CKD时高糖皮质激素通过激活Atrogin-1、MuRF-1引起骨骼肌萎缩  

High Lever of Glucocorticoid Enhanced Muscle Atrophy Though Atrogin-1 in CKD Mice

作　　者：王会玲[1] 桂志红[1] 许烨[1] 张金元[1] 

机构地区：[1]解放军第四五五医院肾脏科,南京军区肾脏病专科中心,上海200052

出　　处：《中国中西医结合肾病杂志》2010年第11期953-957,共5页Chinese Journal of Integrated Traditional and Western Nephrology

基　　金：上海启明星跟踪基金资助项目(No.07QH14020)

摘　　要：目的:瘦体质量丢失和肌肉消耗状态是慢性肾脏病(CKD)严重并发症,并与患者不良预后有关。本研究观察CKD模型小鼠骨骼肌合成和分解代谢,分析肌肉特异性E3连接酶肌萎缩蛋白Fbox-1(Atrogin-1)在肌萎缩中的作用,探讨CKD肌肉消耗的病理机制。方法:采用5/6肾切除制作小鼠CKD模型,以假手术组为对照组。同位素14+C-苯丙氨酸掺入法检测肌肉蛋白合成,酪氨酸释放率分析检测肌肉分解代谢,组织病理学检测胫骨前肌横截面积并计算肌纤维面积分布图,Northern blot检测Atrogin-1和肌环指蛋白-1(MurF-1)mRNA水平,Western blot检测其蛋白表达及Akt/FOXO1信号通路,Elisa方法检测血清糖皮质激素水平。结果:造模1月后,CKD小鼠体重和骨骼肌重量明显下降,形态学表现为胫骨前肌横截面积减少,肌纤维面积分布图明显左移;蛋白质代谢方面显示肌肉蛋白分解增加明显,蛋白质合成代谢亦轻度下降,肌肉组织的Atrogin-1和MuRF-1mRNA表达明显上调,血清糖皮质激素水平较对照组升高13倍,CKD的代谢状态可导致骨骼肌组织Akt/FOXO1信号途径异常。结论:CKD时骨骼肌分解代谢旺盛,肌萎缩关键基因表达升高,致Akt/FOXO1信号途径异常,结果引起的肌肉萎缩,而糖皮质激素水平升高可能是原因之一。Objective：In chronic kidney disease （CKD）,loss of lean body mass and muscle wasting is a serious complication which is associated with excessive morbidity and mortality.In this study,we measured the protein synthesis and degradation in mouse CKD model,and research the mechanism of muscle atrophy.Methods：Methods Mouse CKD model was made by 5/6 nephroctomy,the sham as control.We measured the rate of14＋C-Phenalanine incorporation into the muscle to analyze the protein synthesis,and the Tyrosine released into the medium to analyze the protein degradation.The muscle size of Tibia Anterior（TA） was measured under Microscope and calculated with software.The mRNA expression of Atrogin-1（Muscle Atrophy Fbox-1） and MuRF-1（Muscle RING finger 1） was measured by Northern blot.We also research the signaling pathway of Akt/FoxO1 by Western blot.The serum corticosteroid hormone was measured by Elisa.Results：The bodyweight and TA muscle weight were decreased compared with Control.The cross-sectional area of muscle fibers was significantly smaller than that in Control,the shrinkages of fibers sizes cause leftward shift in fiber size distribution.The protein synthesis decreased slightly,and the protein degradation increased markedly.The mRNA expression of muscle specific Atrogin-1 and MuRF-1 was increased.In the same time,the serum corticosteroid hormone increased 13 folds.The Akt/FoxO1 signaling pathway was abnormal in the muscle of CKD.Conclusion：In CKD condition,there presence accelerating protein degradation in the skeletal muscle,the genes which control muscle atrophy are activated,the signaling pathway of Akt/FoxO1 is abnormal.These might be associated with increased endogenous corticosteroid levels.

关 键 词：慢性肾脏病 骨骼肌 蛋白合成/分解 糖皮质激素 ATROGIN-1 FORKHEAD TRANSCRIPTION factor class 

分 类 号：R692[医药卫生—泌尿科学]