Identification of cathepsin L as a differentially expressed message associated with skeletal muscle wasting
Identification of cathepsin L as a differentially expressed message associated with skeletal muscle wasting
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DOI：
10.1042/0264-6021:3600143
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发表时间：
2001-11-15
影响因子：
4.1
通讯作者：
Ferrara, M
中科院分区：
文献类型：
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作者：
Deval, C;Mordier, S;Ferrara, M
骨骼肌蛋白分解的改变是一系列病理的标志，包括败血症，对恢复有负面影响。本研究的目的是寻找与蛋白质损失相关的肌肉标志物，这有助于预测和理解病理性消耗。利用差异显示逆转录pcr，我们筛选了脓毒症大鼠长期分解代谢状态下肌肉中差异表达的基因。一个克隆被分离出来，证实在脓毒症骨骼肌中过表达，并被鉴定为编码溶酶体半胱氨酸内肽酶组织蛋白酶L. Northern和Western-blot分析脓毒症大鼠腓肠肌或胫骨前肌组织蛋白酶L，证实早在感染后2天mRNA和蛋白水平升高（高达3倍），感染后6天进一步增加（高达13倍）。与此同时，编码其他溶酶体内肽酶或泛素-蛋白酶体途径组分的mrna的增加不超过4倍。糖皮质激素处理后大鼠胫骨前肌组织蛋白酶L mRNA升高。类似物、地塞米松或患有吉田肉瘤的大鼠。荷瘤动物用己氧可可碱（一种抑制肿瘤坏死因子α产生的抑制剂）处理后，组织蛋白酶L mRNA的增加减少了40%。综上所述，这些结果表明组织蛋白酶L mRNA和蛋白水平与蛋白质水解强度呈正相关，并确定组织蛋白酶L是肌肉萎缩的早期标志。推测Cathepsin L参与了导致肌肉损失的病理反应，糖皮质激素和肿瘤坏死因子α可能参与了Cathepsin L的上调。
Alteration of skeletal muscle protein breakdown is a hallmark of a set of pathologies, including sepsis, with negative consequences for recovery. The aim of the present study was to search for muscle markers associated with protein loss, which could help in predicting and understanding pathological wasting. With the use of differential display reverse transcription-PCR, we screened differentially expressed genes in muscle from septic rats in a longlasting catabolic state. One clone was isolated, confirmed as being overexpressed in septic skeletal muscle and identified as encoding the lysosomal cysteine endopeptidase cathepsin L. Northern- and Western-blot analysis of cathepsin L in gastrocnemius or tibialis anterior muscles of septic rats confirmed an elevation (up to 3-fold) of both mRNA and protein levels as early as 2 days post-infection, and a further increase 6 days postinfection (up to 13-fold). At the same time, the increase in mRNAs encoding other lysosomal endopeptidases or components of the ubiquitin-proteasome pathway did not exceed 4-fold. Cathepsin L mRNA was also increased in tibialis anterior muscle of rats treated with the glucocorticoid. analogue, dexamethasone, or rats bearing the Yoshida Sarcoma. The increase in cathepsin L mRNA was reduced by 40% when the tumour-bearing animals were treated with pentoxifylline, an inhibitor of tumour necrosis factor-alpha production. In conclusion, these results demonstrate a positive and direct correlation between cathepsin L mRNA and protein level and the intensity of proteolysis, and identify cathepsin L as an appropriate early marker of muscle wasting. Cathepsin L presumably participates in the pathological response leading to muscle loss, with glucocorticoids and tumour necrosis factor-alpha potentially being involved in the up-regulation of cathepsin L.