失神经骨骼肌萎缩与氯沙坦通过核因子κ B/MuRF1通路的延缓作用

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

背景:在失神经骨骼肌萎缩中,核因子κB/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κB、MuRF1在失神经骨骼肌中的表达及氯沙坦对核因子κB/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10mg/(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2,14,28d时大鼠腓肠肌核因子κB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κB和MuRF1的mRNA和蛋白表达在2,14,28d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14,8d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κB、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κB、MuRF1 mRNA和蛋白质的表达来延缓失神经骨骼肌萎缩。

BACKGROUND：Nuclear factor κB（NF-κB）/ muscle RING finger protein1（MuRF1） pathway is one of the most important molecular mechanisms in skeletal muscle atrophy.Inhibiting of NF-κB / MuRF1 pathway improves denervated skeletal muscle strength,maintains muscle mass,and promotes regeneration.OBJECTIVE：To explore the expression of NF-κB and MuRF1 in denervated skeletal muscle atrophy in rats and the effect of losartan on NF-κB / 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-κB 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-κB 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-κB 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-κB 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-κB and MuRF1 was up-regulated,suggesting the presence of NF-κB / MuRF1 pathway.Results show that losartan can decrease denervated skeletal muscle atrophy through NF-κB/MuRF1 pathway.