Effects of rapamycin on growth hormone receptor knockout mice
Effects of rapamycin on growth hormone receptor knockout mice
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DOI：
10.1073/pnas.1717065115
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发表时间：
2018-02-13
影响因子：
11.1
通讯作者：
Bartke, Andrzej
中科院分区：
文献类型：
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作者：
Fang, Yimin;Hill, Cristal M.;Bartke, Andrzej
有充分的证据表明，抑制mTORC 1（由Raptor定义），一种雷帕霉素（mTOR）的机制靶点复合物，可以延长寿命，但对mTORC 2（由Rictor定义）影响寿命的机制知之甚少。在这里，雷帕霉素（mTOR的抑制剂）被用于GHR-KO（生长激素受体敲除）小鼠，这些小鼠抑制mTORC 1和上调mTORC 2信号传导，以确定同时减少mTORC 1和mTORC 2信号传导对寿命的影响。我们发现雷帕霉素延长了对照正常（N）小鼠的寿命，而它在GHR-KO小鼠中具有相反的效果。在雷帕霉素处理的GHR-KO小鼠中，mTORC 2信号传导减少，而肝脏、肌肉和皮下注射中的mTORC 1没有进一步抑制。胖了葡萄糖和脂质稳态受损，用雷帕霉素治疗的老年GHR-KO小鼠失去了功能性免疫细胞，炎症增加。在GHR-KO MEF细胞中，Rictor而不是Raptor的敲低降低了mTORC 2信号传导。我们的结论是mTORC 2的急剧减少通过破坏全身稳态在GHR-KO小鼠的寿命受损中起重要作用。
It is well documented that inhibition of mTORC1 (defined by Raptor), a complex of mechanistic target of rapamycin (mTOR), extends life span, but less is known about the mechanisms by which mTORC2 (defined by Rictor) impacts longevity. Here, rapamycin (an inhibitor of mTOR) was used in GHR-KO (growth hormone receptor knockout) mice, which have suppressed mTORC1 and up-regulated mTORC2 signaling, to determine the effect of concurrently decreased mTORC1 and mTORC2 signaling on life span. We found that rapamycin extended life span in control normal (N) mice, whereas it had the opposite effect in GHR-KO mice. In the rapamycin-treated GHR-KO mice, mTORC2 signaling was reduced without further inhibition of mTORC1 in the liver, muscle, and s.c. fat. Glucose and lipid homeostasis were impaired, and old GHR-KO mice treated with rapamycin lost functional immune cells and had increased inflammation. In GHR-KO MEF cells, knockdown of Rictor, but not Raptor, decreased mTORC2 signaling. We conclude that drastic reduction of mTORC2 plays important roles in impaired longevity in GHR-KO mice via disruption of whole-body homeostasis.