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首页> 外文学位 >Effects of the calpain proteases on the ubiquitin-proteasome system and protein synthesis signaling in rat skeletal muscle.
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Effects of the calpain proteases on the ubiquitin-proteasome system and protein synthesis signaling in rat skeletal muscle.

机译：钙蛋白酶对大鼠骨骼肌中泛素-蛋白酶体系统和蛋白质合成信号的影响。

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摘要

Skeletal muscle atrophy can be a debilitating problem, and in extreme cases life threatening. Muscle wasting is a consequence of reduced protein synthesis and/or elevated protein degradation. While the ubiquitin-proteasome pathway (UPP) accounts for most of the elevated protein degradation, proteases acting upstream of the UPP may initiate the degradative process. Since the calpain proteases have been implicated in the initial events leading to elevated protein breakdown, one goal of the present investigation was to determine whether the calpain proteases act upstream of the UPP in skeletal muscle. Calpain activation had no discernible effect on the UPP (i.e., the level of myofibrillar/cytosolic ubiquitin-conjugated proteins or proteasome enzyme activity). However, the calpain-mediated rise in total protein degradation was prevented by proteasome inhibition, indicating that the proteasome is necessary for the processing of calpain cleavage products. In fact, acute calpain activation increased proteasome-dependent protein degradation by 45%. Our data indicate that calpain acts upstream of the proteasome system; thus calpain may be an initial step in elevated protein degradation.; Akt plays a critical role in protein synthesis, and the molecular chaperone heat shock protein 90 (HSP90) appears to regulate Akt activity. Since HSP90 is a calpain substrate, calpain activation may subsequently inactivate Akt and its immediate downstream elements. Calpain activation significantly reduced HSP90beta content and Akt activity. Calpain also inhibited Akt's downstream component mammalian target of rapamycin (mTOR). While activated Akt inhibits glycogen synthase kinase-3beta (GSK-3beta), a negative regulator of protein synthesis, calpain activation increased GSK-3beta activation.; Our data implicate calpain as an initial factor in elevated muscle proteolysis since these proteases appear to act upstream of the proteasome. The novel finding that calpain adversely affects the Akt/mTOR/GSK-3beta signaling pathway suggests that calpain also contributes to reduced protein synthesis. Finally, given the multitude of functions carried out by molecular chaperones, the finding that calpain reduces the level HSP90beta suggests that calpain activation may affect an assortment of cellular functions. Taken together, these data indicate that calpain likely plays a prominent role in the loss of muscle proteins during catabolic conditions and thus offers a practical target for intervention.
机译：骨骼肌萎缩可能是使人衰弱的问题，在极端情况下会威胁生命。肌肉浪费是蛋白质合成减少和/或蛋白质降解增加的结果。尽管泛素-蛋白酶体途径（UPP）导致了大部分蛋白质降解升高，但在UPP上游起作用的蛋白酶可能会启动降解过程。由于钙蛋白酶蛋白酶参与了导致蛋白质分解升高的初始事件，因此本研究的目标是确定钙蛋白酶蛋白酶是否在骨骼肌中的UPP上游起作用。钙蛋白酶的活化对UPP没有明显的影响（即肌原纤维/胞质泛素缀合蛋白的水平或蛋白酶体酶的活性）。但是，蛋白酶体抑制作用阻止了钙蛋白酶介导的总蛋白降解的增加，这表明蛋白酶体对于钙蛋白酶裂解产物的加工是必需的。实际上，急性钙蛋白酶激活使蛋白酶体依赖性蛋白降解增加了45％。我们的数据表明钙蛋白酶在蛋白酶体系统的上游起作用。因此，钙蛋白酶可能是提高蛋白质降解的第一步。 Akt在蛋白质合成中起关键作用，分子伴侣热激蛋白90（HSP90）似乎在调节Akt的活性。由于HSP90是钙蛋白酶的底物，因此钙蛋白酶激活可能会随后使Akt及其紧邻的下游元素失活。钙蛋白酶激活显着降低了HSP90beta含量和Akt活性。钙蛋白酶还抑制雷帕霉素（mTOR）的Akt下游成分哺乳动物靶标。活化的Akt抑制糖原合酶激酶3beta（GSK-3beta）（一种蛋白质合成的负调节剂），而钙蛋白酶的激活增加了GSK-3beta的激活。我们的数据暗示钙蛋白酶是肌肉蛋白水解升高的初始因素，因为这些蛋白酶似乎在蛋白酶体的上游起作用。钙蛋白酶对Akt / mTOR / GSK-3beta信号通路产生不利影响的新发现表明，钙蛋白酶也有助于减少蛋白质的合成。最后，鉴于分子伴侣具有多种功能，钙蛋白酶降低了HSP90beta水平的发现表明钙蛋白酶激活可能影响各种细胞功能。总而言之，这些数据表明钙蛋白酶在分解代谢条件下可能在肌肉蛋白质的损失中起着重要作用，因此为干预提供了实用的目标。

著录项

  • 作者

    Smith, Ira J., IV.;

  • 作者单位

    University of Florida.;

  • 授予单位 University of Florida.;
  • 学科 Biology Animal Physiology.; Chemistry Biochemistry.
  • 学位 Ph.D.
  • 年度 2005
  • 页码 78 p.
  • 总页数 78
  • 原文格式 PDF
  • 正文语种 eng
  • 中图分类 生理学;生物化学;
  • 关键词

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