Clinical data suggested that sepsis and systemic inflammation are major risk factors for ICUAW and critical illness myopathy (CIM), and that increased serum levels of inflammatory cytokines, such as interleukin 6 (IL-6), IL-1β and tumor necrosis factor alpha (TNFα) might aggravate muscle atrophy in critically ill patients. We reported that IL-6 is continuously increased in muscle during inflammation and associated with muscle failure. Increased IL-6 expression in muscles of critically ill patients was indicative for inflammation directly occurring in muscle. We also reported that inflammation causes acute-phase response (APR) directly in skeletal muscle of critically ill patients. The APR protein serum amyloid A (SAA) 1 was increased in the skeletal muscle of CIM patients were it accumulated in the interstitium, around myofibers. Increased SAA1 mRNA expression and protein content was inversely correlated with excitability of muscle membranes indicating that SAA1 plays a role in muscle function. We showed that differentiated human and murine myocytes synthesize SAA1, and that SAA1 synthesis was increased by inflammatory cytokines (i.e. IL-6, TNFα). Importantly, both IL-6 and SAA1 induce atrophy by increasing protein degradation in muscle of patients and rodents. Together, our data indicated that inflammation induces APR directly in muscle possibly contributing to ICUAW. However, the mechanisms how inflammatory cytokines and APR proteins mediate muscle atrophy, and the receptors and signaling pathways involved in this process are unknown.
