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

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 andidentified 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. Zebrafish: At 1 dpf, embryos from single-pair in-crossings of mtm1+/zf711 adults were divided equally into three chemical treatment groups: DMSO, sodium valproate (VPA), or trichostatin A. For tissue collection, the posterior section of larvae and fin fold tissues was dissected and snap frozen on dry ice at 4 dpf. A total of n=6-10 larvae per pool per condition with 5 biological replicates were used for RNA extraction. Mice: Bulk RNA sequencing was performed on RNA extracts from tibialis anterior muscle from 35 day old Mtm1KO and WT mice, either treated with PBS or valproic acid (VPA) starting at 21 days.