01.015
Keywords
Diaphragm; Oxidative stress; NF-kappa B; Duchenne muscular dystrophy; Free radicals
Funding
- NIH [AR054084]
- J.L. & Sydney Huffines Institute for Sports Medicine
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Duchenne muscular dystrophy (DMD) is a common and devastating type of childhood-onset muscular dystrophy, attributed to an X-linked defect in the gene that encodes dystrophin. Myopathy with DMD is most pronounced in the diaphragm muscle and fast-twitch limb muscles and is dependent upon susceptibility to damage, inflammatory cell infiltration, and proinflammatory signaling (nuclear factor-kappa B: NF-kappa B). Although recent papers have reawakened the notion that oxidative stress links inflammatory signaling with pathology in DMD in limb muscle, the importance of redox mechanisms had been clouded by inconsistent results from indirect scavenger approaches, including in the diaphragm muscle. Therefore, we used a novel catalytic mimetic of superoxide dismutase and catalase (EUK-134) as a direct scavenger of oxidative stress in myopathy in the diaphragm of the mdx mouse model. EUK-134 reduced 4-hydroxynonenal and total hydroperoxides, markers of oxidative stress in the mdx diaphragm. EUK-134 also attenuated positive staining of macrophages and T-cells as well as activation of NF-kappa B and p65 protein abundance. Moreover, EUK-134 ameliorated markers of muscle damage including internalized nuclei, variability of cross-sectional area, and type Ilc fibers. Finally, impairment of contractile force was partially rescued by EUK-134 in the diaphragm of mdx mice. We conclude that oxidative stress amplifies DMD pathology in the diaphragm muscle. (c) 2012 Elsevier Inc. All rights reserved.
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