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Evaluation of Injury-induced Senescence and In Vivo Reprogramming in the Skeletal Muscle
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Numb is required to prevent p53-dependent senescence following skeletal muscle injury

Isabelle Le Roux1, Julie Konge1, Laurent Le Cam2

  • 1Department of Developmental and Stem Cell Biology, Stem Cells and Development, CNRS URA 2578, Institut Pasteur, 25 rue du Dr Roux, Paris 75015, France.

Nature Communications
|October 28, 2015
PubMed

Insights

Inactivating Numb in muscle stem cells causes persistent senescence, impairing regeneration. Antioxidant treatment or p53 ablation rescues muscle repair by reducing senescence and inflammation.

Area of Science:

  • Muscle regeneration
  • Cellular senescence
  • Stem cell biology

Background:

  • Regeneration requires coordinated cell activity.
  • The role of Numb in muscle stem cell function during regeneration is unclear.
  • Cellular senescence can impact tissue repair.

Purpose of the Study:

  • To investigate the role of the endocytic adaptor protein Numb in skeletal muscle regeneration.
  • To characterize the types and regulation of cellular senescence during muscle repair.
  • To identify mechanisms underlying impaired regeneration in Numb-deficient muscle.

Main Methods:

  • Inactivation of the Numb gene in mouse skeletal muscle stem cells.
  • Induction of chronic or severe muscle injury.
  • Analysis of cellular senescence markers (e.g., INK4a/ARF, p53).
  • Assessment of muscle regenerative potential and fibrosis.
  • Ex vivo co-culture experiments with senescent cells and macrophages.

Main Results:

  • Two types of senescence were observed: transient in non-myogenic cells and persistent in Numb-deficient myogenic cells.
  • Persistent senescence in Numb mutants was linked to sustained inflammation and fibrosis.
  • Antioxidant treatment or p53 ablation reduced senescence and rescued regenerative potential.
  • Numb-deficient senescent cells promoted macrophage recruitment.

Conclusions:

  • Numb is critical for preventing persistent senescence in myogenic cells during muscle regeneration.
  • Senescence in Numb-deficient muscle drives inflammation and fibrosis, impairing repair.
  • Targeting senescence pathways, like p53 or oxidative stress, can restore muscle regeneration.

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