PIK3C2B inhibition improves function and prolongs survival in myotubular myopathy animal models
Nesrin Sabha, … , Eva L. Feldman, James J. Dowling
Nesrin Sabha, … , Eva L. Feldman, James J. Dowling
Published September 1, 2016; First published August 22, 2016
Citation Information: J Clin Invest. 2016;126(9):3613-3625. https://doi.org/10.1172/JCI86841.
View: Text | PDF
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

×

Figure 1

Muscle-specific knockout of Pik3c2b prevents the phenotype associated with Mtm1 knockout.

Options: View larger image (or click on image) Download as PowerPoint
Muscle-specific knockout of Pik3c2b prevents the phenotype associated wi...
(A) Mtm1–/y (Mtm1 KO) mice have diminished size, hunched posture, and splayed hindlimbs (indicative of limb weakness), while Pik3c2b Mtm1 double KOs (dKOs) appear indistinguishable from WT. (B) Kaplan-Meier survival curve reveals that Pik3c2b knockout confers a survival benefit to the MTM mouse model (dKO median survival > 300 days, n = 11, vs. Mtm1 KO mice = 35 days, n = 24). (C) Plot of body weight versus postnatal age for WT, Mtm1 KO, and dKO mice. Mtm1 KO (n = 12) mice are significantly smaller than male WT siblings from 20 days onward, while dKO animals have weights indistinguishable from WT at all time points examined (n = 24, last age measured = 100 days). (D) dKO mice have restored muscle power. Mtm1 KO animal mean grip strength = 68% ± 4.8% compared with 100% ± 7.2% in the WT (***P < 0.001) and 92% ± 4.8% in dKOs (**P < 0.01 vs. Mtm1 KO). Values were normalized to the mean grip strength of WT littermates (n = 5 per condition). (E) dKO animals have normal motor function, as measured by treadmill analysis. The average propulsion time measurement at age 28 days for WT was 110 ± 9.7 ms (n = 4), for Mtm1 KO was 77 ± 6.9 ms (n = 5, **P < 0.01 compared with WT or dKO), and for dKO was 110 ± 7.2 ms (n = 4, P = 0.91 compared with WT). All comparisons in C–E done by 1-way ANOVA followed by Dunnett’s multicomparison test.