Phosphatidylinositol 3-kinase inhibition restores Ca2+ release defects and prolongs survival in myotubularin-deficient mice

Proc Natl Acad Sci U S A. 2016 Dec 13;113(50):14432-14437. doi: 10.1073/pnas.1604099113. Epub 2016 Nov 28.


Mutations in the gene encoding the phosphoinositide 3-phosphatase myotubularin (MTM1) are responsible for a pediatric disease of skeletal muscle named myotubular myopathy (XLMTM). Muscle fibers from MTM1-deficient mice present defects in excitation-contraction (EC) coupling likely responsible for the disease-associated fatal muscle weakness. However, the mechanism leading to EC coupling failure remains unclear. During normal skeletal muscle EC coupling, transverse (t) tubule depolarization triggers sarcoplasmic reticulum (SR) Ca2+ release through ryanodine receptor channels gated by conformational coupling with the t-tubule voltage-sensing dihydropyridine receptors. We report that MTM1 deficiency is associated with a 60% depression of global SR Ca2+ release over the full range of voltage sensitivity of EC coupling. SR Ca2+ release in the diseased fibers is also slower than in normal fibers, or delayed following voltage activation, consistent with the contribution of Ca2+-gated ryanodine receptors to EC coupling. In addition, we found that SR Ca2+ release is spatially heterogeneous within myotubularin-deficient muscle fibers, with focally defective areas recapitulating the global alterations. Importantly, we found that pharmacological inhibition of phosphatidylinositol 3-kinase (PtdIns 3-kinase) activity rescues the Ca2+ release defects in isolated muscle fibers and increases the lifespan and mobility of XLMTM mice, providing proof of concept for the use of PtdIns 3-kinase inhibitors in myotubular myopathy and suggesting that unbalanced PtdIns 3-kinase activity plays a critical role in the pathological process.

Keywords: excitation–contraction coupling; myotubularin; ryanodine receptor; sarcoplasmic reticulum Ca2+ release; skeletal muscle.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Androstadienes / pharmacology
  • Animals
  • Calcium Signaling / drug effects
  • Calcium Signaling / physiology*
  • Disease Models, Animal
  • Enzyme Inhibitors / pharmacology
  • Excitation Contraction Coupling / drug effects
  • Excitation Contraction Coupling / physiology
  • In Vitro Techniques
  • Male
  • Mice
  • Mice, 129 Strain
  • Mice, Knockout
  • Muscle Fibers, Skeletal / drug effects
  • Muscle Fibers, Skeletal / physiology
  • Myopathies, Structural, Congenital / drug therapy
  • Myopathies, Structural, Congenital / genetics
  • Myopathies, Structural, Congenital / physiopathology
  • Patch-Clamp Techniques
  • Phosphoinositide-3 Kinase Inhibitors*
  • Protein Tyrosine Phosphatases, Non-Receptor / deficiency*
  • Protein Tyrosine Phosphatases, Non-Receptor / genetics
  • Wortmannin


  • Androstadienes
  • Enzyme Inhibitors
  • Phosphoinositide-3 Kinase Inhibitors
  • Protein Tyrosine Phosphatases, Non-Receptor
  • myotubularin
  • Wortmannin