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首页> 外文期刊>Journal of orthopaedic research >mTOR signaling plays a critical role in the defects observed in muscle-derived stem/progenitor cells isolated from a murine model of accelerated aging
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mTOR signaling plays a critical role in the defects observed in muscle-derived stem/progenitor cells isolated from a murine model of accelerated aging

机译：MTOR信号传导在从加速老化的小鼠模型中分离的肌肉衍生的茎/祖细胞中观察到的缺陷中起重要作用

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摘要

Mice expressing reduced levels of ERCC1-XPF (Ercc1(-/) mice) demonstrate premature onset of age-related changes due to decreased repair of DNA damage. Muscle-derived stem/progenitor cells (MDSPCs) isolated from Ercc1(-/) mice have an impaired capacity for cell differentiation. The mammalian target of rapamycin (mTOR) is a critical regulator of cell growth in response to nutrient, hormone, and oxygen levels. Inhibition of the mTOR pathway extends the lifespan of several species. Here, we examined the role of mTOR in regulating the MDSPC dysfunction that occurs with accelerated aging. We show that mTOR signaling pathways are activated in Ercc1(-/) MDSPCs compared with wild-type (WT) MDSPCs. Additionally, inhibiting mTOR with rapamycin promoted autophagy and improved the myogenic differentiation capacity of the Ercc1(-/) MDSPCs. The percent of apoptotic and senescent cells in Ercc1(-/) MDSPC cultures was decreased upon mTOR inhibition. These results establish that mTOR signaling contributes to stem cell dysfunction and cell fate decisions in response to endogenous DNA damage. Therefore, mTOR represents a potential therapeutic target for improving defective, aged stem cells. (c) 2016 The Authors. Journal of Orthopaedic Research Published by Wiley Periodicals, Inc. on behalf of Orthopaedic Research Society. J Orthop Res 35:1375-1382, 2017.
机译：表达Ircc1-XPF（Ercc1（/）小鼠水平降低的小鼠证明了由于DNA损伤的修复减少而导致的年龄相关变化过早。从ERCC1（ - /）小鼠中分离的肌肉衍生的茎/祖细胞（MDSPC）具有损害的细胞分化能力。哺乳动物的雷帕霉素（MTOR）的靶标是细胞生长的临界调节因子，响应营养，激素和氧水平。 MTOR途径的抑制延伸了几种物种的寿命。在这里，我们检查了MTOR在调节加速老化的MDSPC功能障碍方面的作用。我们表明，与野生型（WT）MDSPC相比，MTOR信令途径在ERCC1（ - /）MDSPC中激活。另外，抑制雷帕霉素的MTOR促进了自噬并改善了ERCC1（ - /）MDSPC的肌基分化能力。在MTOR抑制时，ERCC1（ - /）MDSPC培养物中凋亡和衰老细胞的百分比降低。这些结果确定MTOR信号传导有助于响应内源性DNA损伤的干细胞功能障碍和细胞命运决策。因此，MTOR代表改善缺陷的老化干细胞的潜在治疗靶标。 （c）2016年作者。 Wiley Hearyicals，Inc。代表骨科研究会出版的骨科研究杂志。 J Orthop Res 35：1375-1382,2017。

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