Ten neuro-ICU patients exposed to long-term controlled mechanical ventilation were followed with repeated muscle biopsies, electrophysiology and plasma collection three times per week for up to 12 days. Single muscle fibre contractile recordings were conducted on the first and final biopsy, and a multiomics approach was taken to analyse gene and protein expression in muscle and plasma at all collection time points.
(i) A progressive preferential myosin loss, the hallmark of CIM, was observed in all neuro-ICU patients during the observation period (myosin:actin ratio decreased from 2.0 in the first to 0.9 in the final biopsy, P < 0.001). The myosin loss was coupled to a general transcriptional downregulation of myofibrillar proteins (P < 0.05; absolute fold change >2) and activation of protein degradation pathways (false discovery rate [FDR] <0.1), resulting in significant muscle fibre atrophy and loss in force generation capacity, which declined >65% during the 12 day observation period (muscle fibre cross-sectional area [CSA] and maximum single muscle fibre force normalized to CSA [specific force] declined 30% [P < 0.007] and 50% [P < 0.0001], respectively). (ii) Membrane excitability was not affected as indicated by the maintained compound muscle action potential amplitude upon supramaximal stimulation of upper and lower extremity motor nerves. (iii) Analyses of plasma revealed early activation of inflammatory and proinflammatory pathways (FDR < 0.1), as well as a redistribution of zinc ions from plasma.
The mechanical ventilation-induced lung injury with release of cytokines/chemokines and the complete mechanical silencing uniquely observed in immobilized ICU patients affecting skeletal muscle gene/protein expression are forwarded as the dominant factors triggering CIM.
方法:对10名长期接受机械通气控制的神经ICU患者进行反复肌肉活检,电生理学和血浆收集每周三次,最长12天。在第一次和最后一次活检中进行单肌纤维收缩记录,在所有收集时间点,采用多组学方法分析肌肉和血浆中的基因和蛋白质表达。
结果:(i)进行性优先肌球蛋白损失,CIM的标志,在观察期间在所有神经ICU患者中观察到(肌球蛋白:肌动蛋白比率从最初的2.0下降到最终活检的0.9,P<0.001)。肌球蛋白损失与肌原纤维蛋白的一般转录下调(P<0.05;绝对倍数变化>2)和蛋白质降解途径的激活(错误发现率[FDR]<0.1)有关,导致显著的肌肉纤维萎缩和力量产生能力的丧失,在12天的观察期内下降>65%(肌纤维横截面积[CSA]和归一化为CSA的最大单肌纤维力[比力]下降30%[P<0.007]和50%[P<0.0001],分别)。(ii)膜兴奋性不受上肢和下肢运动神经超刺激时维持的复合肌肉动作电位振幅所指示的影响。(iii)血浆分析显示炎症和促炎途径的早期激活(FDR<0.1),以及等离子体中锌离子的重新分布。
结论:在固定ICU患者中唯一观察到的影响骨骼肌基因/蛋白表达的机械通气诱导的具有细胞因子/趋化因子释放的肺损伤和完全机械沉默是触发CIM的主要因素。