Anabolic resistance of skeletal muscle in cancer cachexia is caused by impaired IGF1 expression to mechanical loading

Cachexia is a systemic metabolic syndrome characterized by loss of fat and skeletal muscle mass in chronic wasting diseases such as cancer. The regulation of cellular protein synthesis in response to workload in skeletal muscle is generally blunted in cancer cachexia; however, the precise molecular regulation is largely unknown. In this study, to examine the molecular mechanism of skeletal muscle protein metabolism in cancer cachexia, we analyzed comprehensive gene expression in skeletal muscle using microarrays. CD2F1 mice (male, 7 weeks old) were subcutaneously transplanted (1*10^6 cells per mouse) with a mouse colon cancer-derived cell line (C26) as a model of cancer cachexia. Functional overload of the plantaris muscle by synergist ablation was performed at the 2nd week, and the plantaris muscle was sampled at the 4th week of cancer transplantation. The hypertrophy of skeletal muscle (increased skeletal muscle weight/protein synthesis efficiency and activation of mTOR signaling) associated with compensatory overload was significantly suppressed with the cancer cachexia. Gene expression profiling and pathway analysis by microarray showed that resistance to muscle protein synthesis associated with cancer cachexia was induced by downregulation of insulin-like growth factor-1. These observations show that cancer cachexia induces resistance to muscle protein synthesis, which could be a potential factor inhibiting the adaptation of skeletal muscle growth to physical exercise. Colon 26 (C26) carcinoma tumor-bearing CD2F1 mice were employed as the model for the study of cancer cachexia. The C26 carcinoma (RCB2657) was provided by RIKEN BRC through the National Bio-Resource Project of MEXT, Japan. All cell culture experiments were performed in a humidified environment at 37 °C in a 5% CO2 atmosphere. The C26 cells were grown in RPMI-1640 medium (FUJIFILM Wako Pure Chemical Corporation, Osaka, Japan) supplemented with 10% FBS and penicillin–streptomycin. After trypsinization and neutralization, 1 × 10^6 C26 cells per individual were suspended with 100 μL of PBS and subcutaneously implanted into the flank region of the abdominal wall unilaterally using a 26G syringe as previously described. The control group was injected with an equal amount of PBS.