Abstract：
Due to an unexpected activation of different zinc (Zn) transporters in a recent prospective clinical study, we have revisited the role of Zn homeostasis and the activation of matrix metalloproteinases (MMPs) in skeletal muscle exposed to the intensive care unit (ICU) condition (immobilization and mechanical ventilation). ICU patients exposed to 12 days ICU condition were followed longitudinally with six repeated muscle biopsies while they showed a progressive preferential myosin loss, i.e., the hallmark of Critical Illness Myopathy (CIM), in parallel with the activation of Zn-transporters. In this study, we have revisited the expression of Zn-transporters and the activation of MMPs in clinical as well as in experimental studies using an established ICU model. MMPs are a group Zn-dependent endopeptidases which do not only target and cleave extracellular proteins but also intracellular proteins including multiple sarcomeric proteins. MMP-9 is of specific interest since the hallmark of CIM, the preferential myosin loss, has also been reported in dilated cardiomyopathy and coupled to MMP-9 activation. Transcriptional activation of Zn-transporters was observed in both clinical and experimental studies as well as the activation of MMPs, in particular MMP-9, in various limb and respiratory muscles in response to long-term exposure to the ICU condition. The activation of Zn-transporters was paralleled by increased Zn levels in skeletal muscle which in turn showed a negative linear correlation with the preferential myosin loss associated with CIM, offering a potential intervention strategy. Thus, activation of Zn-transporters, increased intramuscular Zn levels, and activation of the Zn-dependent MMPs are forwarded as a probable mechanism involved in CIM pathophysiology. These effects were confirmed in different rat strains subjected to a model of CIM and exacerbated by old age. This is of specific interest since old age and muscle wasting are the two factors most strongly associated with ICU mortality.
摘要：
由于在最近的前瞻性临床研究中，不同锌（Zn）转运蛋白的意外激活，我们重新探讨了锌稳态和基质金属蛋白酶(MMPs)活化在暴露于重症监护病房(ICU)条件(固定和机械通气)的骨骼肌中的作用.暴露于12天ICU条件的ICU患者纵向随访六次重复肌肉活检，同时他们表现出进行性优先肌球蛋白损失，即，危重病肌病（CIM）的标志，同时激活锌转运蛋白。在这项研究中,我们使用已建立的ICU模型在临床和实验研究中重新研究了锌转运蛋白的表达和MMP的激活.MMP是一组Zn依赖性内肽酶,其不仅靶向和切割细胞外蛋白,而且还靶向和切割细胞内蛋白,包括多个肌节蛋白。MMP-9是特别感兴趣的，因为CIM的标志，优先肌球蛋白损失，在扩张型心肌病中也有报道，并与MMP-9激活相关。在临床和实验研究中观察到锌转运蛋白的转录激活以及MMP的激活，特别是MMP-9，在各种肢体和呼吸肌中响应于长期暴露于ICU状况。锌转运蛋白的激活与骨骼肌中锌水平的增加平行，这反过来又与CIM相关的优先肌球蛋白损失呈负线性相关，提供潜在的干预策略。因此，锌转运蛋白的活化，肌肉内锌水平增加，锌依赖性MMP的激活被认为是CIM病理生理学的可能机制。这些作用在接受CIM模型的不同大鼠品系中得到了证实，并随着年龄的增长而加剧。这是特别令人感兴趣的,因为老年和肌肉萎缩是与ICU死亡率最密切相关的两个因素。
