Activation of Calpain Contributes to Mechanical Ventilation-Induced Depression of Protein Synthesis in Diaphragm Muscle.
Activation of Calpain Contributes to Mechanical Ventilation-Induced Depression of Protein Synthesis in Diaphragm Muscle.
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钙蛋白酶的激活对机械通气引起的膈肌蛋白质合成抑制的作用
DOI：
10.3390/cells11061028
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发表时间：
2022-03-18
期刊：
影响因子：
6
通讯作者：
Powers SK
中科院分区：
文献类型：
--
作者：
Hyatt HW;Ozdemir M;Bomkamp MP;Powers SK
机械通气(MV)是一种临床工具，它为无法独立维持足够的肺泡通气量的患者提供呼吸支持。虽然机械通气通常是危重患者的救命措施，但机械通气时间延长的一个不良副作用是由于蛋白质分解加速和蛋白质合成受抑而导致的横隔膜萎缩。对MV诱导的横隔肌萎缩的机制(S)的研究表明，钙激活的蛋白水解酶calain的激活在促进横隔肌纤维的蛋白分解中起着关键作用。此外，据报道，活性的钙蛋白酶可以阻断促进蛋白质合成的信号事件(即抑制哺乳动物的雷帕霉素靶标(MTOR)激活)。虽然这一发现表明，活跃的钙蛋白酶可以抑制肌肉蛋白质的合成，但这一假设尚未得到实验验证。因此，我们验证了这一假说，即活性钙蛋白酶在MV诱导的横隔肌合成信号事件和蛋白质合成的抑制中起关键作用。内源性钙蛋白酶抑制剂calastatin的转基因过表达可阻止MV诱导的横隔肌纤维中钙蛋白酶的激活。我们的研究结果表明，过表达calastatin可以避免MV诱导的横隔肌纤维中钙蛋白酶的激活，并挽救MV诱导的横隔肌蛋白质合成抑制。令人惊讶的是，抑制Calain的激活并没有阻止MV对包括mTOR激活在内的关键合成代谢信号事件的抑制。然而，阻断钙蛋白酶的激活可以阻止钙蛋白酶诱导的横隔膜纤维中谷氨酰-tRNA合成酶的裂解；这一发现具有潜在的重要意义，因为氨基酰-tRNA合成酶在蛋白质合成中发挥着核心作用。无论Calain抑制蛋白质合成的机制是什么(S)，这些结果首次证明了活性Calain在MV诱导的隔膜纤维蛋白质合成抑制中起重要作用。
Mechanical ventilation (MV) is a clinical tool that provides respiratory support to patients unable to maintain adequate alveolar ventilation on their own. Although MV is often a life-saving intervention in critically ill patients, an undesired side-effect of prolonged MV is the rapid occurrence of diaphragmatic atrophy due to accelerated proteolysis and depressed protein synthesis. Investigations into the mechanism(s) responsible for MV-induced diaphragmatic atrophy reveal that activation of the calcium-activated protease, calpain, plays a key role in accelerating proteolysis in diaphragm muscle fibers. Moreover, active calpain has been reported to block signaling events that promote protein synthesis (i.e., inhibition of mammalian target of rapamycin (mTOR) activation). While this finding suggests that active calpain can depress muscle protein synthesis, this postulate has not been experimentally verified. Therefore, we tested the hypothesis that active calpain plays a key role in the MV-induced depression of both anabolic signaling events and protein synthesis in the diaphragm muscle. MV-induced activation of calpain in diaphragm muscle fibers was prevented by transgene overexpression of calpastatin, an endogenous inhibitor of calpain. Our findings indicate that overexpression of calpastatin averts MV-induced activation of calpain in diaphragm fibers and rescues the MV-induced depression of protein synthesis in the diaphragm muscle. Surprisingly, deterrence of calpain activation did not impede the MV-induced inhibition of key anabolic signaling events including mTOR activation. However, blockade of calpain activation prevented the calpain-induced cleavage of glutaminyl-tRNA synthetase in diaphragm fibers; this finding is potentially important because aminoacyl-tRNA synthetases play a central role in protein synthesis. Regardless of the mechanism(s) responsible for calpain’s depression of protein synthesis, these results provide the first evidence that active calpain plays an important role in promoting the MV-induced depression of protein synthesis within diaphragm fibers.
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影响因子：
8.8
作者：
Kim, Won Young;Suh, Hee Jung;Lim, Chae-Man
通讯作者：
Lim, Chae-Man
影响因子：
2.5
作者：
Tonnelier, Alexandre;Tonnelier, Jean-Marie;L'Her, Erwan
通讯作者：
L'Her, Erwan
DOI：
10.1164/rccm.200202-088oc
发表时间：
2002-11-15
影响因子：
24.7
作者：
Shanely, RA;Zergeroglu, MA;Powers, SK
通讯作者：
Powers, SK
影响因子：
4
作者：
Hyatt HW;Powers SK
通讯作者：
Powers SK
DOI：
10.1186/s13054-018-1992-2
发表时间：
2018-03-20
期刊：
Critical care (London, England)
影响因子：
--
作者：
Dres M;Demoule A
通讯作者：
Demoule A