Myotubular myopathy is a fatal neuromuscular disease associated with severe morbidities (including
wheelchair and ventilator dependence) and early mortality. There are critical barriers hindering treatment for
this devastating disease. These include the need to uncover new therapeutic strategies, particularly ones with
applicability for a broader spectrum of congenital myopathies, and to develop non-invasive biomarkers that
correlate with treatment response and are thus suitable for use in clinical trials. Our overarching goal is to
translate therapies for MTM. In this proposal, we will address this goal by establishing the first serum
biomarker for MTM and identifying a novel therapeutic approach with broad treatment potential.
MTM is an X-linked disorder caused by mutations in MTM1, a phosphatase that regulates endosomal sorting.
We have shown that MTM1 mutation results in disruption of the triad, a muscle structure responsible for
excitation-contraction coupling, and that triad disorganization is a critical driver of MTM pathogenesis. Several
groups have demonstrated that myofiber hypotrophy is also an important contributor to MTM pathology. While
the precise mechanisms underlying these changes remain to be elucidated, overexpression of DNM2 is a key
driver of the triad defects, and unbalanced AKT-TOR pathway signaling is associated with the reduced
myofiber size. In this study, we propose a treatment aimed at targeting and correcting these defects.
MicroRNAs (miRNAs) are small, non-coding RNAs that modulate gene expression and serve as important
regulators of myriad cellular processes. MiRNAs are emerging as both treatment effect biomarkers and
potential therapeutics. In several disorders (including other muscle diseases), circulating miRNAs correlate
with disease severity and treatment response, and are under consideration as biomarkers in clinical trials.
The miRNAs miR-486 and miR-133a have direct relevance to MTM pathogenesis. We have shown that miR-
486 regulates myofiber size by rebalancing AKT signaling, and others have demonstrated that miR-133a
directly down-regulates DNM2. These miRNAs are thus attractive as potential therapeutic targets, a concept
validated by our demonstration of miR-486 overexpression as a treatment strategy for DMD.
In preliminary data, we profiled miRNAs from MTM mouse muscle and found significant changes in 50
miRNAs including downregulation of miR-486 and miR-133a. Based on this, we hypothesize that changes in
the levels of miRNAs will correlate with disease status and treatment response, and thus function as an ideal
non-invasive biomarker for MTM. Further, we predict that restoring expression of miR-486 and miR-133a will
increase myofiber size and reverse triad defects respectively, and thus rescue the MTM phenotype. We will
test these hypotheses using rigorous methodology in the murine model of MTM. Successful completion of our
study will identify the first biomarker of MTM suitable for clinical translation, and establish a novel
treatment with applicability to muscle diseases that feature myofiber hypotrophy and/or triad defects.