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This Article Full Text Full Text (PDF) All Versions of this Article: 288/3/E493    most recent 00186.2004v1 Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in ISI Web of Science Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via ISI Web of Science (3) Citing Articles via Google Scholar Google Scholar Articles by Lin, S.-Y. Articles by Sheu, W. H.-H. Search for Related Content PubMed PubMed Citation Articles by Lin, S.-Y. Articles by Sheu, W. H.-H.

Activation of ubiquitin-proteasome pathway is involved in skeletal muscle wasting in a rat model with biliary cirrhosis: potential role of TNF-

¹Division of Endocrinology and Metabolism, Department of Medicine, ²Department of Medical Education and Research, Taichung Veterans General Hospital, Taichung; ³Division of Gastroenterology, Department of Medicine, Taipei Veterans General Hospital; ⁴Department of Biochemical Science and Technology, College of Life Science, National Taiwan University; and ⁵Institute of Clinical Medicine, School of Medicine, National Yang Ming University, Taipei, Taiwan

Submitted 28 April 2004 ; accepted in final form 24 October 2004

Hepatic cirrhosis is associated with negative nitrogen balance and loss of lean body mass. This study aimed to identify the specific proteolytic pathways activated in skeletal muscles of cirrhotic rats. TNF- can stimulate muscle proteolysis; therefore, a potential relationship between TNF- and muscle wasting in liver cirrhosis was also evaluated. Cirrhosis was induced by bile duct ligation (BDL) in male adult Sprague-Dawley rats. mRNA and protein levels of various targets were determined by RT-PCR and Western blotting, respectively. The proteolytic rate was measured ex vivo using isolated muscles. Compared with sham-operated controls, BDL rats had an increased degradation rate of muscle proteins and enhanced gene expression of ubiquitin, 14-kDa ubiquitin carrier protein E2, and the proteasome subunits C2 and C8 (P < 0.01). The muscle protein levels of free ubiquitin and conjugated ubiquitin levels were also elevated (P < 0.01). However, there was no difference between the two groups with regard to cathepsin and calpain mRNA levels. Cirrhotic muscle TNF- levels were increased and correlated positively with free and conjugated ubiquitin (P < 0.01). We conclude that the ubiquitin-proteasome system is involved in muscle wasting of rats with BDL-induced cirrhosis. TNF- might play a role in mediating activation of this proteolytic pathway, probably through a local mechanism.

atrophy; cachexia; catabolism; liver; tumor necrosis factor-

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