Muscle wasting in insulinopenic rats results from activation of the ATP-dependent, ubiquitin-proteasome proteolytic pathway by a mechanism including gene transcription
Muscle wasting in insulinopenic rats results from activation of the ATP-dependent, ubiquitin-proteasome proteolytic pathway by a mechanism including gene transcription
复制标题
DOI：
10.1172/jci118968
复制
发表时间：
1996-10-15
影响因子：
15.9
通讯作者：
Mitch, WE
中科院分区：
文献类型：
--
作者：
Price, SR;Bailey, JL;Mitch, WE
在正常受试者和糖尿病患者中，胰岛素抑制全身蛋白水解，表明胰岛素缺乏症中瘦体重的损失和肌肉萎缩与肌肉蛋白降解增加有关。为了记录胰岛素减少如何影响器官重量并确定肌肉中加速蛋白水解的途径，研究了链脲霉素处理和溶剂注射、成对喂养的对照大鼠。肝脏、脂肪组织和肌肉的重量降低，而肌肉蛋白质降解增加75%。这种蛋白水解反应并没有消除阻断溶酶体功能和钙依赖性蛋白酶在7或3天后链脲佐菌素。当肌肉中的ATP合成被抑制时，蛋白水解的速率在胰岛素缺乏和对照大鼠中降低到相同的水平，这表明ATP依赖性的泛素-蛋白酶体途径被激活。肌肉中该途径激活的其他证据包括：（a）蛋白酶体活性抑制剂消除了增加的蛋白质降解;（B）编码泛素和蛋白酶体亚基的mRNA增加了2 - 3倍;（c）泛素基因的转录增加。我们的结论是胰岛素缺乏症肌肉蛋白质消耗的机制包括泛素-蛋白酶体途径的激活和泛素基因表达的增加。
In normal subjects and diabetic patients, insulin suppresses whole body proteolysis suggesting that the loss of lean body mass and muscle wasting in insulinopenia is related to increased muscle protein degradation. To document how insulinopenia affects organ weights and to identify the pathway for accelerated proteolysis in muscle, streptozotocin-treated and vehicle-injected, pair-fed control rats were studied. The weights of liver, adipose tissue, and muscle were decreased while muscle protein degradation was increased 75% by insulinopenia. This proteolytic response was not eliminated by blocking lysosomal function and calcium-dependent proteases at 7 or 3 d after streptozotocin. When ATP synthesis in muscle was inhibited, the rates of proteolysis were reduced to the same level in insulinopenic and control rats suggesting that the ATP-dependent, ubiquitin-proteasome pathway is activated. Additional evidence for activation of this pathway in muscle includes: (a) an inhibitor of proteasome activity eliminated the increased protein degradation; (b) mRNAs encoding ubiquitin and proteasome subunits were increased two- to threefold; and (c) there was increased transcription of the ubiquitin gene. We conclude that the mechanism for muscle protein wasting in insulinopenia includes activation of the ubiquitin-proteasome pathway with increased expression of the ubiquitin gene.