TRANSIENT EXPOSURE OF HUMAN MYOBLASTS TO TUMOR-NECROSIS-FACTOR-ALPHA INHIBITS SERUM AND INSULIN-LIKE GROWTH-FACTOR-I STIMULATED PROTEIN-SYNTHESIS

Tumor necrosis factor-alpha (TNF-alpha) induces cachexia and is postul ated to be responsible for muscle wasting in several pathophysiologica l conditions. The purpose of the present study was to investigate whet her exposure of human myoblasts to TNF-alpha could directly inhibit th e ability of serum or insulin-like growth factor I (IGF-I) to stimulat e protein synthesis as assessed by the incorporation of [H-3] phenylal anine into protein. Serum and IGF-I stimulated protein synthesis dose dependently. Half-maximal stimulation of protein synthesis occurred at 05% serum and 8 ng/ml of IGF-I, respectively. TNF-alpha inhibited IGF -I-stimulated protein synthesis in a dose-dependent manner. Additional ly, as little as 2 ng/ml of TNF-alpha impaired the ability of IGF-I to stimulate protein synthesis by 33% and, at a dose of 100 ng/ml, TNF-a lpha completely prevented the increase in protein synthesis induced by either serum or a maximally stimulating dose of IGF-I. Inhibition of protein synthesis was independent of whether TNF-alpha and growth fact ors were added to cells simultaneously or if the cells were pretreated with growth factors. Exposure of myoblasts to TNF-alpha for 10 min co mpletely inhibited serum-induced stimulation of protein synthesis. TNF -alpha inhibited protein synthesis up to 48 h after addition of the cy tokine. TNF-alpha also inhibited serum-stimulated protein synthesis in human myoblasts that were differentiated into myotubes. In contrast, exposure of myoblasts to TNF-alpha had no effect on IGF-I binding and failed to alter the ability of either IGF-I or serum to stimulate [H-3 ]thymidine uptake. These data indicate that transient exposure of myob lasts or myotubes to TNF-alpha inhibits protein synthesis. Thus, the a nabolic actions of IGF-I on muscle protein synthesis may be impaired d uring catabolic conditions in which TNF-alpha is over expressed.