The effect of intermittent hemidiaphragm stimulation during surgery on mitochondrial function, single fiber contractile force and catabolic pathways in humans

虽然机械通气（MV）是呼吸衰竭患者的生命维持，但它是有成本的。 MV显著降低膈肌收缩力，诱导呼吸机诱导的膈肌功能障碍（VIDD）， 有时会导致断奶失败。VIDD包括线粒体呼吸减少和氧化应激增加。 应力、肌纤维损伤和横膈膜力产生减少。在动物模型中， MV支持期间的隔膜收缩减弱了VIDD。然而，只有有限的数据寻址 这个问题在人类身上。在这里，我们建议直接测试间歇性电刺激的假设， (ES)在使用MV支持的长时间心脏手术期间， 活动的半横膈膜中的VIDD。 线粒体功能是慢性活动性心肌病中能量代谢和骨骼肌功能的核心。 肌肉，如隔膜。尽管线粒体功能异常被认为是导致VIDD的原因， 在动物模型中，关于线粒体对人类VIDD的贡献的数据有限。甚至 更重要的是，没有干预措施可用于减轻人类的这些缺陷。在这里，我们将 测试创新的实验治疗的影响，间歇性电刺激（ES）的 长时间MV手术期间的侧膈，对线粒体功能、单纤维收缩的影响 性质和分解代谢肌肉途径在人类隔膜。采用受试者内实验设计， 来自受刺激的半横膈膜的肌肉样品将与来自未受刺激的半横膈膜的样品进行比较。 半横膈我们将研究长时间CTS/MV期间的线粒体功能障碍和氧化应激， 以及ES减弱或预防VIDD的潜力（目的1）。接下来，我们将研究ES对 单纤维收缩性能和肌联蛋白完整性（目的2）。最后，我们将研究ES对蛋白水解的影响， 途径（半胱天冬酶，钙蛋白酶和泛素-蛋白酶体）和蛋白质减少的核糖体RNA标志物 VIDD中涉及的合成（Aim 3）。 这项研究将提供证据，说明在刺激的情况下， 半膈，并确定机制有助于人类VIDD。我们的长期目标是测试各种 在更大的人群中进行间歇性半膈ES方案，以确定其预防或减轻 VIDD来自R 01应用程序的数据将促进我们对引起人类疾病的机制的理解。 VIDD，并可能激发新的治疗策略，以维持人类隔膜功能，在MV支持。

Although mechanical ventilation (MV) is life-sustaining in patients with respiratory failure, it comes with a cost. MV dramatically reduces diaphragm contractility, induces ventilator-induced diaphragm dysfunction (VIDD) and sometimes leads to weaning failure. VIDD includes reduced mitochondrial respiration and increased oxidative stress, muscle fiber damage and decreased diaphragm force production. In animal models, intermittent diaphragm contraction during MV support attenuates VIDD. However, there are only limited data addressing this problem in humans. Here, we propose to directly test the hypothesis that intermittent electrical stimulation (ES) of the human hemidiaphragm during prolonged cardiac surgeries with MV support prevents/attenuates VIDD in the active hemidiaphragm. Mitochondrial function is central to energy metabolism and skeletal muscle function in a chronically active muscle, such as the diaphragm. Although abnormal mitochondrial function is thought to precipitate VIDD in animal models, limited data are available concerning mitochondrial contributions to VIDD in humans. Of even greater importance, there are no interventions available to attenuate these defects in humans. Here, we will test the impact of an innovative experimental treatment, intermittent electrical stimulation (ES) of the hemidiaphragm during prolonged surgeries with MV, on mitochondrial function, single fiber contractile properties and catabolic muscle pathways in human diaphragm. Using a within-subjects experimental design, muscle samples from a stimulated hemidiaphragms will be compared with samples from the unstimulated hemidiaphragm. We will investigate mitochondrial dysfunction and oxidative stress during prolonged CTS/MV, and the potential of ES to attenuate or prevent VIDD (Aim 1). Next, we will investigate the effects of ES on single fiber contractile properties and Titin integrity (Aim 2). Finally, we will study the effect of ES on proteolytic pathways (caspase, calpain and ubiquitin-proteasome) and ribosomal RNA markers of decreased protein synthesis implicated in VIDD (Aim 3). This research will provide evidence concerning the ability to improve mitochondrial function in the stimulated hemidiaphragm, and identify mechanisms contributing to human VIDD. Our long-term goal is to test various intermittent hemidiaphragm ES protocols on a larger population to determine its ability to prevent or attenuate VIDD. Data from this R01 application will advance our understanding of mechanisms giving rise to human VIDD, and may inspire new therapeutic strategies to maintain human diaphragm function during MV support.