UBIQUITIN GENE-EXPRESSION IS INCREASED IN SKELETAL-MUSCLE OF TUMOR-BEARING RATS

Rats bearing the fast-growing AH-130 Yoshida ascites hepatoma showed a marked cachectic response which has been previously reported [Tessitore et al. (1987) Biochem. J. 241, 153-159]. Thus tumour-bearing animals showed significant decreases in body and muscle weight (soleus and gastrocnemius) as compared to both pair-fed and ad libitum-fed animals. These decreases were related to an enhanced proteolytic rate in the muscles of the tumour-bearing animals as measured by the tyrosine released in in vitro assays. In an attempt to elucidate which proteolytic system is directly responsible for the decrease in muscle mass, we have studied both lysosomal and non-lysosomal (ATP-dependent) proteolytic systems in this animal model. While the enzymatic activities of the main cathepsin (B and B + L) systems were actually decreased in gastrocnemius muscles of tumour-bearing rats, thus indicating that lysosomal proteolysis was not involved, the ubiquitin pools (both free and conjugated) were markedly altered as a result of tumour burden. These were associated with an increased ubiquitin gene expression in muscle of tumour-bearing rats, over 500% in relation to non-tumour bearers, thus suggesting that the ATP-dependent proteolytic system may be responsible for the muscle proteolysis and wastage observed in this animal tumour model. The fact that we have previously shown that TNF enhances the ubiquitination of muscle proteins [Garcia-Martinez et al. (1993) FEBS Lett. 323, 211-214], together with the high circulating levels of TNF detected in rats bearing the Yoshida hepatoma allows us to suggest that the cytokine may be responsible, most probably indirectly, for the activation of the referred proteolytic system in tumour-bearing rats.