The regulation of skeletal muscle protein turnover during the progression of cancer cachexia in the Apc Min/+ mouse

James P. White, John W. Baynes, Stephen L. Welle, Matthew C. Kostek, Lydia E. Matesic, Shuichi Sato, James Carson

Research output: Contribution to journalArticle

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Abstract

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 ~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.

Original languageEnglish (US)
Article numbere24650
JournalPloS one
Volume6
Issue number9
DOIs
StatePublished - Sep 19 2011

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cachexia
Cachexia
Muscle Proteins
muscle protein
protein metabolism
skeletal muscle
Skeletal Muscle
Muscle
Degradation
AMP-Activated Protein Kinases
neoplasms
mice
protein degradation
Insulin-Like Growth Factor I
Proteolysis
Interleukin-6 Receptors
Interleukin-6
Neoplasms
Phosphorylation
interleukin-6

All Science Journal Classification (ASJC) codes

  • Biochemistry, Genetics and Molecular Biology(all)
  • Agricultural and Biological Sciences(all)

Cite this

The regulation of skeletal muscle protein turnover during the progression of cancer cachexia in the Apc Min/+ mouse. / White, James P.; Baynes, John W.; Welle, Stephen L.; Kostek, Matthew C.; Matesic, Lydia E.; Sato, Shuichi; Carson, James.

In: PloS one, Vol. 6, No. 9, e24650, 19.09.2011.

Research output: Contribution to journalArticle

White, James P. ; Baynes, John W. ; Welle, Stephen L. ; Kostek, Matthew C. ; Matesic, Lydia E. ; Sato, Shuichi ; Carson, James. / The regulation of skeletal muscle protein turnover during the progression of cancer cachexia in the Apc Min/+ mouse. In: PloS one. 2011 ; Vol. 6, No. 9.
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abstract = "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 ~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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