肌肉mTOR通过NRF2,HIF和AKT/PKB信号通路控制铁稳态和铁
Agnès Conjard-Duplany1, Alexis Osseni2, Aline Lamboux3
1Laboratoire Physiopathologie et Génétique du Neurone et du Muscle (PGNM), Institut NeuroMyoGène, Université Claude Bernard Lyon 1, INSERM U1315, CNRS UMR 5261, 8 avenue Rockefeller, Lyon, 69008, France. agnes.duplany@univ-lyon1.fr.
Cellular and molecular life sciences : CMLS
|April 28, 2025
概括
哺乳动物目标的拉巴胺素 (mTOR) 缺乏会破坏肌肉的铁代谢,导致铁失调和肌肉病变. 精子胺补充剂可能有助于通过改善ferritinophagy恢复铁平衡和肌肉健康.
科学领域:
- 肌肉生理学 肌肉生理学
- 细胞铁代谢 细胞铁代谢
- 分子信号通道的分子信号通道.
背景情况:
- 拉巴胺素 (mTOR) 活性和铁平衡的平衡机械标对于肌肉完整性至关重要.
- mTOR与调节细胞铁水平有关,但其在肌肉铁代谢和肌肉病变中的特定作用尚未完全理解.
研究的目的:
- 为了研究mTOR缺乏,铁代谢和肌肉特异性mTOR淘汰 (mTORmKO) 小鼠中的肌肉病之间的关系.
- 阐明在mTOR缺陷肌肉中的铁失调背后的分子机制.
主要方法:
- 在mTORmKO小鼠的不同肌肉类型中分析铁含量,铁代谢蛋白 (TFR1,FTL,FPN) 和mRNA水平.
- 研究包括NRF2,HIF,AKT/PKB在内的信号通路及其对铁基因调节的影响.
- 评估精子胺补充剂对老年mTORmKO小鼠信号通路和铁代谢的影响.
主要成果:
- 尽管Ftl和FpnmRNA下调,mTORmKO小鼠显示出改变的铁模式和铁过剩标记 (TFR1降低,FTL和FPN蛋白增加) .
- mTOR 缺陷损害了NRF2和HIF介导的转录调节,并导致通过NRF2依赖机制和损害自的费里丁积累.
- 在老年mTORmKO小鼠中,精氨酸治疗使AKT/PKB-FOXO信号正常化,减少了总费里丁,并增加了索利乌斯肌肉中的内分泌体费里丁.
结论:
- mTOR在维持骨肌肉铁平衡中发挥着至关重要的作用.
- 不调节的铁代谢,特别是由于ferritinophagy受损而导致的费里丁积累,导致mTOR缺乏的肌肉病理.
- 精子胺显示出作为肌肉疾病的治疗剂的潜力,其特点是自阻塞和铁失调.
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