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Am J Physiol Endocrinol Metab (November 2, 2004). doi:10.1152/ajpendo.00186.2004
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Submitted on April 28, 2004
Accepted on October 24, 2004

Activation of Ubiquitin-Proteasome Pathway is Involved in Skeletal Muscle Wasting in a Rat Model with Biliary Cirrhosis: Potential Role of Tumor Necrosis Factor-{alpha}

Shih-Yi Lin1, Wen-Yin Chen2, Fa-Yauh Lee3, Ching-Jang Huang4, and Wayne Huey-Herng Sheu2*

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

* To whom correspondence should be addressed. E-mail: whhsheu{at}vghtc.vghtc.gov.tw.

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. Tumor necrosis factor-{alpha} (TNF-{alpha}) can stimulate muscle proteolysis. Therefore, a potential relationship between TNF-{alpha} and muscle wasting in liver cirrhosis was also evaluated. Cirrhosis was induced by bile duct ligation (BDL) in male adult Sprague Dawley rats. Messenger RNA (mRNA) and protein levels of various targets were determined by reverse transcription-polymerase chain reaction (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-{alpha} 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-{alpha} might play a role in mediating activation of this proteolytic pathway, probably through a local mechanism.




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