Critical illness with and without sepsis is associated with loss of skeletal muscle mass and muscle weakness. The skeletal muscle weakness results in hypoventilation, difficulties in weaning off respirators, contractures and decreased mobilization. Despite increased survival rates following burns and critical illness, the survivors have prolonged rehabilitation extending from months to years.

One recognized pathway for accelerated muscle protein breakdown is the ubiquitin-proteosome pathway. Our group has identified apoptosis as an additional mechanism for loss of muscle mass. In contrast to necrosis, this form of cell death is a gene-mediated, energy-dependent event. Our studies have demonstrated apoptosis in muscles following critical illness and/or immobilization alone, with upregulation of certain death-inducing molecules and downregulation of some anti-apoptotic genes and/or their proteins. Currently, our group is further characterizing the pro-apoptotic signaling pathways and finding methods to attenuate the apoptosis in these tissues. Inhibition of apoptosis may decrease critical illness-induced skeletal muscle wasting and weakness.

Critically ill patients also have insulin resistance, which leads to hyperglycemia, decreased glucose uptake in muscle, enhanced gluconeogenesis and glycogenolysis and decreased protein anabolism. Our group recently has characterized the molecular mechanism inducing this state in critical illness. The post receptor pathways that cause the insulin resistance include decreased phosphorylation of insulin receptor, insulin receptor substrate-1 and activation of Akt/PKB.

Similar biochemical changes in insulin signaling can be seen in immobilization and denervation states concomitantly associated with critical illness. Therefore, the anabolic actions of insulin, including glucose uptake and protein synthesis are impaired in critical illness of burns. Studies are ongoing on methods to enhance insulin signaling.