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Adaptations to chronic rapamycin in mice

机译:适应小鼠慢性雷帕霉素

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摘要

Rapamycin inhibits mechanistic (or mammalian) target of rapamycin (mTOR) that promotes protein production in cells by facilitating ribosome biogenesis (RiBi) and eIF4E-mediated 5'cap mRNA translation. Chronic treatment with encapsulated rapamycin (eRapa) extended health and life span for wild-type and cancer-prone mice. Yet, the long-term consequences of chronic eRapa treatment are not known at the organ level. Here, we report our observations of chronic eRapa treatment on mTORC1 signaling and RiBi in mouse colon and visceral adipose. As expected, chronic eRapa treatment decreased detection of phosphorylated mTORC1/S6K substrate, ribosomal protein (rpS6) in colon and fat. However, in colon, contrary to expectations, there was an upregulation of 18S rRNA and some ribosomal protein genes (RPGs) suggesting increased RiBi. Among RPGs, eRapa increases rpl22l1 mRNA but not its paralog rpl22. Furthermore, there was an increase in the cap-binding protein, eIF4E relative to its repressor 4E-BP1 suggesting increased translation. By comparison, in fat, there was a decrease in the level of 18S rRNA (opposite to colon), while overall mRNAs encoding ribosomal protein genes appeared to increase, including rpl22, but not rpl22l1 (opposite to colon). In fat, there was a decrease in eIF4E relative to actin (opposite to colon) but also an increase in the eIF4E/4E-BP1 ratio likely due to reductions in 4E-BP1 at our lower eRapa dose (similar to colon). Thus, in contrast to predictions of decreased protein production seen in cell-based studies, we provide evidence that colon from chronically treated mice exhibited an adaptive ‘pseudo-anabolic’ state, which is only partially present in fat, which might relate to differing tissue levels of rapamycin, cell-type-specific responses, and/or strain differences.
机译:雷帕霉素抑制雷帕霉素(mTOR)的机制(或哺乳动物)靶标,雷帕霉素通过促进核糖体生物发生(RiBi)和eIF4E介导的5'cap mRNA翻译来促进细胞中蛋白质的产生。封装的雷帕霉素(eRapa)的慢性治疗延长了野生型和易发癌小鼠的健康和寿命。然而,在器官一级尚不清楚慢性eRapa治疗的长期后果。在这里,我们报告对小鼠结肠和内脏脂肪中mTORC1信号传导和RiBi的慢性eRapa治疗的观察结果。如预期的那样,慢性eRapa治疗降低了结肠和脂肪中磷酸化的mTORC1 / S6K底物,核糖体蛋白(rpS6)的检测。然而,与预期相反,在结肠中,18S rRNA和某些核糖体蛋白基因(RPG)上调,提示RiBi增加。在RPG中,eRapa增加rpl22l1 mRNA,但不增加其旁系同源rpl22。此外,相对于其阻遏物4E-BP1,帽结合蛋白eIF4E有所增加,提示翻译增加。相比之下,在脂肪中,18S rRNA的水平(与结肠相对)降低了,而编码核糖体蛋白基因的总体mRNA却出现了增加,包括rpl22,而不是rpl22l1(与结肠相对)。在脂肪中,相对于肌动蛋白,eIF4E减少(与结肠相反),但eIF4E / 4E-BP1比率也增加,这可能是由于在我们较低的eRapa剂量(类似于结肠)下4E-BP1减少所致。因此,与基于细胞的研究中蛋白质产量减少的预测相反,我们提供的证据表明,经过长期治疗的小鼠的结肠表现出一种适应性的“拟合成代谢”状态,仅部分存在于脂肪中,这可能与不同的组织有关雷帕霉素的水平,细胞类型特异性反应和/或菌株差异。

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