Expression of the ubiquitin-proteasome pathway and muscle loss in experimental cancer cachexia


Muscle protein degradation is thought to play a major role in muscle atrophy in cancer cachexia. To investigate the importance of the ubiquitin-proteasome pathway, which has been suggested to be the main degradative pathway mediating progressive protein loss in cachexia, the expression of mRNA for proteasome subunits C2 and C5 as well as the ubiquitin-conjugating enzyme, E2(14k), has been determined in gastrocnemius and pectoral muscles of mice bearing the MAC16 adenocarcinoma, using competitive quantitative reverse transcriptase polymerase chain reaction. Protein levels of proteasome subunits and E2(14k) were determined by immunoblotting, to ensure changes in mRNA were reflected in changes in protein expression. Muscle weights correlated linearly with weight loss during the course of the study. There was a good correlation between expression of C2 and E2(14k) mRNA and protein levels in gastrocnemius muscle with increases of 6-8-fold for C2 and two-fold for E2(14k) between 12 and 20% weight loss, followed by a decrease in expression at weight losses of 25-27%, although loss of muscle protein continued. In contrast, expression of C5 mRNA only increased two-fold and was elevated similarly at all weight losses between 7.5 and 27%. Both proteasome functional activity, and proteasome-specific tyrosine release as a measure of total protein degradation was also maximal at 18-20% weight loss and decreased at higher weight loss. Proteasome expression in pectoral muscle followed a different pattern with increases in C2 and C5 and E2(14k) mRNA only being seen at weight losses above 17%, although muscle loss increased progressively with increasing weight loss. These results suggest that activation of the ubiquitin-proteasome pathway plays a major role in protein loss in gastrocnemius muscle, up to 20% weight loss, but that other factors such as depression in protein synthesis may play a more important role at higher weight loss. © 2005 Cancer Research.

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Divisions: College of Health & Life Sciences > Aston Pharmacy School
College of Health & Life Sciences > School of Biosciences
College of Health & Life Sciences
College of Health & Life Sciences > School of Biosciences > Cellular and Molecular Biomedicine
College of Health & Life Sciences > Chronic and Communicable Conditions
Additional Information: © 2005 Cancer Research UK Creative Commons Attribution-NonCommercial-Share-Alike 3.0 licence, subject to the conditions listed at
Uncontrolled Keywords: cachexia,gastrocnemius muscle,protein degradation,ubiquitin-proteasome proteolysis,Cancer Research,Oncology
Publication ISSN: 1532-1827
Last Modified: 27 Mar 2024 08:08
Date Deposited: 19 Aug 2019 08:50
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Related URLs: http://www.scop ... tnerID=8YFLogxK (Scopus URL)
http://www.natu ... l/6602780a.html (Publisher URL)
PURE Output Type: Article
Published Date: 2005-09-06
Authors: Khal, J.
Wyke, S.M.
Russell, Steve T. (ORCID Profile 0000-0002-5491-900X)
Hine, Anna V. (ORCID Profile 0000-0003-4065-831X)
Tisdale, Michael J.

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