Abstract：
Immobilization-induced Neuromuscular Dysfunction (NMD) increases morbidity and mortality of patients in Intensive Care Units. However, the underlying mechanism of NMD remain poorly elucidated which limited the development of therapeutic method for NMD. Here we developed an immobilization rat model and tested the hypothesis that decreased expression of NRG-1, abnormal expression and distribution of nicotinic acetylcholine receptors (nAChRs) in skeletal muscle caused by immobilization can lead to NMD. To investigate the role of NRG-1/ErbB pathway on immobilization-induced NMD, exogenous recombinant human neuregulin-1 (rhNRG-1) was used to increase the expression of NRG-1 in skeletal muscle during immobilization. It was observed rhNRG-1 significantly alleviated the muscle loss and enhanced the expression of ε-nAChR, while diminished the expression of γ- and α7-nAChR and NMD. Interestingly, ErbB inhibitor PD158780 blocked the protective effects of rhNRG-1. Collectively, the results of present study suggested that rhNRG-1 attenuated immobilization-induced muscle loss and NMD, suppressed γ- and α7-nAChR production, enhanced ε-nAChR synthesis via activating NRG-1/ErbB pathway. Taken together, our findings provide novel insights into NMD contribution, suggesting that the rhNRG-1 is a promising therapy to protect against immobilization-induced myopathy.
摘要：
固定引起的神经肌肉功能障碍（NMD）会增加重症监护病房患者的发病率和死亡率。然而,NMD的潜在机制仍未阐明，这限制了NMD治疗方法的发展。在这里，我们建立了一个固定大鼠模型，并测试了以下假设：NRG-1的表达降低，固定引起的烟碱乙酰胆碱受体（nAChRs）在骨骼肌中的异常表达和分布可导致NMD。探讨NRG-1/ErbB通路在固定化诱导的NMD中的作用,外源性重组人神经调节蛋白-1（rhNRG-1）用于增加固定过程中骨骼肌中NRG-1的表达。观察到rhNRG-1显著减轻肌肉损失，增强ε-nAChR的表达，同时减少了γ-和α7-nAChR和NMD的表达。有趣的是,ErbB抑制剂PD158780阻断rhNRG-1的保护作用。总的来说，本研究的结果表明，rhNRG-1减轻了固定引起的肌肉损失和NMD，抑制γ-和α7-nAChR的产生，通过激活NRG-1/ErbB途径增强ε-nAChR合成。一起来看,我们的发现为国家导弹防御系统的贡献提供了新的见解，表明rhNRG-1是一种有前途的治疗方法，可以预防固定引起的肌病。
