Price S R, Bailey J L, Wang X, Jurkovitz C, England B K, Ding X, Phillips L S, Mitch W E
Renal Division, Emory University School of Medicine, Atlanta, Georgia 30322, USA.
J Clin Invest. 1996 Oct 15;98(8):1703-8. doi: 10.1172/JCI118968.
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.
在正常受试者和糖尿病患者中，胰岛素可抑制全身蛋白质水解，这表明胰岛素缺乏时瘦体重的减少和肌肉萎缩与肌肉蛋白质降解增加有关。为了记录胰岛素缺乏如何影响器官重量，并确定肌肉中加速蛋白质水解的途径，我们研究了用链脲佐菌素处理和注射溶媒的成对喂养对照大鼠。胰岛素缺乏使肝脏、脂肪组织和肌肉的重量减轻，而肌肉蛋白质降解增加了75%。在链脲佐菌素处理7天或3天后，通过阻断溶酶体功能和钙依赖性蛋白酶并不能消除这种蛋白水解反应。当肌肉中的ATP合成受到抑制时，胰岛素缺乏大鼠和对照大鼠的蛋白质水解速率降低到相同水平，这表明ATP依赖的泛素-蛋白酶体途径被激活。肌肉中该途径被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增加了两到三倍；(c)泛素基因的转录增加。我们得出结论，胰岛素缺乏时肌肉蛋白质消耗的机制包括泛素-蛋白酶体途径的激活以及泛素基因表达的增加。
