MUSCLE PROTEIN WASTE IN TUMOR-BEARING RATS IS EFFECTIVELY ANTAGONIZEDBY A BETA(2)-ADRENERGIC AGONIST (CLENBUTEROL) - ROLE OF THE ATP-UBIQUITIN-DEPENDENT PROTEOLYTIC PATHWAY

Tissue protein hypercatabolism (TPH) is a most important feature in ca ncer cachexia, particularly with regard to the skeletal muscle. The ra t ascites hepatoma Yoshida AH-130 is a very suitable model system for studying the mechanisms involved in the processes that lead to tissue depletion, since it induces in the host a rapid and progressive muscle waste mainly due to TPH (Tessitore, L., G. Bonelli, and P. M. Baccino . 1987. Biochem. J. 241:153-159). Detectable plasma levels of tumor ne crosis factor-alpha associated with marked perturbations in the hormon al homeostasis have been shown to concur in forcing metabolism into a catabolic setting (Tessitore, L., P. Costelli, and F. M. Baccino. 1993 . Br. J. Cancer. 67:15-23). The present study was directed to investig ate if beta(2)-adrenergic agonists, which are known to favor skeletal muscle hypertrophy, could effectively antagonize the enhanced muscle p rotein breakdown in this cancer cachexia model. One such agent, i.e., clenbuterol, indeed largely prevented skeletal muscle waste in AH-130- bearing rats by restoring protein degradative rates close to control v alues. This normalization of protein breakdown rates was achieved thro ugh a decrease of the hyperactivation of the ATP-ubiquitin-dependent p roteolytic pathway, as previously demonstrated in our laboratory (Llov era, M., C. Garcia-Martinez, N. Agell, M. Marzabal, F. J. Lopez-Sorian o, and J. M. Argiles. 1994. FEES (Fed. fur. Biochem. Sec.) Lett. 338:3 11-318). By contrast, the drug did not exert any measurable effect on various parenchymal organs, nor did it modify the plasma level of cort icosterone and insulin, which were increased and decreased, respective ly, in the tumor hosts. The present data give new insights into the me chanisms by which clenbuterol exerts its preventive effect on muscle p rotein waste and seem to warrant the implementation of experimental pr otocols involving the use of clenbuterol or alike drugs in the treatme nt of pathological states involving TPH, particularly in skeletal musc le and heart, such as in the present model of cancer cachexia.