X-chromosome linked inhibitor of apoptosis protein inhibits muscle proteolysis in insulin-deficient mice.
Loss of muscle protein is a serious complication of catabolic diseases and contributes substantially to patients' morbidity and mortality. This muscle loss is mediated largely by the activation of the ubiquitin-proteasome system; however, caspase-3 catalyzes an initial step in this process by cleaving actomyosin into small protein fragments that are rapidly degraded by the proteasome-dependent proteolytic pathway. We hypothesized that X-chromosome linked inhibitor of apoptosis protein (XIAP), an endogenous caspase-3 inhibitor, would block this first step in the cleavage of actomyosin that would make XIAP a candidate for treating muscle wasting. To determine if XIAP could attenuate muscle protein degradation, we used a recombinant lentivirus (Len-XIAP) encoding the full-length human XIAP cDNA to express XIAP in vivo. In muscle of streptozotocin-treated insulin-deficient mice, total muscle protein degradation, caspase-3 activity, and myofibril destruction were increased while XIAP was decreased. Overexpression of XIAP in these mice attenuated the excessive muscle protein degradation. Increased proteasome activity, caspase-3 activity and myofibril protein breakdown were all reduced. The ability of XIAP to prevent the loss of muscle protein suggests that XIAP could be a therapeutic reagent for muscle atrophy in catabolic diseases.
Wang
X H
XH
Renal Division, Department of Medicine, Emory University, Atlanta, GA 30322, USA. xwang03@emory.edu
Hu
J
J
Du
J
J
Klein
J D
JD
D000199:Actins / Q000032:analysis; D000818:Animals; D017209:Apoptosis; D015415:Biomarkers / Q000032:analysis; D053148:Caspase 3 / Q000378:metabolism; D053453:Caspase 9 / Q000378:metabolism; D061945:Caspase Inhibitors; D002460:Cell Line; D003921:Diabetes Mellitus, Experimental / Q000378:metabolism; D015870:Gene Expression; D015316:Genetic Therapy / Q000379:methods; D006801:Humans; D015151:Immunoblotting; D007150:Immunohistochemistry; D020287:In Situ Nick-End Labeling; D007328:Insulin / Q000172:deficiency* / Q000378:metabolism; D016086:Lentivirus / Q000235:genetics; D051379:Mice; D008810:Mice, Inbred C57BL; D018485:Muscle Fibers, Skeletal / Q000378:metabolism / Q000473:pathology; D009124:Muscle Proteins / Q000378:metabolism*; D018482:Muscle, Skeletal / Q000737:chemistry / Q000378:metabolism*; D009133:Muscular Atrophy / Q000378:metabolism; D046988:Proteasome Endopeptidase Complex; D014161:Transduction, Genetic / Q000379:methods; D051636:X-Linked Inhibitor of Apoptosis Protein / Q000235:genetics* / Q000378:metabolism
D000199:Actins; D015415:Biomarkers; D061945:Caspase Inhibitors; D007328:Insulin; D009124:Muscle Proteins; D051636:X-Linked Inhibitor of Apoptosis Protein; D053148:Caspase 3; D053453:Caspase 9; D046988:Proteasome Endopeptidase Complex