Objective

Cachexia is a systemic metabolic syndrome characterized by loss of body weight and skeletal muscle mass during chronic wasting diseases, such as cancer. Skeletal muscle in cancer cachexia is less responsive to anabolic factors including mechanical loading; however, the precise molecular mechanism is largely unknown. In this study, we examined the underlying mechanism of anabolic resistance in skeletal muscle in a cancer cachexia model.

Methods

CD2F1 mice (male, 8 weeks old) were subcutaneously transplanted (1 × 10⁶ cells per mouse) with a mouse colon cancer-derived cell line (C26) as a model of cancer cachexia. Mechanical overload of the plantaris muscle by synergist tenotomy was performed during the 2nd week and the plantaris muscle was sampled at the 4th week following C26 transplantation.

Results

The hypertrophic response of skeletal muscle (increased skeletal muscle weight/protein synthesis efficiency and activation of mechanistic target of rapamycin complex 1 signaling) associated with mechanical overload was significantly suppressed during cancer cachexia. Screening of gene expression profile and pathway analysis using microarray revealed that blunted muscle protein synthesis was associated with cancer cachexia and was likely induced by downregulation of insulin-like growth factor-1 (IGF-1) and impaired activation of IGF-1-dependent signaling.

Conclusions

These observations indicate that cancer cachexia induces resistance to muscle protein synthesis, which may be a factor for inhibiting the anabolic adaptation of skeletal muscle to physical exercise in cancer patients.

中文翻译：

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机械负荷导致的胰岛素样生长因子 1 表达减少与癌症恶病质中的骨骼肌合成代谢抵抗相关

客观的

恶病质是一种全身代谢综合征，其特征是慢性消耗性疾病（例如癌症）期间体重和骨骼肌质量下降。癌症恶病质中的骨骼肌对机械负荷等合成代谢因素的反应较弱；然而，确切的分子机制在很大程度上尚不清楚。在这项研究中，我们研究了癌症恶病质模型中骨骼肌合成代谢抵抗的潜在机制。

方法

将小鼠结肠癌衍生细胞系（C26）皮下移植到CD2F1小鼠（雄性，8周龄）（每只小鼠1×10 ^{6 个细胞）作为癌症恶病质模型。}在 C26 移植后的第 2 周内，通过增效剂腱切断术对跖肌进行机械超负荷，并在第 4 周对跖肌进行取样。

结果

在癌症恶病质期间，与机械超负荷相关的骨骼肌肥大反应（骨骼肌重量/蛋白质合成效率增加和雷帕霉素复合物 1 信号传导的机械靶点激活）被显着抑制。使用微阵列筛选基因表达谱和通路分析表明，肌肉蛋白合成减弱与癌症恶病质有关，并且可能是由胰岛素样生长因子-1 (IGF-1) 下调和 IGF-1 依赖性信号传导受损激活引起的。

结论

这些观察结果表明，癌症恶病质会诱导肌肉蛋白质合成抵抗，这可能是抑制癌症患者骨骼肌对体育锻炼的合成代谢适应的一个因素。