Lipid peroxidation inhibition blunts nuclear factor-kappaB activation, reduces skeletal muscle degeneration, and enhances muscle function in mdx mice |
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| Authors: | Messina Sonia Altavilla Domenica Aguennouz M'hammed Seminara Paolo Minutoli Letteria Monici Maria C Bitto Alessandra Mazzeo Anna Marini Herbert Squadrito Francesco Vita Giuseppe |
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| Affiliation: | Department of Neuroscience, Psychiatry, and Anaesthesiology, University of Messina, Messina, Italy. |
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| Abstract: | Duchenne muscular dystrophy (DMD) is a progressive muscle-wasting disease resulting from lack of the sarcolemmal protein dystrophin. However, the mechanism leading to the final disease status is not fully understood. Several lines of evidence suggest a role for nuclear factor (NF)-kappaB in muscle degeneration as well as regeneration in DMD patients and mdx mice. We investigated the effects of blocking NF-kappaB by inhibition of oxidative stress/lipid peroxidation on the dystrophic process in mdx mice. Five-week-old mdx mice received three times a week for 5 weeks either IRFI-042 (20 mg/kg), a strong antioxidant and lipid peroxidation inhibitor, or its vehicle. IRFI-042 treatment increased forelimb strength (+22%, P < 0.05) and strength normalized to weight (+23%, P < 0.05) and decreased fatigue (-45%, P < 0.05). It also reduced serum creatine kinase levels (P < 0.01) and reduced muscle-conjugated diene content and augmented muscle-reduced glutathione (P < 0.01). IRFI-042 blunted NF-kappaB DNA-binding activity and tumor necrosis factor-alpha expression in the dystrophic muscles (P < 0.01), reducing muscle necrosis (P < 0.01) and enhancing regeneration (P < 0.05). Our data suggest that oxidative stress/lipid peroxidation represents one of the mechanisms activating NF-kappaB and the consequent pathogenetic cascade in mdx muscles. Most importantly, these new findings may have clinical implications for the pharmacological treatment of patients with DMD. |
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