Lipid peroxidation inhibition blunts nuclear factor-kappaB activation, reduces skeletal muscle degeneration, and enhances muscle function in mdx mice.
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.
Messina
Sonia
S
Department of Neuroscience, Psychiatry, and Anaesthesiology, University of Messina, Messina, Italy.
Altavilla
Domenica
D
Aguennouz
M'hammed
M
Seminara
Paolo
P
Minutoli
Letteria
L
Monici
Maria C
MC
Bitto
Alessandra
A
Mazzeo
Anna
A
Marini
Herbert
H
Squadrito
Francesco
F
Vita
Giuseppe
G
D000818:Animals; D000975:Antioxidants / Q000494:pharmacology; D001572:Benzofurans / Q000494:pharmacology; D001835:Body Weight; D003402:Creatine Kinase / Q000032:analysis; D004247:DNA / Q000378:metabolism; D005552:Forelimb / Q000502:physiology; D005978:Glutathione / Q000032:analysis; D015227:Lipid Peroxidation / Q000187:drug effects*; D008297:Male; D051379:Mice; D018101:Mice, Inbred mdx; D018763:Muscle Fatigue / Q000502:physiology; D018482:Muscle, Skeletal / Q000737:chemistry / Q000473:pathology* / Q000503:physiopathology; D020388:Muscular Dystrophy, Duchenne / Q000378:metabolism* / Q000473:pathology* / Q000503:physiopathology; D016328:NF-kappa B / Q000378:metabolism*; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism
D000975:Antioxidants; D001572:Benzofurans; C413683:IRFI 042; D016328:NF-kappa B; D014409:Tumor Necrosis Factor-alpha; D004247:DNA; D003402:Creatine Kinase; D005978:Glutathione