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.