Department of Cellular and Molecular Medicine, University of Arizona , Tucson, Arizona.
Department of Physiology, Amsterdam University Medical Center, Amsterdam, The Netherlands.
Am J Physiol Cell Physiol. 2019 Aug 1;317(2):C167-C176. doi: 10.1152/ajpcell.00509.2018. Epub 2019 May 1.
The diaphragm, the main muscle of inspiration, is constantly subjected to mechanical loading. Only during controlled mechanical ventilation, as occurs during thoracic surgery and in the intensive care unit, is mechanical loading of the diaphragm arrested. Animal studies indicate that the diaphragm is highly sensitive to unloading, causing rapid muscle fiber atrophy and contractile weakness; unloading-induced diaphragm atrophy and contractile weakness have been suggested to contribute to the difficulties in weaning patients from ventilator support. The molecular triggers that initiate the rapid unloading atrophy of the diaphragm are not well understood, although proteolytic pathways and oxidative signaling have been shown to be involved. Mechanical stress is known to play an important role in the maintenance of muscle mass. Within the muscle's sarcomere, titin is considered to play an important role in the stress-response machinery. Titin is a giant protein that acts as a mechanosensor regulating muscle protein expression in a sarcomere strain-dependent fashion. Thus titin is an attractive candidate for sensing the sudden mechanical arrest of the diaphragm when patients are mechanically ventilated, leading to changes in muscle protein expression. Here, we provide a novel perspective on how titin and its biomechanical sensing and signaling might be involved in the development of mechanical unloading-induced diaphragm weakness.
膈肌是吸气的主要肌肉，它不断受到机械负荷的作用。只有在接受控制的机械通气时，如在胸外科手术和重症监护病房中，膈肌的机械负荷才会停止。动物研究表明，膈肌对卸载非常敏感，导致肌肉纤维迅速萎缩和收缩力减弱；有人认为，卸载引起的膈肌萎缩和收缩力减弱导致了患者从呼吸机支持中脱机的困难。尽管已经表明蛋白水解途径和氧化信号参与其中，但启动膈肌快速卸载萎缩的分子触发因素仍未得到很好的理解。机械应激已知在维持肌肉质量方面起着重要作用。在肌肉的肌节内，肌联蛋白被认为在应激反应机制中发挥重要作用。肌联蛋白是一种巨大的蛋白质，作为机械感受器，以肌节应变依赖性的方式调节肌肉蛋白表达。因此，肌联蛋白是一种很有吸引力的候选蛋白，可以感知患者进行机械通气时膈肌的突然机械停止，从而导致肌肉蛋白表达的变化。在这里，我们提供了一个新的视角，探讨肌联蛋白及其生物力学传感和信号转导如何参与机械卸载引起的膈肌无力的发展。
