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

Gene Therapy volume 14, pages 711–720 (2007)Cite this article

Abstract

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.

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Abbreviations

EDL:

extensor digitorum longus

MuLV:

murine leukemia virus

STZ:

streptozotocin

XIAP:

X-chromosome linked inhibitor of apoptosis protein.

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Acknowledgements

We thank Dr Didier Trono for providing the packaging plasmid; Drs James Wilson and Gary Koringer for providing the five lentivirus envelope plasmids; Dr Yili Yang for the pEBB.XIAP plasmid, Dr Joe M LeDoux for pCCL.CMV.GFP plasmid. We thank Dr Russ Price and Dr James Bailey for their critical reading of this manuscript. This study was supported by a Norman S Coplon Extramural Research Grant from Satellite Health, an American Diabetes Association Junior Faculty Award 1-04-JF-48 and NIH R21 Grant DK62796 to XHW, and NIH R01 DK062081 to JDK.

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Authors and Affiliations

  1. Renal Division, Department of Medicine, Emory University, Atlanta, GA, USA

    X H Wang, J Hu & J D Klein

  2. Nephrology Division, Baylor College of Medicine, Houston, TX, USA

    J Du

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  1. X H Wang
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Correspondence to X H Wang.

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Wang, X., Hu, J., Du, J. et al. X-chromosome linked inhibitor of apoptosis protein inhibits muscle proteolysis in insulin-deficient mice. Gene Ther 14, 711–720 (2007). https://doi.org/10.1038/sj.gt.3302927

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