Fig. 1.

Summary of the role of calpain activation in sepsis-induced muscle wasting. Uptake and cellular concentrations of calcium are increased in skeletal muscle during sepsis (34). Calpains are activated by calcium (39), although other mechanisms may also contribute to calpain activation. The most important muscle wasting-related consequence of calpain activation is cleavage of myofibrillar cytsokeletal proteins resulting in disruption of the sarcomere and release of myofilaments that are subsequently ubiquitinated and degraded by the 26S proteasome (47, 52, 93, 94). In addition, calpain activation may regulate the degradation of various transcription factors involved in muscle wasting (42, 66, 111). Calpains may regulate the 26S proteasome activity (69, 92), and it is possible that calcium can activate the 26S proteasome through other mechanisms as well (69). Finally, recent studies (92) suggest that calpain activation in skeletal muscle results in inhibited Akt activity, which in turn results in activation of Foxo transcription factors and GSK-3β (stimulating muscle proteolysis) and inactivation of mammalian target of rapamycin (mTOR), inhibiting protein synthesis.