MUSCLE WASTING ASSOCIATED WITH CANCER CACHEXIA IS LINKED TO AN IMPORTANT ACTIVATION OF THE ATP-DEPENDENT UBIQUITIN-MEDIATED PROTEOLYSIS

Rats bearing the Yoshida AH-130 ascites hepatoma for 7 days showed an important decrease in muscle mass-over 30% in gastrocnemius and extens or digitorum longus (EDL)-in relation to non-tumour-bearing controls, which is associated with an increased proteolytic rate in in vitro inc ubation. In order to identify the precise biochemical process which wa s involved, we measured different proteolytic systems in incubated EDL muscles. The capacity for intralysosomal proteolysis, as measured by sensitivity to methylamine, was not increased in tumour-bearing rats, suggesting that the mechanism involved in the increased proteolytic ra te was extralysosomal. Incubations using the Ca2+ ionophore A23187 rev ealed no change in the activity of calcium dependent proteases as a co nsequence of tumour growth. Finally, muscle incubation in an ATP-deple ted medium allowed us to conclude that energy-dependent proteases were involved in the activation of muscle proteolysis in tumour-bearing ra ts. In particular, the ubiquitin-dependent proteolytic system is invol ved, since there is an important increase in ubiquitin conjugates in t he skeletal muscle of tumour-bearing rats. It may thus be suggested th at extralysosomal ATP- and ubiquitin-dependent proteases underlie the biochemical mechanism of muscle wastage associated with cancer cachexi a. (C) 1995 Wiley-Liss, Inc.