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、肌肉质量丧失和虚弱，通常会导致长期康复和永久性残疾。炎症和急性时相反应是导致ICU获得性虚弱的重要因素。急性时相反应蛋白血清淀粉样蛋白A(SAA)1在危重病患者的肌肉中积聚，并与肌膜兴奋性和肌力降低有关。然而，SAA1在心肌细胞中激活的信号通路尚不清楚。我们验证并证实了SAA1在炎症性肌萎缩发病机制中起关键作用的假说。我们发现SAA1通过激活Toll样受体(TLR)2和4直接作用于心肌细胞，导致转录因子NF-kB的激活。我们发现，SAA1不是直接的，而是通过白细胞介素1β间接地介导萎缩。我们发现Toll样受体2、核因子-kB和白介素1β是治疗炎症性萎缩的可能靶点。现在，我们想测试抑制这些蛋白质是否可以抑制炎性萎缩并保护肌肉功能。我们还想描述肌肉炎症过程中SAA1的合成、分泌和积累的动力学。我们的目标是研究额外的肌肉SAA1受体和下游信号通路的重要性。我们的目标是更详细地描述SAA1在炎症诱导的萎缩中的作用。我们想要研究抑制SAA1信号通路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.