Fujita J, Tsujinaka T, Yano M, Ebisui C, Saito H, Katsume A, Akamatsu K, Ohsugi Y, Shiozaki H, Monden M
Department of Surgery II, Osaka University Medical School, Japan.
Int J Cancer. 1996 Nov 27;68(5):637-43. doi: 10.1002/(SICI)1097-0215(19961127)68:5<637::AID-IJC14>3.0.CO;2-Z.
Progression of skeletal muscle atrophy is one of the characteristic features in cancer patients. Interleukin-6 (IL-6) has been reported to be responsible for the loss of lean body mass during cancer cachexia in colon-26 adenocarcinoma (C-26)-bearing mice. This study was carried out to elucidate the intracellular proteolytic pathways operating in skeletal muscle in C-26-bearing mice, and to examine the effect of anti IL-6 receptor antibody on muscle atrophy. On day 17 after tumor inoculation, the gastrocnemius muscle weight of C-26-bearing mice had significantly decreased to 69% of that of the pair-fed control mice. This weight loss occurred in association with increases in the mRNA levels of cathepsins B and L, poly-ubiquitin (Ub) and the subunits of proteasomes in the muscles. Furthermore, enzymatic activity of cathepsin B+L in the muscles also increased to 119% of the control. The administration of anti-murine IL-6 receptor antibody to C-26-bearing mice reduced the weight loss of the gastrocnemius muscles to 84% of that of the control mice, whose enzymatic activity of cathepsin B+L and mRNA levels of cathepsin L and poly-Ub were significantly suppressed compared with those of the C-26-bearing mice. Our data indicate that both the lysosomal cathepsin pathway and the ATP-dependent proteolytic pathway might be involved in the muscle atrophy of C-26-bearing mice. The results also suggest that anti IL-6 receptor antibody could be a potential therapeutic agent against muscle atrophy in cancer cachexia by inhibiting these proteolytic systems.
骨骼肌萎缩的进展是癌症患者的特征之一。据报道，白细胞介素-6（IL-6）是导致携带结肠26腺癌（C-26）的小鼠发生癌症恶病质期间瘦体重丧失的原因。本研究旨在阐明携带C-26的小鼠骨骼肌中起作用的细胞内蛋白水解途径，并研究抗IL-6受体抗体对肌肉萎缩的影响。在接种肿瘤后的第17天，携带C-26的小鼠腓肠肌重量显著下降至配对喂养对照小鼠的69%。这种体重减轻与肌肉中组织蛋白酶B和L、多聚泛素（Ub）以及蛋白酶体亚基的mRNA水平升高有关。此外，肌肉中组织蛋白酶B+L的酶活性也增加至对照的119%。给携带C-26的小鼠注射抗小鼠IL-6受体抗体后腓肠肌的体重减轻降至对照小鼠的84%，与携带C-26的小鼠相比，其组织蛋白酶B+L的酶活性以及组织蛋白酶L和多聚泛素的mRNA水平均受到显著抑制。我们的数据表明，溶酶体组织蛋白酶途径和ATP依赖性蛋白水解途径可能都参与了携带C-26的小鼠的肌肉萎缩。结果还表明，抗IL-6受体抗体可能通过抑制这些蛋白水解系统成为治疗癌症恶病质中肌肉萎缩的潜在治疗剂。
