Muscle wasting is a serious complication of chronic renal failure (CRF) identified in virtually every survey of dialysis patients, and it is a strong predictor of morbidity and mortality. Although the mechanisms of CRF-induced muscle wasting have been intensively investigated, there are still many unknown aspects of the pathological processes. Our long-term goal is to identify cellular mechanisms of muscle wasting in chronic renal failure and to develop new therapeutic strategies. It has been known that the ubiquitin-proteasome proteolysis is one of important pathways in muscle protein degradation. The process of the proteolysis can be activated by uremia, a low extra-cellular pH, elevated glucocorticoid levels and inadequate insulin action. In our preliminary studies, we have observed that caspase-3, a protease activated by apoptotic stimuli, plays an initiatory role in muscle wasting; and inactivation of caspase-3 prevents the muscle wasting. X-chromosome linked inhibitor of apoptosis protein (XlAP) is an endogenous caspase inhibitor that regulates the function of the caspase signaling pathway. Over-expression of XlAP in L6 skeletal muscle cells can block muscle protein degradation induced by caspase-3 activation. Thus, we hypothesize that increasing of XlAP cellular function will block caspase-3 and CRF-induced muscle wasting, and that augmentation of XlAP cellular function will exert a therapeutic effect on CRF-induced muscle wasting. To examine our hypotheses, we propose: 1) to test if XlAP blocks muscle protein degradation induced by growth factor withdraw and staurosporine (activating caspase-3) in human skeletal muscle cells; 2) to examine if XlAP can inhibit the CRF-induced muscle protein degradation in vivo using a transgenic mouse with muscle specific XlAP expression; 3) to examine if the intramuscular injection of the recombinant XlAP lentivirus (Len-XlAP) prevents CRF-induced muscle protein degradation in mice. We believe that the experimental results will shed the insight on the mechanisms of muscle protein degradation, and provide a possible new approach to treat the pathological process of muscle wasting.
