Nuclear factor kappa-B blockade reduces skeletal muscle degeneration and enhances muscle function in Mdx mice
Nuclear factor kappa-B blockade reduces skeletal muscle degeneration and enhances muscle function in Mdx mice
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DOI：
10.1016/j.expneurol.2005.11.021
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发表时间：
2006-03-01
影响因子：
5.3
通讯作者：
Vita, G
中科院分区：
文献类型：
--
作者：
Messina, S;Bitto, A;Vita, G
Duchenne肌营养不良症(DMD)是一种进行性肌肉萎缩疾病，由肌营养不良蛋白基因突变和相应的肌肉蛋白质缺乏引起。肌膜蛋白Dstrophin的缺乏如何导致最终的疾病状态仍不清楚。一些证据表明核因子-kappa-B(核因子-kappa-B)，一种多效性转录因子，在DMD患者和mdx小鼠的肌肉退化和再生中发挥作用。我们研究了著名的核因子-kappa B抑制剂吡咯烷二硫代氨基甲酸酯(PDTC)对mdx小鼠营养不良过程的影响。PDTC治疗：(I)增加MDX小鼠的前肢强度(+20%；P<；0.05)和归一化重量强度(+24%；P<；0.05)，降低疲劳百分比(-61%；P<；0.05)，(Ii)钝化营养不良肌肉中增强的核因子-kappaB核结合活性和增强的TNF-α表达(P<；0.05)。在对趾长伸肌(EDL)和二头肌的定量形态评估中，(Iii)在定量形态评估中，指长伸肌(EDL)和二头肌的正常纤维面积增加(P<；0.05，EDL)，肌肉坏死减少(P<；0.05，EDL；0.01)，肌肉再生增强(P<；0.01，二头肌)。我们的数据支持这样的假设，即NF-kappa B有助于MDX小鼠营养不良损伤的持续，并表明其阻断对MDX小鼠的功能、生化和形态参数产生了有益的影响。最重要的是，这些新发现可能对DMD患者的药物治疗具有临床意义。(C)2005 Elsevier Inc.保留所有权利。
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-kappa B), a pleiotropic transcription factor, in muscle degeneration and regeneration in DMD patients and mdx mice. We investigated the effects of NF-kappa B blocking by pyrrolidine dithiocarbarnate (PDTC), a well-known NF-kappa B 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-kappa B 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-kappa B 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. (c) 2005 Elsevier Inc. All rights reserved.