The Essential Role of the Spermidine-eIF5A Axis in Muscle Stem Cell Activation via Translational Control

Life Sciences Immunology Biochemistry Medicine Cell Biology
spermidine eIF5A muscle stem cell translational control muscle regeneration

New Discovery in Metabolic Regulation of Muscle Stem Cell Activation: The Crucial Role of the Spermidine-eIF5A Axis

Background and Research Objectives

Adult skeletal muscle satellite cells (SCs) are the main type of stem cells in skeletal muscle and play a pivotal role in muscle injury repair. However, the activation mechanism of quiescent satellite cells (qSCs) remains largely unclear, especially concerning metabolic and translational control. Previous studies have shown that qSC activation requires metabolic reprogramming, but how these cells coordinate metabolic changes with protein synthesis remains unknown. This study aims to reveal a critical metabolic pathway, specifically polyamine metabolism, and its regulatory role in SC activation, delving into the underlying mechanisms.

Research Source

This research was conducted by Qianying Zhang and colleagues from institutions including the Guangzhou Regenerative Medicine and Health Guangdong Laboratory and the Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences. The paper was published in the journal Cell Discovery in 2024, with the DOI 10.1038/s41421-024-00712-w.

Experimental Design and Research Workflow

The study utilized a multi-stage experimental design based on mouse models, incorporating metabolomics, single-cell RNA sequencing (scRNA-seq), genetically modified mouse models, and an in vitro single-fiber culture system. The specific workflow includes:

  1. Metabolomics Analysis: Targeted metabolomics was used to compare the metabolic changes between qSCs and activated satellite cells (aSCs). It was found that polyamine metabolites, such as spermidine, were significantly elevated in aSCs.
  2. Gene Expression and Single-Cell Sequencing: scRNA-seq was used to analyze the expression of key enzymes in polyamine metabolism. The results showed that related enzymes (e.g., ODC1, SRM) were significantly upregulated in aSCs.
  3. Functional Validation Experiments: The inhibition of polyamine biosynthesis using drugs like DFMO resulted in suppressed SC activation and muscle regeneration, whereas supplementation with exogenous spermidine restored or enhanced SC activation.
  4. Molecular Mechanism Analysis: The study revealed that spermidine promotes hypusination modification of translation initiation factor eIF5A, which then selectively promotes Myod mRNA translation, a process essential for SC activation.
  5. Aging Model Verification: In aged mice, spermidine supplementation not only enhanced SC activation but also significantly improved muscle regeneration capacity and function.

Main Findings

  1. Polyamine Metabolism and SC Activation: During the transition from qSCs to aSCs, polyamine metabolism is significantly enhanced, particularly with a 2.25-fold increase in spermidine levels. Blocking polyamine biosynthesis leads to impaired SC activation and muscle regeneration.
  2. The Role of the Spermidine-eIF5A Axis: Spermidine activates eIF5A via hypusination, and eIF5A further selectively translates the key transcription factor Myod. The absence of eIF5A completely blocks SC activation.
  3. Aging-Related Mechanism Exploration: Polyamine metabolism pathways in aged mice are impaired, leading to decreased SC activation. Spermidine supplementation partially restores these functions.

Research Highlights

  • First Discovery: Spermidine acts as a key regulatory factor in SC activation, with eIF5A hypusination as the core mechanism for its action.
  • Novel Mechanism: The study introduces the spermidine-eIF5A-Myod translational regulation axis, uncovering a link between metabolic regulation and protein translation.
  • Breakthrough in Aging Mechanism: The research reveals the metabolic basis for impaired SC activation in aging and presents new evidence of reversing aging effects through spermidine.

Research Significance and Future Directions

This study provides a new perspective for understanding the molecular mechanisms of adult stem cell activation, especially regarding the interaction between metabolic reprogramming and translational control. The spermidine-eIF5A axis could be a novel drug target for treating muscle degenerative diseases. Furthermore, this discovery provides a scientific basis for developing anti-aging therapies.

Future research could further explore: 1. The interactions between spermidine and other transcription factors or metabolic pathways. 2. The role of the spermidine-eIF5A axis in other cell types. 3. The therapeutic potential of spermidine-based strategies in humans.

Conclusion

This study is the first to comprehensively elucidate the critical role of spermidine in SC activation and muscle regeneration through the eIF5A-mediated translational control mechanism. This groundbreaking discovery not only deepens our understanding of muscle stem cell biology but also provides crucial clues for developing innovative therapies for muscle degeneration and age-related diseases.