Patients receiving mechanical ventilation in the intensive care unit (ICU) frequently develop contractile weakness of the diaphragm. Consequently, they may experience difficulty weaning from mechanical ventilation, which increases mortality and poses a high economic burden. Because of a lack of knowledge regarding the molecular changes in the diaphragm, no treatment is currently available to improve diaphragm contractility. We compared diaphragm biopsies from ventilated ICU patients ( N = 54) to those of non-ICU patients undergoing thoracic surgery ( N = 27). By integrating data from myofiber force measurements, x-ray diffraction experiments, and biochemical assays with clinical data, we found that in myofibers isolated from the diaphragm of ventilated ICU patients, myosin is trapped in an energy-sparing, super-relaxed state, which impairs the binding of myosin to actin during diaphragm contraction. Studies on quadriceps biopsies of ICU patients and on the diaphragm of previously healthy mechanically ventilated rats suggested that the super-relaxed myosins are specific to the diaphragm and not a result of critical illness. Exposing slow- and fast-twitch myofibers isolated from the diaphragm biopsies to small-molecule compounds activating troponin restored contractile force in vitro. These findings support the continued development of drugs that target sarcomere proteins to increase the calcium sensitivity of myofibers for the treatment of ICU-acquired diaphragm weakness.

中文翻译：

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超松弛肌球蛋白有助于机械通气患者的呼吸肌冬眠


在重症监护病房 （ICU） 接受机械通气的患者经常出现隔膜收缩无力。因此，他们可能难以从机械通气中撤机，这会增加死亡率并造成沉重的经济负担。由于缺乏关于隔膜分子变化的知识，目前没有治疗方法可以改善隔膜收缩力。我们比较了通气 ICU 患者 （ N = 54） 与接受胸部手术的非 ICU 患者 （ N = 27） 的隔膜活检。通过将肌纤维力测量、X 射线衍射实验和生化测定的数据与临床数据相结合，我们发现在从通气 ICU 患者隔膜中分离的肌纤维中，肌球蛋白被困在能量节省、超级松弛的状态，这会损害肌球蛋白与肌动蛋白的结合在膈肌收缩过程中。对 ICU 患者股四头肌活检和先前健康的机械通气大鼠膈肌的研究表明，超松弛的肌球蛋白是膈肌特有的，而不是危重疾病的结果。将从膈肌活检中分离的慢肌纤维和快肌纤维暴露于激活肌钙蛋白的小分子化合物中，可在体外恢复收缩力。这些发现支持靶向肌节蛋白的药物的持续开发，以增加肌纤维的钙敏感性，以治疗 ICU 获得性膈肌无力。