X-chromosome linked inhibitor of apoptosis protein inhibits muscle proteolysis in insulin-deficient mice

Gene Ther. 2007 May;14(9):711-20. doi: 10.1038/sj.gt.3302927. Epub 2007 Feb 22.


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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Actins / analysis
  • Animals
  • Apoptosis
  • Biomarkers / analysis
  • Caspase 3 / metabolism
  • Caspase 9 / metabolism
  • Caspase Inhibitors*
  • Cell Line
  • Diabetes Mellitus, Experimental / metabolism
  • Gene Expression
  • Genetic Therapy / methods
  • Humans
  • Immunoblotting
  • Immunohistochemistry
  • In Situ Nick-End Labeling
  • Insulin / deficiency*
  • Insulin / metabolism
  • Lentivirus / genetics
  • Mice
  • Mice, Inbred C57BL
  • Muscle Fibers, Skeletal / metabolism
  • Muscle Fibers, Skeletal / pathology
  • Muscle Proteins / metabolism*
  • Muscle, Skeletal / chemistry
  • Muscle, Skeletal / metabolism*
  • Muscular Atrophy / metabolism
  • Proteasome Endopeptidase Complex
  • Transduction, Genetic / methods
  • X-Linked Inhibitor of Apoptosis Protein / genetics*
  • X-Linked Inhibitor of Apoptosis Protein / metabolism


  • Actins
  • Biomarkers
  • Caspase Inhibitors
  • Insulin
  • Muscle Proteins
  • X-Linked Inhibitor of Apoptosis Protein
  • Caspase 3
  • Caspase 9
  • Proteasome Endopeptidase Complex