Myotubular myopathy: valproic acid improves mouse models and leads to the identification of a specific epigenetic signature

Screening of 1280 molecules on zebrafish models of X-linked myotubular myopathy (XLMTM) showed that histone deacetylase (HDAC) inhibitors such as valproic acid or trichostatin A improved their swimming speed in a dose-dependent manner. Similarly, Mtm1-/y model mice had their survival prolonged and their motor capacity (suspension test) improved by these molecules, and this to a greater extent with valproic acid:

• histologically, this anti-epileptic drug decreases the number of central nuclei, increases the size of muscle fibers and normalizes the proportion of IIb and I fibers, without acting on the triad abnormalities;
• at the molecular level (RNAmacromolécule constituée d’une seule chaîne de nucléotides (simple brin) résultant de la transcription (copie) de l’ADN. and protein), it restores muscle development and endocytosis pathways, as well as the organization of the extracellular matrix, without modifying the high level of dynamin 2 in mouse models;
• it also corrects the increased DNAmacromolécule complexe, l’ADN est le support de l’hérédité (gènes). C’est le constituant des chromosomes. L’ADN est organisé en double hélice (deux brins complémentaires) et constitué de nucléotides de quatre types : adénine, guanine, cytosine et thymine. methylation of Mm1 KO mice;
• analysis of blood samples from 19 XLMTM patients revealed DNA methylation abnormalities similar to those found in animal models, which proved to be specific and distinctive of this disease.

X-linked myotubular myopathy is associated with epigenetic alterations and is ameliorated by HDAC inhibition. Volpatti JR, Ghahramani-Seno MM, Mansat M et al. Acta Neuropathol. 2022 Sep;144(3):537-563.