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

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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.