In order to elucidate the acute and chronic effects of interleukin-6 (IL-6) on muscle protein degradation, the weight of skeletal muscles and the activities of lysosomal cathepsins (B and L) in the muscles were examined in two animal models. Two intraperitoneal injections of recombinant human IL-6 into rats did neither significantly affect the cathepsin activities in the soleus and the extensor digitorum longus muscles nor the weight of these muscles. On the other hand, the gastrocnemius muscles of the IL-6 transgenic mice underwent severe atrophy accompanied by a marked increase in cathepsin activities. We conclude that IL-6 mediates muscle protein degradation with enhancing lysosomal cathepsin activity, and that these muscle reactions are mandated by chronic exposure to a high level of IL-6.