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

J Clin Invest. 2016 Sep 1;126(9):3613-25. doi: 10.1172/JCI86841. Epub 2016 Aug 22.


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.

MeSH terms

  • Androstadienes / chemistry
  • Animals
  • Animals, Genetically Modified
  • Class II Phosphatidylinositol 3-Kinases / genetics*
  • Class II Phosphatidylinositol 3-Kinases / physiology
  • Class III Phosphatidylinositol 3-Kinases
  • Disease Models, Animal
  • Female
  • Male
  • Mice
  • Mice, Knockout
  • Motor Skills / drug effects
  • Muscle, Skeletal / metabolism*
  • Myopathies, Structural, Congenital / genetics*
  • Myopathies, Structural, Congenital / therapy
  • Phenotype
  • Phosphatidylinositol 3-Kinases / genetics*
  • Phosphatidylinositol 3-Kinases / physiology
  • Protein Tyrosine Phosphatases, Non-Receptor / metabolism
  • Wortmannin
  • Zebrafish


  • Androstadienes
  • Phosphatidylinositol 3-Kinases
  • Class II Phosphatidylinositol 3-Kinases
  • Class III Phosphatidylinositol 3-Kinases
  • PIK3C3 protein, mouse
  • Pik3c2b protein, mouse
  • Protein Tyrosine Phosphatases, Non-Receptor
  • myotubularin
  • Wortmannin