Department of Physiology and Pharmacology, Karolinska Institutet, Stockholm, Sweden.
Department of Neuroscience, Clinical Neurophysiology, Uppsala University, Uppsala, Sweden.
Acta Physiol (Oxf). 2018 Mar;222(3). doi: 10.1111/apha.12980. Epub 2017 Oct 30.
Muscle wasting is one of the factors most strongly predicting mortality and morbidity in critically ill intensive care unit (ICU). This muscle wasting affects both limb and respiratory muscles, but the understanding of underlying mechanisms and muscle-specific differences remains incomplete. This study aimed at investigating the temporal expression and phosphorylation of the Janus kinase/signal transducer and activator of transcription (JAK/STAT) pathway in muscle wasting associated with the ICU condition to characterize the JAK/STAT proteins and the related changes leading or responding to their activation during exposure to the ICU condition.
A novel experimental ICU model allowing long-term exposure to the ICU condition, immobilization and mechanical ventilation, was used in this study. Rats were pharmacologically paralysed by post-synaptic neuromuscular blockade and mechanically ventilated for durations varying between 6 hours and 14 days to study muscle-specific differences in the temporal activation of the JAK/STAT pathway in plantaris, intercostal and diaphragm muscles.
The JAK2/STAT3 pathway was significantly activated irrespective of muscle, but muscle-specific differences were observed in the temporal activation pattern between plantaris, intercostal and diaphragm muscles.
The JAK2/STAT3 pathway was differentially activated in plantaris, intercostal and diaphragm muscles in response to the ICU condition. Thus, JAK2/STAT3 inhibitors may provide an attractive pharmacological intervention strategy in immobilized ICU patients, but further experimental studies are required in the study of muscle-specific effects on muscle mass and function in response to both short- and long-term exposure to the ICU condition prior to the translation into clinical research and practice.
肌肉减少症是预测重症监护病房（ICU）中死亡率和发病率的最重要因素之一。这种肌肉减少症影响四肢和呼吸肌，但对其潜在机制和肌肉特异性差异的理解仍不完整。本研究旨在研究与 ICU 状况相关的肌肉减少症中 Janus 激酶/信号转导和转录激活因子（JAK/STAT）通路的时间表达和磷酸化，以表征 JAK/STAT 蛋白及其相关变化，这些变化导致或响应其在 ICU 条件下的激活。
本研究使用了一种新的实验性 ICU 模型，允许长期暴露于 ICU 条件、固定和机械通气。通过突触后神经肌肉阻滞使大鼠药理学瘫痪，并进行 6 小时至 14 天的机械通气，以研究 JAK/STAT 通路在跖肌、肋间肌和膈肌中的时间激活在肌肉特异性方面的差异。
JAK2/STAT3 通路无论肌肉如何均明显激活，但在跖肌、肋间肌和膈肌之间观察到时间激活模式的肌肉特异性差异。
JAK2/STAT3 通路在 ICU 条件下以不同的方式激活跖肌、肋间肌和膈肌。因此，JAK2/STAT3 抑制剂可能为固定 ICU 患者提供有吸引力的药理干预策略，但在将其转化为临床研究和实践之前，需要在研究 ICU 条件下短期和长期暴露对肌肉质量和功能的肌肉特异性影响方面进行进一步的实验研究。
