title: Nuclear factor kappa-B blockade reduces skeletal muscle degeneration and enhances muscle function in Mdx mice.
abstract: Duchenne muscular dystrophy (DMD) is a progressive muscle-wasting disease due to a mutation in the dystrophin gene and the consequential protein deficiency in muscle. How the lack of the sarcolemmal protein dystrophin gives rise to the final disease status is still not clear. Several evidences suggest a role of nuclear factor kappa-B (NF-kappaB), a pleiotropic transcription factor, in muscle degeneration and regeneration in DMD patients and mdx mice. We investigated the effects of NF-kappaB blocking by pyrrolidine dithiocarbamate (PDTC), a well-known NF-kappaB inhibitor, on dystrophic process in mdx mice. Five-week-old mdx and wild-type mice received three times a week for 5 weeks either PDTC (50 mg/kg) or its vehicle. PDTC treatment: (i) increased forelimb strength (+20%; P < 0.05) and strength normalized to weight (+24%; P < 0.05) and a decreased fatigue percentage (-61%; P < 0.05) in mdx mice, (ii) blunted the augmented NF-kappaB nuclear binding activity and the enhanced TNF-alpha expression in dystrophic muscles (P < 0.01), (iii) at a quantitative morphological evaluation of extensor digitorum longus (EDL) and biceps muscles, increased area with normal fibers (P < 0.05, in EDL), reduced muscle necrosis (P < 0.05 in biceps; P < 0.01 in EDL), and enhanced muscle regeneration (P < 0.01, in biceps). Our data support the hypothesis that NF-kappaB contributes to the perpetuation of the dystrophic damage and show that its blockade produces beneficial effects on functional, biochemical, and morphological parameters in mdx mice. Most importantly, these new findings may have clinical implications for the pharmacological treatment of patients with DMD.
authors.affiliation: Department of Neuroscience, Psychiatry and Anaesthesiology, University of Messina, Italy.
authors.forename: Sonia
authors.initials: S
authors.lastname: Messina
authors.forename: Alessandra
authors.initials: A
authors.lastname: Bitto
authors.forename: M'hammed
authors.initials: M
authors.lastname: Aguennouz
authors.forename: Letteria
authors.initials: L
authors.lastname: Minutoli
authors.forename: Maria C
authors.initials: MC
authors.lastname: Monici
authors.forename: Domenica
authors.initials: D
authors.lastname: Altavilla
authors.forename: Francesco
authors.initials: F
authors.lastname: Squadrito
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Vita
mesh_terms: D000818:Animals; D015153:Blotting, Western / Q000379:methods; D001835:Body Weight / Q000187:drug effects; D004195:Disease Models, Animal; D024202:Electrophoretic Mobility Shift Assay / Q000379:methods; D004791:Enzyme Inhibitors / Q000627:therapeutic use; D005552:Forelimb / Q000187:drug effects / Q000503:physiopathology; D051379:Mice; D008810:Mice, Inbred C57BL; D018101:Mice, Inbred mdx; D018482:Muscle, Skeletal / Q000187:drug effects / Q000503:physiopathology*; D009137:Muscular Dystrophy, Animal / Q000188:drug therapy / Q000378:metabolism* / Q000503:physiopathology*; D016328:NF-kappa B / Q000037:antagonists & inhibitors / Q000502:physiology*; D011392:Proline / Q000031:analogs & derivatives / Q000627:therapeutic use; D012038:Regeneration / Q000187:drug effects / Q000502:physiology*; D013859:Thiocarbamates / Q000627:therapeutic use
chemical_list: D004791:Enzyme Inhibitors; D016328:NF-kappa B; D013859:Thiocarbamates; C066229:prolinedithiocarbamate; D011392:Proline