Phosphatidylinositol 3-kinase inhibition restores Ca 2+ release defects and prolongs survival in myotubularin-deficient mice

Significance Myotubular myopathy is a fatal muscle disease due to deficiency in a phosphoinositide 3-phosphatase called myotubularin. We identify critical alterations involved in the pathophysiology of the disease, and we reveal the beneficial effect of a pharmacological treatment. Specifically, we demonstrate that the disease-associated dysfunction of Ca2+ signaling is strongly heterogeneous at the subcellular level, affects the amplitude and activation kinetics of sarcoplasmic reticulum Ca2+ release, and promotes a Ca2+ -gated opening mode of the calcium release channels. Pharmacological inhibition of phosphoinositide 3-kinase activity substantially alleviates these functional defects and prolongs survival of myotubularin-deficient mice, suggesting a crucial role of this kinase activity in the dysfunction of Ca2+ homeostasis and a potential benefit of this therapeutic approach for the disease.