Department of Integrative Physiology, Graduate School of Biomedical and Health Sciences, Hiroshima University, Japan; Department of Physical Therapy, School of Rehabilitation Sciences, Health Sciences University of Hokkaido, Japan.
Department of Physical Therapy, School of Rehabilitation Sciences, Health Sciences University of Hokkaido, Japan.
Growth Horm IGF Res. 2023 Apr-Jun;69-70:101536. doi: 10.1016/j.ghir.2023.101536. Epub 2023 May 18.
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.
CD2F1 mice (male, 8 weeks old) were subcutaneously transplanted (1 × 10 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.
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.
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.
恶病质是一种全身性代谢综合征，其特征是在慢性消耗性疾病（如癌症）过程中出现体重和骨骼肌量的减少。癌症恶病质患者的骨骼肌对合成代谢因子（包括机械负荷）的反应性降低；然而，其确切的分子机制在很大程度上尚不清楚。在本研究中，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。
用鼠结肠癌细胞系（C26）皮下移植 CD2F1 小鼠（雄性，8 周龄）（每只小鼠 1×10 个细胞）作为癌症恶病质模型。在 C26 移植后的第 2 周对比目鱼肌进行协同肌切断术的机械超负荷，在第 4 周时取样比目鱼肌。
与机械超负荷相关的骨骼肌肥大反应（骨骼肌重量/蛋白合成效率增加和雷帕霉素靶蛋白复合体 1 信号通路的激活）在癌症恶病质过程中受到显著抑制。使用微阵列进行基因表达谱和通路分析的筛选表明，肌肉蛋白合成的减弱与癌症恶病质有关，可能是由胰岛素样生长因子 1（IGF-1）下调和 IGF-1 依赖性信号通路激活受损引起的。
这些观察结果表明，癌症恶病质会导致肌肉蛋白合成的抵抗，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。
