失神经骨骼肌萎缩与氯沙坦通过核因子kB/MuRF1通路的延缓作用

背景:在失神经骨骼肌萎缩中,核因子kB/MuRF1通路是最关键的分子机制之一,抑制该通路可以提高失神经骨骼肌的力量,保持肌肉数量和促进肌肉再生.目的:探讨核因子KB、MuRF1存失神经骨骼肌中的表达及氯沙坦对核因子KB/MuRF1通路的影响作用,以期寻找延缓失神经骨骼肌萎缩的新途径.方法:将Wista大鼠随机分为3组:失神经对照组、氯沙坦治疗组建立右下肢失神经腓肠肌动物模型.氯沙坦治疗组大鼠采用氯沙坦以10 mg/(kg·d)空腹灌胃;失神经对照组大鼠以等剂量生理盐水灌胃,以不做处理的大鼠为正常对照.采用RT-PCR和Western Blotting 检测术后2,14,28 d时大鼠腓肠肌核因子KB和MuRF1的mRNA和蛋白表达水平,并结合肌肉失质量比分析其相关性.结果与结论:大鼠腓肠肌失神经支配后核因子KB和MuRFl的mRNA和蛋白表达在2,14,28 d持续增加(P<0.05),而且二因子的表达线性相关有显著性意义(P<0.05).失神经支配后14,8 d氯沙坦治疗组腓肠肌湿质量比高于同期失神经对照组(P<0.05),氯沙坦治疗组两因子mRNA和蛋白的表达在各个时间点低于失神经对照组(P<0.05).核因子KB、MuRF1在失神经肌萎缩中表达增高,而且是同一通路.结果提示氯沙坦可以通过干扰核因子KB、MuRF1mRNA和蛋白质的表达来延缓失神经骨骼肌萎缩.

Losartan decreases denervated skeletal muscle atrophy through nuclear factor-kappaB / muscle RING finger protein 1

BACKGROUND:Nuclear factor kB (NF-kB)/ muscle RING finger protein 1 (MuRF1) pathway is one of the most important molecular mechanisms in skeletal muscle atrophy. Inhibiting of NF-kB / MuRF1 pathway improves denervated skeletal muscle strength, maintains muscle mass, and promotes regeneration. OBJECTIVE: To explore the expression of NF-kB and MuRF1 in denervated skeletal muscle atrophy in rats and the effect of losartan on NF-kB / MuRF1 pathway. METHODS: Wistar rats were randomly divided into 3 groups. The denervated and Losartan groups were subjected to establishment of denervated gastrocnemius models followed by normal saline perfusion or losartan 10 mg/kg per day. The control group was not treated. After 2,14 and 28 days, levels of NF-kB and MuRF1 mRNA and protein in the gastrocnemius were detected respectively by RT-PCR and Western bloting. The ratio of muscle wet weight was also analyzed for comparison. RESULTS AND CONCLUSION: Expressions of NF-kB and MuRF1 mRNA and protein in denervated skeletal muscle were up-regulated at 2,14, and 28 days following denervation (P < 0.05). Moreover, NF-kB expression of positively correlated with MuRF1 expression (P< 0.05). At 14 and 28 days after denervation, the losartan group had a greater ratio of muscle wet weight compared with denervated group (P < 0.05). The expression of NF-kB and MuRF1 mRNA and protein in losartan group remarkably reduced compared with denervated group (P < 0.05) at each time point. At the early stage of denervated skeletal muscle atrophy, expression of NF-kB and MuRF1 was up-regulated, suggesting the presence of NF-kB / MuRF1 pathway. Results show that losartan can decrease denervated skeletal muscle atrophy through NF-kB/MuRF1 pathway.