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Wasting of skeletal muscle protein is a prominent feature of the metabolic response to sepsis. Persistent protein wasting leads to muscle dysfunction and prolongs recovery from the septic insult. Unfortunately, conventional nutritional support alone does not prevent the sepsis-induced weight loss and catabolism of muscle. Hence, mechanisms other than substrate deficiency appear to be involved in the derangements in protein metabolism during sepsis. The catabolism of muscle during sepsis results from a stimulation of proteolysis and an inhibition of protein synthesis. Despite the importance of these pathways in maintaining muscle mass, the regulation of protein synthesis and proteolysis during sepsis remains poorly understood. This review summarizes the mechanisms responsible for alterations in protein synthesis and degradation in muscle during sepsis at the biochemical level. The ability of hormones (insulin, insulin-like growth factor I, glucocorticoids) or cytokines (tumor necrosis factor, interleukin-1) to act as mediators or modulators of protein catabolism is also examined. A picture is emerging suggesting that cytokines may influence skeletal muscle protein metabolism during sepsis both indirectly, through inhibition of the regulatory actions of anabolic hormones on protein turnover, and directly, through modulation of the protein synthesis and degradation enzymatic machinery.