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

Abstract

X-linked myotubular myopathy (XLMTM) is a fatal neuromuscular disorder caused by loss of function mutations in MTM1. At present, there are no directed therapies for XLMTM, and incomplete understanding of disease pathomechanisms. To address these knowledge gaps, we performed a drug screen in mtm1 mutant zebrafish and identified four positive hits, including valproic acid, which functions as a potent suppressor of the mtm1 zebrafish phenotype via HDAC inhibition. We translated these findings to a mouse XLMTM model, and showed that valproic acid ameliorates the murine phenotype. These observations led us to interrogate the epigenome in Mtm1 knockout mice; we found increased DNA methylation, which is normalized with valproic acid, and likely mediated through aberrant 1-carbon metabolism. Finally, we made the unexpected observation that XLMTM patients share a distinct DNA methylation signature, suggesting that epigenetic alteration is a conserved disease feature amenable to therapeutic intervention.

• Authors: Jonathan R Volpatti, Mehdi M Ghahramani-Seno, Mélanie Mansat, Nesrin Sabha, Ege Sarikaya, Sarah J Goodman, Eric Chater-Diehl, Alper Celik, Emanuela Pannia, Carine Froment, Lucie Combes-Soia, Nika Maani, Kyoko E Yuki, Gaëtan Chicanne, Liis Uusküla-Reimand, Simon Monis, Sana Akhtar Alvi, Casie A Genetti, Bernard Payrastre, Alan H Beggs, Carsten G Bonnemann, Francesco Muntoni, Michael D Wilson, Rosanna Weksberg, Julien Viaud, James J Dowling
• Journal: Acta neuropathologica (Acta Neuropathol) Vol. 144 Issue 3 Pg. 537-563 (09 2022) ISSN: 1432-0533 [Electronic] Germany
• PMID: 35844027 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
• Copyright: © 2022. The Author(s).

Chemical References

• Valproic Acid
• Protein Tyrosine Phosphatases, Non-Receptor

Topics

• Animals
• Disease Models, Animal
• Epigenesis, Genetic
• Mice
• Muscle, Skeletal (metabolism)
• Myopathies, Structural, Congenital (drug therapy, genetics, metabolism)
• Protein Tyrosine Phosphatases, Non-Receptor (genetics, metabolism)
• Valproic Acid (metabolism, pharmacology)
• Zebrafish (metabolism)