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

• Type of Material: Article
• Authors: Xiaonan Wang, Emory University; J Hu, Emory University; J Du, Baylor College of Medicine; Janet D Klein, Emory University
• Language: English
• Date: 2007-02-22
• Publisher: Nature Publishing Group: Open Access Hybrid Model Option B
• Publication Version: Author Accepted Manuscript (After Peer Review)
• Copyright Statement: © 2007 Nature Publishing Group All rights reserved
• Final Published Version (URL): http://www.nature.com/gt/journal/v14/n9/full/3302927a.html#aff1
• Title of Journal or Parent Work: Gene Therapy
• ISSN: 0969-7128
• Volume: 14
• Issue: 9
• Start Page: 711
• End Page: 720
• Grant/Funding Information: 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.
• Keywords: lentivirus; muscle protein degradation; XIAP; gene transfer; diabetes mellitus; caspase-3
• Research Categories: Biology, Physiology; Biology, Genetics; Health Sciences, General

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.