The acute-phase protein serum amyloid A1 plays a key role in inflammation induced skeletal muscle atrophy in critically ill patients.

重症监护病房（ICU）获得性虚弱是危重疾病期间的一种破坏性并发症，其特征是肌肉萎缩、肌肉量减少和虚弱，往往导致长期康复和永久残疾。炎症和急性期反应是导致重症监护病房获得性虚弱的重要因素。急性期反应蛋白血清淀粉样蛋白A (SAA) 1在危重患者肌肉中积累，并与肌膜兴奋性和肌肉力降低有关。然而，肌细胞中SAA1激活的信号通路尚不清楚。我们检验并证实了SAA1在炎性肌萎缩的发病机制中起关键作用的假设。我们发现SAA1通过激活toll样受体（Tlr） 2和4直接作用于肌细胞，导致转录因子NF-kB的激活。我们发现SAA1不是直接介导萎缩，而是通过白细胞介素1 β间接介导。我们发现toll样受体2、NF-kB和白细胞介素1 β可能是治疗炎症诱导的萎缩的靶点。现在我们想测试抑制这些蛋白质是否能抑制炎症性萎缩并保持肌肉功能。我们还想描述肌肉炎症期间SAA1合成、分泌和积累的动力学。我们的目的是研究额外的肌肉SAA1受体和下游信号通路的重要性。我们的目的是进一步详细描述SAA1在炎症诱导的萎缩中的功能。我们想研究SAA1信号通路的抑制是否是对抗危重患者肌肉衰竭的合适靶点。

Intensive care unit (ICU)-acquired weakness is a devastating complication during critical illness, characterized by muscle atrophy, loss of muscle mass and weakness often resulting in protracted rehabilitation and permanent disability. Inflammation and acute phase response are important contributors leading to ICU-acquired weakness. The acute phase-response protein serum amyloid A (SAA) 1 accumulates in muscle of critically ill patients and is associated with reduced muscle membrane excitability and muscle force. However, SAA1 activated signaling pathways in myocytes were unknown. We tested and confirmed the hypothesis that SAA1 plays a key role in pathogenesis of inflammatory muscle atrophy. We show that SAA1 acts direct on myocytes via activation of toll-like receptors (Tlr) 2 and 4 leading to an activation of the transcription factor NF-kB. We found that SAA1 mediates atrophy not directly but rather indirect via interleukin 1 beta. We identified Toll-like receptor 2, NF-kB and interleukin 1 beta as possible targets to treat inflammation induced atrophy. Now we want to test if inhibition of these proteins inhibits inflammatory atrophy and preserves muscle function. We also want to describe the kinetics of SAA1 synthesis, secretion and accumulation during inflammation in muscle. We aim to investigate the importance of additional muscular SAA1 receptors and downstream signalling pathways. We aim to describe the function of SAA1 in inflammation induced atrophy in further detail. We want to investigate if inhibition of the SAA1 signalling pathway is a suitable target to combat muscle failure in critically ill patients.