As part of a grant made by the Myotubular Trust, the team of Professor Jim Dowling at Sick Kids Toronto, Canada, uncovered a new disease-causing mechanism. This discovery was published earlier this year (2022) and highlights how targeting this mechanism could be a potential strategy for developing treatments for myotubular myopathy.
First, the researchers tested more than 1200 approved and investigational drugs to identify those that suppress mtm fin degeneration in zebrafish with a mutant mtm1 gene. Among the four drugs that tested positive, valproic acid suppressed mtm1 disease manifestations in zebrafish, including muscle phenotypes, by inhibiting a protein family called histone deacetylases (HDACs, see below for further explanations). Valproic acid is a commonly used anti-epileptic drug, known as sodium valproate, that is known to inhibit HDACs.
Next, they tested valproic acid in a mouse model of XLMTM and found that the drug lessens disease manifestations in mice, as well. In addition, they further studied mice with XLMTM and found that they have increased DNA methylation compared to healthy mice. DNA methylation is a process that can modify gene function and affect gene expression (see sidebar). Best of all, they showed that valproic acid can, in part, correct the increased DNA methylation present in XLMTM mice.
Finally, they looked at DNA methylation in blood samples from patients with and without XLMTM. Patients with XLMTM have a distinct DNA methylation pattern that was not seen among control patients. This suggests that this alteration is a disease feature conserved between patients and pre-clinical XLMTM models and thus may respond to therapeutic intervention that targets DNA methylation and the epigenome.
This is good news for the XLMTM community and the larger centronuclear myopathy community. XLMTM shares common disease mechanisms with other centronuclear myopathies, so targeting this newly identified mechanism may prove beneficial in the treatment of XLMTM and other centronuclear myopathies.
DNA methylation and HDAC explained
DNA methylation is a biochemical process that regulates gene expression and is vital to human growth and development. It is one form of modification of the epigenome.
HDAC is an enzyme that modifies certain proteins on DNA in a way that disrupts gene transcription.
DNA methylation and HDAC can both inhibit gene transcription. This means they can stop or disrupt the process where genes are transcribed to RNA in order to make proteins (such as myotubularin) that the body needs to function.
Cells develop a stable and unique DNA methylation pattern that regulates how genes are transcribed. DNA methylation attracts HDAC to the place on DNA where gene transcription begins. In this way, increased DNA methylation increases the amount of HDAC at the transcription site, where it can stop or disrupt the making of mRNAS, which in turn are translated in to proteins. Alteration of transcription can affect many cellular pathways, including muscle differentiation and growth, two pathways affected in XLMTM and other forms of CNM.
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