Abstract
Muscle wasting that occurs with cancer cachexia is caused by an imbalance in the rates of muscle protein synthesis and degradation. The ApcMin/+ 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 ApcMin/+ mouse is not known. Cachexia progression was studied in ApcMin/+ 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.
Highlights
Skeletal muscle mass loss is a hallmark of cachexia, and muscle mass preservation is critical for the survival of many cancer patients [1]
Our current study provides further evidence that a surge in circulating IL-6 is critical for the progression of cachexia in the ApcMin/+ mouse
We report a 3–4 fold induction of IL-6 levels in mice transitioning from the initiation of muscle mass loss to more severe loss, and that administration of an IL-6 receptor antibody after the initiation of cachexia essentially blocks the transition towards more severe body weight and muscle mass loss
Summary
Skeletal muscle mass loss is a hallmark of cachexia, and muscle mass preservation is critical for the survival of many cancer patients [1]. Patients diagnosed during initial stages of cachexia (,5% body weight loss) have a much better survival time and chemotherapy treatment outcomes [5,6]. Understanding the regulation of muscle wasting throughout the progression of cachexia is critical for developing both prevention and intervention strategies for treatment of cachexia [4]. We have a limited understanding of muscle protein turnover regulation during the initial stages of cachexia. The progression of muscle wasting accelerates during the progression of cachexia [5]. This nonlinear process creates gaps in our knowledge, which is based largely on regulatory changes during the later stages of cachexia
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