Spermidine-eIF5A axis is essential for muscle stem cell activation via translational control

IF 13 1区 生物学 Q1 CELL BIOLOGY Cell Discovery Pub Date : 2024-09-10 DOI:10.1038/s41421-024-00712-w
Qianying Zhang, Wanhong Han, Rimao Wu, Shixian Deng, Jiemiao Meng, Yuanping Yang, Lili Li, Mingwei Sun, Heng Ai, Yingxi Chen, Qinyao Liu, Tian Gao, Xingchen Niu, Haixia Liu, Li Zhang, Dan Zhang, Meihong Chen, Pengbin Yin, Licheng Zhang, Peifu Tang, Dahai Zhu, Yong Zhang, Hu Li
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Abstract

Adult skeletal muscle stem cells, also known satellite cells (SCs), are quiescent and activate in response to injury. However, the activation mechanisms of quiescent SCs (QSCs) remain largely unknown. Here, we investigated the metabolic regulation of SC activation by identifying regulatory metabolites that promote SC activation. Using targeted metabolomics, we found that spermidine acts as a regulatory metabolite to promote SC activation and muscle regeneration in mice. Mechanistically, spermidine activates SCs via generating hypusinated eIF5A. Using SC-specific eIF5A-knockout (KO) and Myod-KO mice, we further found that eIF5A is required for spermidine-mediated SC activation by controlling MyoD translation. More significantly, depletion of eIF5A in SCs results in impaired muscle regeneration in mice. Together, the findings of our study define a novel mechanism that is essential for SC activation and acts via spermidine-eIF5A-mediated MyoD translation. Our findings suggest that the spermidine-eIF5A axis represents a promising pharmacological target in efforts to activate endogenous SCs for the treatment of muscular disease.

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精氨酸-eIF5A 轴对通过翻译控制激活肌肉干细胞至关重要
成人骨骼肌干细胞又称卫星细胞(SCs),具有静止状态,在受伤时会激活。然而,静止骨骼肌干细胞(QSCs)的活化机制在很大程度上仍不为人知。在这里,我们通过鉴定促进SC活化的调控代谢物,研究了SC活化的代谢调控。通过靶向代谢组学研究,我们发现亚精胺是促进小鼠SC活化和肌肉再生的调节代谢物。从机理上讲,亚精胺通过产生高浓度的 eIF5A 来激活 SC。通过使用 SC 特异性 eIF5A 基因敲除(KO)和 Myod-KO 小鼠,我们进一步发现 eIF5A 是通过控制 MyoD 翻译来实现亚精胺介导的 SC 激活的必要条件。更重要的是,消耗 SC 中的 eIF5A 会导致小鼠肌肉再生能力受损。总之,我们的研究结果确定了一种新的机制,它对 SC 的活化至关重要,并通过精胺-eIF5A 介导的 MyoD 翻译发挥作用。我们的研究结果表明,精胺-eIF5A 轴是激活内源性 SCs 治疗肌肉疾病的一个很有前景的药理靶点。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
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来源期刊
Cell Discovery
Cell Discovery Biochemistry, Genetics and Molecular Biology-Molecular Biology
CiteScore
24.20
自引率
0.60%
发文量
120
审稿时长
20 weeks
期刊介绍: Cell Discovery is a cutting-edge, open access journal published by Springer Nature in collaboration with the Center for Excellence in Molecular Cell Science, Chinese Academy of Sciences (CAS). Our aim is to provide a dynamic and accessible platform for scientists to showcase their exceptional original research. Cell Discovery covers a wide range of topics within the fields of molecular and cell biology. We eagerly publish results of great significance and that are of broad interest to the scientific community. With an international authorship and a focus on basic life sciences, our journal is a valued member of Springer Nature's prestigious Molecular Cell Biology journals. In summary, Cell Discovery offers a fresh approach to scholarly publishing, enabling scientists from around the world to share their exceptional findings in molecular and cell biology.
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