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Myotube-specific vulnerability to clozapine.

Gloria Buffi1, Mara Fiorani1, Andrea Guidarelli1

  • 1Department of Biomolecular Sciences, University of Urbino Carlo Bo, Urbino, Italy.

Biomedicine & Pharmacotherapy = Biomedecine & Pharmacotherapie
|October 28, 2025
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Summary

Clozapine (CLZ) causes muscle cell death (myotoxicity) by inducing apoptosis in mature muscle cells, but not in muscle stem cells. This selective toxicity explains a rare side effect of this antipsychotic drug.

Keywords:
ClozapineMyoblastsMyotoxicityMyotubesReserve cells

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Area of Science:

  • Biochemistry
  • Cell Biology
  • Pharmacology

Background:

  • Clozapine (CLZ) is an atypical antipsychotic for treatment-resistant schizophrenia.
  • Serious adverse reactions limit CLZ's clinical use.
  • Myotoxicity is a rare, poorly understood CLZ side effect.

Purpose of the Study:

  • Investigate the mechanisms of CLZ-induced myotoxicity.
  • Determine the effects of CLZ on different muscle cell types.

Main Methods:

  • Utilized C2C12-derived myotubes and mouse primary myotubes.
  • Assessed morphological and biochemical markers of muscle cell health.
  • Examined apoptotic features and cell viability under varying CLZ concentrations and conditions.
  • Simulated CLZ protein binding using albumin.

Main Results:

  • CLZ induced time- and concentration-dependent toxicity in myotubes.
  • Muscle-specific markers and ryanodine receptor activity were reduced by CLZ.
  • Apoptotic features were observed in CLZ-treated myotubes.
  • Mononuclear reserve cells and myoblasts remained viable and functional, showing resistance to CLZ.

Conclusions:

  • CLZ selectively induces apoptosis in mature myotubes.
  • Proliferating myoblasts and reserve cells are resistant to CLZ toxicity.
  • CLZ myotoxicity is specific to differentiated muscle cells, sparing muscle stem cells.