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X-linked myotubular myopathy is associated with epigenetic alterations and is ameliorated by HDAC inhibition

Jonathan R Volpatti1,2, Mehdi M Ghahramani-Seno2, Mélanie Mansat3

  • 1Department of Molecular Genetics, University of Toronto, Toronto, ON, M5S 1A1, Canada.

Acta Neuropathologica
|July 17, 2022
PubMed

Insights

Valproic acid shows promise in treating X-linked myotubular myopathy (XLMTM), a severe neuromuscular disorder. This drug normalizes DNA methylation in mouse models and patients, suggesting a new therapeutic avenue for XLMTM.

Area of Science:

  • Neuromuscular Disorders
  • Epigenetics
  • Pharmacology

Background:

  • X-linked myotubular myopathy (XLMTM) is a severe, fatal neuromuscular disease with no targeted treatments.
  • The underlying pathomechanisms of XLMTM remain incompletely understood.
  • Current therapeutic strategies for XLMTM are limited.

Purpose of the Study:

  • To identify potential therapeutic agents for XLMTM through drug screening.
  • To investigate the role of epigenetic modifications, specifically DNA methylation, in XLMTM.
  • To explore valproic acid as a potential therapeutic intervention for XLMTM.

Main Methods:

  • Conducted a drug screen in a zebrafish model of XLMTM (mtm1 mutant).
  • Utilized a mouse model of XLMTM to validate drug efficacy.
  • Performed epigenomic analysis (DNA methylation profiling) in mouse models and XLMTM patients.

Main Results:

  • Identified valproic acid as a suppressor of the XLMTM phenotype in zebrafish.
  • Demonstrated that valproic acid ameliorates XLMTM symptoms in a mouse model.
  • Observed increased DNA methylation in Mtm1 knockout mice, which was reversed by valproic acid.
  • Discovered a distinct DNA methylation signature in XLMTM patients.

Conclusions:

  • Valproic acid is a promising therapeutic candidate for XLMTM, acting via HDAC inhibition.
  • Aberrant DNA methylation, potentially linked to 1-carbon metabolism, is a conserved feature of XLMTM.
  • Epigenetic alterations represent a druggable target for XLMTM treatment.
Keywords:
Congenital myopathiesDrug discoveryEpigeneticsX-linked myotubular myopathy

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