INCREASED ATP-UBIQUITIN-DEPENDENT PROTEOLYSIS IN SKELETAL-MUSCLES OF TUMOR-BEARING RATS

Little information is available on proteolytic pathways responsible fo r muscle wasting in cancer cachexia. Experiments were carried out in y oung rats to demonstrate whether a small (<0.3% body weight) tumor may activate the lysosomal, Ca2+-dependent, and/or ATP-ubiquitin-dependen t proteolytic pathway(s) in skeletal muscle. Five days after tumor imp lantation, protein mass of extensor digitorum longus and tibialis ante rior muscles close to a Yoshida sarcoma was significantly reduced comp ared to the contralateral muscles. According to in vitro measurements, protein loss totally resulted from increased proteolysis and not from depressed protein synthesis. Inhibitors of lysosomal and Ca2+-depende nt proteases did not attenuate increased rates of proteolysis in the a trophying extensor digitorum longus. Accordingly, cathepsin B and B+L activities, and mRNA levels for cathepsin B were unchanged. By contras t, ATP depletion almost totally suppressed the increased protein break down. Furthermore, mRNA levels for ubiquitin, 14 kDa ubiquitin carrier protein E2, and the C8 or C9 proteasome subunits increased in the atr ophying muscles. Similar adaptations occurred in the muscles from cach ectic animals 12 days after tumor implantation. These data strongly su ggest that the activation of the ATP-ubiquitin-dependent proteolytic p athway is mainly responsible for muscle atrophy in Yoshida sarcoma-bea ring rats.