title: Amplification of proinflammatory phenotype, damage, and weakness by oxidative stress in the diaphragm muscle of mdx mice.
abstract: 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-κB; NF-κB). 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-κB and p65 protein abundance. Moreover, EUK-134 ameliorated markers of muscle damage including internalized nuclei, variability of cross-sectional area, and type IIc 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.
authors.affiliation: Redox Biology and Cell Signaling Laboratory, Department of Health & Kinesiology, Texas A&M University, College Station, TX 77843-4243, USA.
authors.forename: Jong-Hee
authors.initials: JH
authors.lastname: Kim
authors.forename: John M
authors.initials: JM
authors.lastname: Lawler
mesh_terms: D000818:Animals; D055162:Biocatalysis; D002374:Catalase / Q000378:metabolism; D003964:Diaphragm / Q000201:enzymology / Q000378:metabolism* / Q000502:physiology; D005455:Fluorescent Antibody Technique; D007150:Immunohistochemistry; D007249:Inflammation / Q000378:metabolism*; D051379:Mice; D018101:Mice, Inbred mdx; D009119:Muscle Contraction; D018908:Muscle Weakness; D018384:Oxidative Stress; D010641:Phenotype; D013482:Superoxide Dismutase / Q000378:metabolism
chemical_list: D002374:Catalase; D013482:Superoxide Dismutase