HIV Antiretroviral agents inhibit protein synthesis and decrease ribosomal protein S6 and 4EBP1 phosphorylation in C2C12 myocytes
HIV Antiretroviral agents inhibit protein synthesis and decrease ribosomal protein S6 and 4EBP1 phosphorylation in C2C12 myocytes
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DOI：
10.1089/aid.2005.21.854
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发表时间：
2005-10-01
影响因子：
1.5
通讯作者：
Lang, CH
中科院分区：
文献类型：
--
作者：
Hong-Brown, LQ;Brown, CR;Lang, CH
联合抗逆转录病毒药物治疗方案促进了艾滋病患者的临床、免疫和病毒学改善。然而，这些疗法与脂质和碳水化合物代谢紊乱有关。在这项研究中，我们检测了代表性蛋白酶抑制剂（奈非那韦）、非核苷类逆转录酶抑制剂（奈韦拉平）和核苷类逆转录酶抑制剂（齐多夫定）对骨骼肌细胞中蛋白质合成的影响。为了检查这些过程，C2C12肌细胞用增加浓度的奈非那韦、奈韦拉平或齐多夫定处理1或2天，并通过测量[S-35]蛋氨酸/半胱氨酸并入细胞蛋白来测定蛋白质合成率。用治疗浓度的奈非那韦、奈韦拉平或齐多夫定治疗肌细胞48小时可使蛋白质合成降低14-20%。在用高浓度奈韦拉平或奈非那韦处理的细胞中观察到类似60%的下降。相比之下，当细胞与这些化合物孵育24小时时，蛋白质合成的基础速率不受影响。奈非那韦和奈韦拉平的治疗浓度不影响胰岛素对蛋白质合成的合成代谢作用。而齐多夫定抑制了胰岛素的刺激作用。奈非那韦和齐多夫定诱导的蛋白合成减少与S6核糖体蛋白（rpS6）和阻遏物结合蛋白4EBP1磷酸化降低有关，而奈韦拉平的抑制作用主要与磷酸化4EBP1下降有关。总之，奈非那韦、奈韦拉平和齐多夫定治疗降低了肌细胞中的蛋白质合成，这种作用与调节翻译起始的蛋白质磷酸化水平的降低有关。
Combined antiretroviral drug regimens have promoted clinical, immunologic, and virologic improvements in AIDS patients. Nevertheless, these therapies are associated with derangements in lipid and carbohydrate metabolism. In this study, we examined the effects of a representative protease inhibitor (nelfinavir), a nonnucleoside reverse transcriptase inhibitor (nevirapine), and a nucleoside reverse transcriptase inhibitor (zidovudine) on protein synthesis in skeletal muscle cells. To examine these processes, C2C12 myocytes were treated with increasing concentrations of nelfinavir, nevirapine, or zidovudine for 1 or 2 days, and rates of protein synthesis were determined by measuring [S-35] methionine/cysteine incorporation into cellular proteins. Treatment of myocytes with therapeutic concentrations of nelfinavir, nevirapine, or zidovudine for 48 hr decreased protein synthesis by 14-20%. An similar to 60% decline was observed in cells treated with higher concentrations of nevirapine or nelfinavir. In contrast, the basal rate of protein synthesis was not affected when cells were incubated with these compounds for 24 hr. Therapeutic concentrations of nelfinavir and nevirapine did not impair the anabolic effect of insulin on protein synthesis. However, zidovudine suppressed the stimulatory effect of insulin. The decreased protein synthesis induced by nelfinavir and zidovudine was associated with decreases in the phosphorylation of the S6 ribosomal protein (rpS6) and the repressor binding protein 4EBP1, while the inhibitory effect of nevirapine was mainly associated with a decline in phosphorylated 4EBP1. In conclusion, nelfinavir, nevirapine, and zidovudine treatments decreased protein synthesis in myocytes and this effect was correlated with a reduction in the phosphorylation level of proteins that regulate translation initiation.