The Regulation of Skeletal Muscle Protein Turnover during the Progression of Cancer Cachexia in the ApcMin/+ Mouse

被引:174
作者
White, James P. [1 ]
Baynes, John W. [1 ]
Welle, Stephen L. [2 ]
Kostek, Matthew C. [1 ]
Matesic, Lydia E. [3 ]
Sato, Shuichi [1 ]
Carson, James A. [1 ]
机构
[1] Univ S Carolina, Dept Exercise Sci, Columbia, SC 29208 USA
[2] Univ Rochester, Sch Med, Dept Med, Rochester, NY USA
[3] Univ S Carolina, Dept Biol Sci, Columbia, SC 29208 USA
关键词
UBIQUITIN-PROTEASOME PATHWAY; TUMOR-BEARING RATS; FOXO TRANSCRIPTION FACTORS; APC(MIN/+) MICE; AMPK ACTIVATION; MESSENGER-RNA; GROWTH-FACTOR; PROTEOLYTIC SYSTEMS; MAMMALIAN TARGET; BINDING-PROTEINS;
D O I
10.1371/journal.pone.0024650
中图分类号
O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];
学科分类号
07 ; 0710 ; 09 ;
摘要
Muscle wasting that occurs with cancer cachexia is caused by an imbalance in the rates of muscle protein synthesis and degradation. The Apc(Min/+) mouse is a model of colorectal cancer that develops cachexia that is dependent on circulating IL-6. However, the IL-6 regulation of muscle protein turnover during the initiation and progression of cachexia in the Apc(Min/+) mouse is not known. Cachexia progression was studied in Apc(Min/+) mice that were either weight stable (WS) or had initial (<= 5%), intermediate (6-19%), or extreme (>= 20%) body weight loss. The initiation of cachexia reduced % MPS 19% and a further similar to 50% with additional weight loss. Muscle IGF-1 mRNA expression and mTOR targets were suppressed with the progression of body weight loss, while muscle AMPK phosphorylation (Thr 172), AMPK activity, and raptor phosphorylation (Ser 792) were not increased with the initiation of weight loss, but were induced as cachexia progressed. ATP dependent protein degradation increased during the initiation and progression of cachexia. However, ATP independent protein degradation was not increased until cachexia had progressed beyond the initial phase. IL-6 receptor antibody administration prevented body weight loss and suppressed muscle protein degradation, without any effect on muscle % MPS or IGF-1 associated signaling. In summary, the % MPS reduction during the initiation of cachexia is associated with IGF-1/mTOR signaling repression, while muscle AMPK activation and activation of ATP independent protein degradation occur later in the progression of cachexia. IL-6 receptor antibody treatment blocked cachexia progression through the suppression of muscle protein degradation, while not rescuing the suppression of muscle protein synthesis. Attenuation of IL-6 signaling was effective in blocking the progression of cachexia, but not sufficient to reverse the process.
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页数:17
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