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DNA damage response by single-strand breaks in terminally differentiated muscle cells and the control of muscle

P Fortini1, C Ferretti, B Pascucci

  • 1Department of Environment and Primary Prevention, Istituto Superiore di Sanità, Rome, Italy.

Cell Death and Differentiation
|June 19, 2012
PubMed

Insights

Terminally differentiated muscle cells resist DNA single-strand break (SSB) inducers due to defective p53 signaling. Specific damage, like menadione, can activate p53 and induce cell death in myotubes.

Area of Science:

  • Molecular Biology
  • Cellular Biology
  • Genetics

Background:

  • DNA single-strand breaks (SSB) are crucial for muscle development, and their repair defects cause disease.
  • The DNA damage response to SSB in terminally differentiated cells remains largely uncharacterized.

Purpose of the Study:

  • To investigate the DNA damage response to SSB in post-mitotic muscle cells (myotubes).
  • To explore the mechanisms underlying resistance to SSB-inducing agents in these cells.
  • To identify specific damage types that can trigger cell death in myotubes.

Main Methods:

  • Induction of SSB using alkylation agents and SSB-inducers in mouse post-mitotic muscle cells.
  • Assessment of H2AX phosphorylation and its dependence on ataxia telangiectasia mutated (ATM).
  • Evaluation of p53 activation, stabilization (using nutlin-3), and downstream signaling.
  • Treatment with doxorubicin and menadione to assess cell killing and p53 dependence.

Main Results:

  • Post-mitotic muscle cells accumulate SSB but exhibit resistance to common SSB inducers.
  • SSB induction triggers ATM-dependent H2AX phosphorylation, but downstream p53 signaling is impaired.
  • Nutlin-3 stabilization of p53 fails to induce cell death, indicating a defect in p53-mediated pathways.
  • Mitochondria-specific inhibitor menadione effectively kills myotubes in a p53-dependent manner, though with restricted p53-activated gene expression.

Conclusions:

  • Terminally differentiated muscle cells possess a unique DNA damage response characterized by resistance to many SSB inducers due to defective p53 signaling.
  • Targeting specific damage pathways, such as mitochondrial damage with menadione, can overcome this resistance and induce p53-mediated cell death.
  • Understanding these mechanisms offers potential therapeutic strategies to prevent muscle cell toxicity.

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