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 [Tessito re et al. (1987) Biochem. J. 241, 153-159]. Thus tumour-bearing animal s showed significant decreases in body and muscle weight (soleus and g astrocnemius) as compared to both pair-fed and ad libitum-fed animals. These decreases were related to an enhanced proteolytic rate in the m uscles of the tumour-bearing animals as measured by the tyrosine relea sed in in vitro assays. In an attempt to elucidate which proteolytic s ystem 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 ma in cathepsin (B and B + L) systems were actually decreased in gastrocn emius muscles of tumour-bearing rats, thus indicating that lysosomal p roteolysis was not involved, the ubiquitin pools (both free and conjug ated) were markedly altered as a result of tumour burden. These were a ssociated with an increased ubiquitin gene expression in muscle of tum our-bearing rats, over 500% in relation to non-tumour bearers, thus su ggesting 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 ub iquitination of muscle proteins [Garcia-Martinez et al. (1993) FEBS Le tt. 323, 211-214], together with the high circulating levels of TNF de tected in rats bearing the Yoshida hepatoma allows us to suggest that the cytokine may be responsible, most probably indirectly, for the act ivation of the referred proteolytic system in tumour-bearing rats.