Nuclear factor kappa-B blockade reduces skeletal muscle degeneration and enhances muscle function in Mdx mice

详细信息    查看全文

• 作者：Sonia Messina ; Alessandra Bitto ; M'hammed Aguennouz ; Letteria Minutoli ; Maria C. Monici ; Domenica Altavilla ; Francesco Squadrito and Giuseppe Vita
• 关键词：mdx mice ; NF-κ ; B ; PDTC ; Duchenne muscular dystrophy ; TNF-α
• 刊名：Experimental Neurology
• 出版年：2006
• 出版时间：March 2006
• 年：2006
• 卷：198
• 期：1
• 页码：234-241
• 全文大小：398 K

文摘

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-κB), a pleiotropic transcription factor, in muscle degeneration and regeneration in DMD patients and mdx mice. We investigated the effects of NF-κB blocking by pyrrolidine dithiocarbamate (PDTC), a well-known NF-κB 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-κB nuclear binding activity and the enhanced TNF-α 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-κB 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.