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 (RNA 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 DNA 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.
