Calpains play an essential role in mechanical ventilation-induced diaphragmatic weakness and mitochondrial dysfunction.
Calpains play an essential role in mechanical ventilation-induced diaphragmatic weakness and mitochondrial dysfunction.
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DOI：
10.1016/j.redox.2020.101802
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发表时间：
2021-01
期刊：
影响因子：
11.4
通讯作者：
Powers SK
中科院分区：
文献类型：
--
作者：
Hyatt HW;Ozdemir M;Yoshihara T;Nguyen BL;Deminice R;Powers SK
机械通气(MV)是许多危重病人的救命措施。不幸的是，延长机械通气的一个意想不到的后果是迅速发展的横隔膜萎缩和收缩功能障碍，称为呼吸机诱发的横隔膜功能障碍(VIDD)。尽管导致VIDD的机制(S)还不完全清楚，但大量的证据表明，氧化应激导致主要的蛋白分解系统(即自噬、泛素-蛋白酶体、半胱氨酸酶和钙蛋白酶)的激活起着主导作用。在VIDD涉及的蛋白分解系统中，由于长期以来的教条认为Calain在不活动诱导的肌肉萎缩中只起到很小的作用，所以Calain在实验上受到的关注有限。在前期实验的指导下，我们验证了钙蛋白酶的激活在MV诱导的氧化应激和VIDD的发生中起重要作用的假说。这一前提通过转基因过量表达calastatin得到了严格的检验，calastatin是一种内源性Calpains抑制剂。在横隔肌纤维中导入/不导入calastatin基因的动物暴露于12h的MV中。结果证实，过表达Calastatin可抑制MV诱导的隔膜纤维中的Calain的激活。重要的是，抑制钙激活可以保护横隔膜免受MV引起的氧化应激、纤维萎缩和收缩功能障碍的影响。此外，阻止肌动蛋白激活可阻止MV诱导的线粒体功能障碍，并阻止MV诱导的caspase-3的激活以及肌肉特异性E3连接酶的转录。总而言之，这些结果支持了这样的假设，即Calain激活在VIDD的早期发展中发挥着重要作用。此外，这些发现提供了第一个直接证据，表明Calain在不活动诱导的线粒体功能障碍和骨骼肌纤维中的氧化应激中发挥重要作用。在机械通风过程中抑制钙化酶可保护横隔膜。钙调蛋白在肌肉萎缩和收缩功能障碍中起着重要作用。机械通气过程中抑制钙蛋白酶可防止线粒体功能障碍。钙蛋白酶裂解的分子可能发挥重要的信号作用。钙蛋白酶的激活与其他蛋白分解系统相互作用。
Mechanical ventilation (MV) is a life-saving intervention for many critically ill patients. Unfortunately, an unintended consequence of prolonged MV is the rapid development of diaphragmatic atrophy and contractile dysfunction, known as ventilator-induced diaphragm dysfunction (VIDD). Although the mechanism(s) responsible for VIDD are not fully understood, abundant evidence reveals that oxidative stress leading to the activation of the major proteolytic systems (i.e., autophagy, ubiquitin-proteasome, caspase, and calpain) plays a dominant role. Of the proteolytic systems involved in VIDD, calpain has received limited experimental attention due to the longstanding dogma that calpain plays a minor role in inactivity-induced muscle atrophy. Guided by preliminary experiments, we tested the hypothesis that activation of calpains play an essential role in MV-induced oxidative stress and the development of VIDD. This premise was rigorously tested by transgene overexpression of calpastatin, an endogenous inhibitor of calpains. Animals with/without transfection of the calpastatin gene in diaphragm muscle fibers were exposed to 12 h of MV. Results confirmed that overexpression of calpastatin barred MV-induced activation of calpain in diaphragm fibers. Importantly, deterrence of calpain activation protected the diaphragm against MV-induced oxidative stress, fiber atrophy, and contractile dysfunction. Moreover, prevention of calpain activation in the diaphragm forstalled MV-induced mitochondrial dysfunction and prevented MV-induced activation of caspase-3 along with the transcription of muscle specific E3 ligases. Collectively, these results support the hypothesis that calpain activation plays an essential role in the early development of VIDD. Further, these findings provide the first direct evidence that calpain plays an important function in inactivity-induced mitochondrial dysfunction and oxidative stress in skeletal muscle fibers. Inhibiting calpains during mechanical ventilation protects the diaphragm. Calpains play an important role in muscle atrophy and contractile dysfunction. Calpain inhibition during mechanical ventilation prevents mitochondrial dysfunction. Calpain-cleaved molecules may play important signaling roles. Calpain activation cross-talks with other proteolytic systems.
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影响因子：
8.8
作者：
Azuelos, Ilan;Jung, Boris;Petrof, Basil J.
通讯作者：
Petrof, Basil J.
DOI：
10.1186/s13054-018-1992-2
发表时间：
2018-03-20
期刊：
Critical care (London, England)
影响因子：
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期刊：
Reproductive biology and endocrinology : RB&E
影响因子：
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作者：
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通讯作者：
Kavazis AN
影响因子：
7.4
作者：
Dridi, Haikel;Yehya, Mohamad;Matecki, Stephan
通讯作者：
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影响因子：
9.3
作者：
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