当前位置: X-MOL 学术Redox Biol. › 论文详情
Our official English website, www.x-mol.net, welcomes your feedback! (Note: you will need to create a separate account there.)
Calpains play an essential role in mechanical ventilation-induced diaphragmatic weakness and mitochondrial dysfunction
Redox Biology ( IF 11.4 ) Pub Date : 2020-11-25 , DOI: 10.1016/j.redox.2020.101802
Hayden W Hyatt 1 , Mustafa Ozdemir 2 , Toshinori Yoshihara 3 , Branden L Nguyen 1 , Rafael Deminice 4 , Scott K Powers 1
Affiliation  

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.



中文翻译:

钙蛋白酶在机械通气引起的diaphragm肌无力和线粒体功能障碍中起重要作用

机械通气(MV)是许多重症患者的挽救生命的干预措施。不幸的是,MV延长的意外后果是diaphragm肌萎缩和收缩功能障碍的迅速发展,称为呼吸机诱发的diaphragm肌功能障碍(VIDD)。尽管尚未完全理解负责VIDD的机制,但大量证据表明,氧化应激导致主要蛋白水解系统(即自噬,泛素-蛋白酶体,胱天蛋白酶和钙蛋白酶)的活化起主导作用。在涉及VIDD的蛋白水解系统中,由于长期存在的教条认为钙蛋白酶在非活动性肌肉萎缩中起次要作用,因此钙蛋白酶受到的实验关注有限。在初步实验的指导下,我们测试了以下假设:钙蛋白酶的激活在MV诱导的氧化应激和VIDD的发展中起着至关重要的作用。钙蛋白酶的转基因过表达(钙蛋白酶的一种内源性抑制剂)对此条件进行了严格的测试。在diaphragm肌纤维中具有/不具有钙蛋白酶抑制剂基因转染的动物暴露于MV 12小时。结果证实钙蛋白酶抑制素的过表达禁止了MV诱导的隔膜纤维中钙蛋白酶的活化。重要的是,抑制钙蛋白酶的活化可以保护隔膜免受MV诱导的氧化应激,纤维萎缩和收缩功能障碍。此外,防止the肌钙蛋白酶激活会阻止MV诱导的线粒体功能障碍,并阻止MV诱导的caspase-3激活以及肌肉特异性E3连接酶的转录。总的来说,这些结果支持了钙蛋白酶激活在VIDD早期发展中起重要作用的假设。此外,这些发现提供了第一个直接证据,即钙蛋白酶在骨骼肌纤维的非活动性诱导的线粒体功能障碍和氧化应激中起重要作用。

更新日期:2020-12-04
down
wechat
bug