PIK3C2B inhibition improves function and prolongs survival in myotubular myopathy animal models
Nesrin Sabha, Jonathan R. Volpatti, Hernan Gonorazky, Aaron Reifler, Ann E. Davidson, Xingli Li, Nadine M. Eltayeb, Claudia Dall’Armi, Gilbert Di Paolo, Susan V. Brooks, Ana Buj-Bello, Eva L. Feldman, James J. Dowling
Nesrin Sabha, Jonathan R. Volpatti, Hernan Gonorazky, Aaron Reifler, Ann E. Davidson, Xingli Li, Nadine M. Eltayeb, Claudia Dall’Armi, Gilbert Di Paolo, Susan V. Brooks, Ana Buj-Bello, Eva L. Feldman, James J. Dowling
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Research Article Muscle biology

PIK3C2B inhibition improves function and prolongs survival in myotubular myopathy animal models

Abstract

Myotubular myopathy (MTM) is a devastating pediatric neuromuscular disorder of phosphoinositide (PIP) metabolism resulting from mutations of the PIP phosphatase MTM1 for which there are no treatments. We have previously shown phosphatidylinositol-3-phosphate (PI3P) accumulation in animal models of MTM. Here, we tested the hypothesis that lowering PI3P levels may prevent or reverse the MTM disease process. To test this, we targeted class II and III PI3 kinases (PI3Ks) in an MTM1-deficient mouse model. Muscle-specific ablation of Pik3c2b, but not Pik3c3, resulted in complete prevention of the MTM phenotype, and postsymptomatic targeting promoted a striking rescue of disease. We confirmed this genetic interaction in zebrafish, and additionally showed that certain PI3K inhibitors prevented development of the zebrafish mtm phenotype. Finally, the PI3K inhibitor wortmannin improved motor function and prolonged lifespan of the Mtm1-deficient mice. In all, we have identified Pik3c2b as a genetic modifier of Mtm1 mutation and demonstrated that PIK3C2B inhibition is a potential treatment strategy for MTM. In addition, we set the groundwork for similar reciprocal inhibition approaches for treating other PIP metabolic disorders and highlight the importance of modifier gene pathways as therapeutic targets.

Authors

Nesrin Sabha, Jonathan R. Volpatti, Hernan Gonorazky, Aaron Reifler, Ann E. Davidson, Xingli Li, Nadine M. Eltayeb, Claudia Dall’Armi, Gilbert Di Paolo, Susan V. Brooks, Ana Buj-Bello, Eva L. Feldman, James J. Dowling

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Figure 8

Wortmannin treatment prolongs survival and improves the phenotype of Mtm1 KO mice.

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Wortmannin treatment prolongs survival and improves the phenotype of Mtm...
(A) Kaplan-Meier survival curve. As compared with a placebo DMSO control treatment (n = 4), wortmannin treatment increases median survival of Mtm1 KO mice from 34.5 to 44 days, with maximum survival changed from 35 to 50 days (n = 6, ***P < 0.001). (B) Histopathological assessment of TA muscle tissue of 32-day-old animals reveals that muscle fibers from Mtm1 KO mice treated with wortmannin have modest improvements in myofiber size and central nucleation (top panel, n =2 per treatment group, scale bars: 20 μm). Immunostaining of PI3P on cross section of TA muscle (60×) reveals reduced labeling in wortmannin-treated Mtm1 KO as compared with the intense staining seen in placebo-exposed Mtm1 KO muscle (bottom panel, n =2 per treatment group, scale bars: 20 μm).