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Phosphorylation of eIF2α Is a Translational Control Mechanism Regulating Muscle Stem Cell Quiescence and Self-Renewal

Victoria Zismanov1, Victor Chichkov1, Veronica Colangelo2

  • 1Lady Davis Institute for Medical Research, Jewish General Hospital, Montreal, QC H3T 1E2, Canada; Department of Human Genetics, McGill University, Montreal, QC H3A 1B1, Canada.

Cell Stem Cell
|November 10, 2015
PubMed

Insights

Skeletal muscle stem cell regeneration relies on maintaining cell dormancy. Phosphorylation of translation factor eIF2α (P-eIF2α) is crucial for this quiescence, promoting self-renewal and tissue repair.

Area of Science:

  • Cellular biology
  • Stem cell research
  • Molecular mechanisms of regeneration

Background:

  • Adult tissue regeneration depends on quiescent somatic stem cells.
  • Molecular regulation of stem cell quiescence is not fully understood.
  • Skeletal muscle stem cells serve as a model for studying stem cell dormancy.

Purpose of the Study:

  • Investigate the role of translation regulation in maintaining skeletal muscle stem cell quiescence.
  • Identify molecular pathways preventing premature stem cell activation.
  • Explore therapeutic strategies to enhance stem cell regenerative capacity.

Main Methods:

  • Utilized mouse skeletal muscle stem cells.
  • Analyzed the phosphorylation of translation initiation factor eIF2α (P-eIF2α).
  • Assessed the impact of eIF2α phosphorylation on stem cell activation, differentiation, and self-renewal.
  • Investigated translational control of specific mRNAs, including those with upstream open reading frames (uORFs).
  • Examined the effects of pharmacological inhibition of eIF2α dephosphorylation.

Main Results:

  • General repression of translation via P-eIF2α is essential for maintaining skeletal muscle stem cell quiescence.
  • Impaired eIF2α phosphorylation leads to stem cell exit from quiescence, myogenic activation, and differentiation, but impairs self-renewal.
  • P-eIF2α contributes to translational silencing of mRNAs, preventing premature stem cell activation.
  • P-eIF2α-dependent translation of uORF-containing mRNAs is part of the stemness molecular signature.
  • Pharmacological inhibition of eIF2α dephosphorylation boosts stem cell self-renewal and regeneration.

Conclusions:

  • Translational control mediated by P-eIF2α is a key regulator of skeletal muscle stem cell quiescence and self-renewal.
  • Targeting eIF2α phosphorylation offers a potential therapeutic avenue for enhancing tissue regeneration.

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