INFLUENCE OF PROGRESSIVE TUMOR-GROWTH ON GLUTAMINE-METABOLISM IN SKELETAL-MUSCLE AND KIDNEY

Objective The effects of progressive malignant growth on glutamine met abolism in skeletal muscle and in kidney were investigated. Summary Ba ckground Data Fast-growing tumors consume considerable quantities of g lutamine and lead to a decrease in circulating glutamine concentration s. Methods Experiments were performed at various stages of tumor growt h in rats implanted subcutaneously with the non-metastasizing methylch olanthrene-induced (MCA) fibrosarcoma and in pair-fed non tumor-bearin g controls. Results Tumor growth stimulated a twofold increase in hind quarter (muscle) glutamine release, which was not due to an increase i n blood flow, but rather to a doubling in the fractional release rate. Consequently, a progressive decrease in skeletal muscle glutamine con centrations was observed over time. Simultaneously, the activity of gl utamine synthetase (GS), the principal enzyme of de novo glutamine bio synthesis, increased more than twofold. This increase in muscle GS act ivity was accompanied by an increase in GS mRNA but the augmentation i n GS expression apparently could not match the increased rate of efflu x since muscle depletion developed. In rats with large tumors and seve re glutamine depletion, GS activity was not elevated. Glutamine feedin g increased muscle glutamine concentrations and glutamine synthetase s pecific activity. Although tumor growth led to the development of mild systemic acidemia, the classic renal adaptations normally observed, i .e., elevated glutaminase activity and accelerated renal glutamine uti lization, were not present in acidotic tumor-bearing rats. Instead, re nal GS activity was increased in tumor-bearing animals and ammoniagene sis was enhanced, in spite of a reduction in net renal glutamine uptak e. Conclusions These data suggest that marked alterations in muscle an d renal glutamine handling occur in the host with cancer; the enhanced muscle glutamine release in conjunction with no increase in renal con sumption is consistent with increased glutamine uptake in other organs , most likely the tumor itself and the liver.