The Regulation of Skeletal Muscle Protein Turnover during the Progression of Cancer Cachexia in the Apc Mouse

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.

癌症恶病质（cancer cachexia）引发的肌肉萎缩，源于肌肉蛋白质合成与降解速率的失衡。ApcMin/+小鼠（ApcMin/+ mouse）是结直肠癌（colorectal cancer）模型，其发生的恶病质依赖于循环白细胞介素6（circulating IL-6）。然而，目前尚不明确在ApcMin/+小鼠恶病质的起始与进展阶段，IL-6对肌肉蛋白质周转的调控作用。
本研究对ApcMin/+小鼠的恶病质进展开展了分析，受试小鼠分为体重稳定（weight stable, WS）组，以及初始体重丢失≤5%、中度（6%~19%）或重度（≥20%）的亚组。恶病质起始阶段可使肌肉蛋白质合成率（%MPS）降低19%，随着体重进一步丢失，%MPS进一步下降约50%。
随着体重丢失进展，肌肉组织的胰岛素样生长因子1（insulin-like growth factor 1, IGF-1）信使核糖核酸（messenger ribonucleic acid, mRNA）表达及哺乳动物雷帕霉素靶蛋白（mammalian target of rapamycin, mTOR）靶点均受到抑制；而肌肉AMP活化蛋白激酶（AMP-activated protein kinase, AMPK）的苏氨酸172（Thr 172）位点磷酸化水平、AMPK活性及raptor蛋白（raptor）的丝氨酸792（Ser 792）位点磷酸化水平，并未在体重丢失起始阶段升高，而是随恶病质进展才被诱导激活。
ATP依赖的蛋白质降解在恶病质起始与进展阶段均有所上调，但ATP非依赖的蛋白质降解直至恶病质进展超出初始阶段后才出现升高。给予IL-6受体抗体可阻止体重丢失，并抑制肌肉蛋白质降解，但对肌肉%MPS或IGF-1相关信号通路无显著影响。
综上，恶病质起始阶段的%MPS降低与IGF-1/mTOR信号通路抑制相关，而肌肉AMPK激活及ATP非依赖蛋白质降解的激活则发生在恶病质进展的较晚阶段。IL-6受体抗体治疗通过抑制肌肉蛋白质降解阻断恶病质进展，但未能逆转肌肉蛋白质合成的抑制。减弱IL-6信号通路可有效阻断恶病质进展，但不足以逆转该病理过程。