Department of Anesthesiology and Operative Intensive Care Medicine, Charité-Universitätsmedizin Berlin, Augustenburger Platz 1, 13353 Berlin, Germany.
Am J Respir Crit Care Med. 2013 Feb 15;187(4):387-96. doi: 10.1164/rccm.201209-1649OC. Epub 2012 Dec 13.
Critical illness myopathy (CIM) has no known cause and no treatment. Immobilization and impaired glucose metabolism are implicated.
We assessed signal transduction in skeletal muscle of patients at risk for CIM. We also investigated the effects of evoked muscle contraction.
In a prospective observational and interventional pilot study, we screened 874 mechanically ventilated patients with a sepsis-related organ-failure assessment score greater than or equal to 8 for 3 consecutive days in the first 5 days of intensive care unit stay. Thirty patients at risk for CIM underwent euglycemic-hyperinsulinemic clamp, muscle microdialysis studies, and muscle biopsies. Control subjects were healthy. In five additional patients at risk for CIM, we performed corresponding analyses after 12-day, daily, unilateral electrical muscle stimulation with the contralateral leg as control.
We performed successive muscle biopsies and assessed systemic insulin sensitivity and signal transduction pathways of glucose utilization at the mRNA and protein level and glucose transporter-4 (GLUT4) localization in skeletal muscle tissue. Skeletal muscle GLUT4 was trapped at perinuclear spaces, most pronounced in patients with CIM, but resided at the sarcolemma in control subjects. Glucose metabolism was not stimulated during euglycemic-hyperinsulinergic clamp. Insulin signal transduction was competent up to p-Akt activation; however, p-adenosine monophosphate-activated protein kinase (p-AMPK) was not detectable in CIM muscle. Electrical muscle stimulation increased p-AMPK, repositioned GLUT4, locally improved glucose metabolism, and prevented type-2 fiber atrophy.
Insufficient GLUT4 translocation results in decreased glucose supply in patients with CIM. Failed AMPK activation is involved. Evoked muscle contraction may prevent muscle-specific AMPK failure, restore GLUT4 disposition, and diminish protein breakdown. Clinical trial registered with http://www.controlled-trials.com (registration number ISRCTN77569430).
危重病性肌病（CIM）的病因不明，也没有治疗方法。有研究认为固定和葡萄糖代谢受损与此病相关。
我们评估了 CIM 高危患者的骨骼肌信号转导，并研究了诱发肌肉收缩的效果。
在一项前瞻性观察性和干预性初步研究中，我们对入住重症监护病房 5 天内连续 3 天的、全身炎症反应相关器官衰竭评估评分≥8 分的 874 例机械通气患者进行了筛查。30 例 CIM 高危患者接受了正常血糖高胰岛素钳夹、肌肉微透析研究和肌肉活检。对照组为健康者。另外 5 例 CIM 高危患者在 12 天的每日单侧电肌肉刺激后接受了相应的分析，另一侧腿部作为对照。
我们连续进行了肌肉活检，并评估了系统胰岛素敏感性和葡萄糖利用的信号转导途径，以及骨骼肌组织中葡萄糖转运蛋白 4（GLUT4）的定位。在 CIM 患者中，骨骼肌 GLUT4 被捕获在核周空间，在对照组中则位于肌膜。在正常血糖高胰岛素钳夹过程中，葡萄糖代谢未被刺激。胰岛素信号转导在 p-Akt 激活时仍然有效，但在 CIM 肌肉中未检测到 p-腺苷单磷酸激活蛋白激酶（p-AMPK）。电肌肉刺激增加了 p-AMPK，重新定位了 GLUT4，局部改善了葡萄糖代谢，防止了 2 型纤维萎缩。
CIM 患者的 GLUT4 转位不足导致葡萄糖供应减少。涉及 AMPK 激活失败。诱发肌肉收缩可能防止肌肉特异性 AMPK 衰竭，恢复 GLUT4 分布，并减少蛋白质分解。该临床试验在 http://www.controlled-trials.com （注册号 ISRCTN77569430）上注册。
