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 I 7 after tumor inoculation, trocnemius muscle weight of C-26-bearing mice had the sign' I F = icantly 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 activiky of cathepsin B+L in the muscles also increased to 119% of the control. The administration of antimurine 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 invoked 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.o 1996 Wiley-Liss, Inc.Cachexia is a characteristic syndrome observed in cancer patients; it reduces the response to chemotherapy and diminishes the chance of success for curative surgical treatment. If the progression of muscle wasting seen in malignant neoplastic diseases could be prevented, it would be of clinical importance in terms of improving the prognosis and the quality of life of patients. In cancer cachexia the host suffers from alterations in the metabolism of proteins and amino acids. These changes are characterized by a decrease in protein synthesis and an increase in protein degradation in skeletal muscle (Smith and Tisdale, 1993); the precise mechanism remains unknown, however.Skeletal muscle contains 3 major proteolytic pathways: lysosomal cathepsins, cytosolic Ca?+-dependent proteases (calpain), and the ATP-ubiquitin (Ub)-dependent system. Increases in the mRNA levels of poly-Ub and in the subunits (Llovera et al., 1994). It has thus been concluded that the ATP-Ub-dependent proteolytic pathway is most responsible for the muscle protein degradation seen in the tumor-bearing state. Studies from our laboratory on interleukin-6 (IL-6) transgenic mice revealed that IL-6 is a potent factor that induces muscle atrophy and that it can modulate not only the ATP-Ub-dependent pathway but also the lysosomal cathepsin systems (Tsujinaka et al., 1996).Murine colon-26 adenocarcinoma (C-26) is an undiffcrentiated carcinoma induced by a carcinogen, N-nitroso-Nmethylurethane. ...