Frost R A, Lang C H, Gelato M C
Department of Medicine, State University of New York at Stony Brook, 11794, USA.
Endocrinology. 1997 Oct;138(10):4153-9. doi: 10.1210/endo.138.10.5450.
Tumor necrosis factor-alpha (TNF-alpha) induces cachexia and is postulated to be responsible for muscle wasting in several pathophysiological conditions. The purpose of the present study was to investigate whether exposure of human myoblasts to TNF-alpha could directly inhibit the ability of serum or insulin-like growth factor I (IGF-I) to stimulate protein synthesis as assessed by the incorporation of [3H]phenylalanine 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. Additionally, 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-alpha 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 factors were added to cells simultaneously or if the cells were pretreated with growth factors. Exposure ofmyoblasts to TNF-alpha for 10 min completely inhibited serum-induced stimulation of protein synthesis. TNF-alpha inhibited protein synthesis up to 48 h after addition of the cytokine. 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 [3H]thymidine uptake. These data indicate that transient exposure of myoblasts or myotubes to TNF-alpha inhibits protein synthesis. Thus, the anabolic actions of IGF-I on muscle protein synthesis may be impaired during catabolic conditions in which TNF-alpha is over expressed.
肿瘤坏死因子-α（TNF-α）可引发恶病质，并被认为在多种病理生理状况下导致肌肉萎缩。本研究的目的是探究人成肌细胞暴露于TNF-α是否会直接抑制血清或胰岛素样生长因子I（IGF-I）刺激蛋白质合成的能力，这一能力通过[3H]苯丙氨酸掺入蛋白质来评估。血清和IGF-I呈剂量依赖性地刺激蛋白质合成。蛋白质合成的半数最大刺激分别出现在0.5%血清和8 ng/ml IGF-I时。TNF-α以剂量依赖性方式抑制IGF-I刺激的蛋白质合成。此外，低至2 ng/ml的TNF-α会使IGF-I刺激蛋白质合成的能力受损33%，而在100 ng/ml的剂量下，TNF-α完全阻止了血清或最大刺激剂量的IGF-I所诱导的蛋白质合成增加。蛋白质合成的抑制与TNF-α和生长因子是同时添加到细胞中，还是细胞先用生长因子预处理无关。成肌细胞暴露于TNF-α 10分钟可完全抑制血清诱导的蛋白质合成刺激。在添加细胞因子后长达48小时，TNF-α均抑制蛋白质合成。TNF-α还抑制分化为肌管的人成肌细胞中血清刺激的蛋白质合成。相比之下，成肌细胞暴露于TNF-α对IGF-I结合没有影响，也未改变IGF-I或血清刺激[3H]胸苷摄取的能力。这些数据表明，成肌细胞或肌管短暂暴露于TNF-α会抑制蛋白质合成。因此，在TNF-α过度表达的分解代谢状态下，IGF-I对肌肉蛋白质合成的合成代谢作用可能会受损。
