Phosphatidylinositol 3-kinase inhibition restores Ca 2+ release defects and prolongs survival in myotubularin-deficient mice - Archive ouverte HAL Accéder directement au contenu
Article Dans Une Revue Proceedings of the National Academy of Sciences of the United States of America Année : 2016

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

Candice Kutchukian
  • Fonction : Auteur
Mirella Lo Scrudato
  • Fonction : Auteur
Yves Tourneur
  • Fonction : Auteur
Karine Poulard
  • Fonction : Auteur
Alban Vignaud
  • Fonction : Auteur
Christine Berthier
  • Fonction : Auteur
Bruno Allard
  • Fonction : Auteur
Michael Lawlor
  • Fonction : Auteur
Vincent Jacquemond
  • Fonction : Auteur

Résumé

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 Ca 2+ signaling is strongly heterogeneous at the subcellular level, affects the amplitude and activation kinetics of sarcoplasmic reticulum Ca 2+ release, and promotes a Ca 2+ -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 Ca 2+ homeostasis and a potential benefit of this therapeutic approach for the disease.

Dates et versions

hal-04481617 , version 1 (28-02-2024)

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Candice Kutchukian, Mirella Lo Scrudato, Yves Tourneur, Karine Poulard, Alban Vignaud, et al.. Phosphatidylinositol 3-kinase inhibition restores Ca 2+ release defects and prolongs survival in myotubularin-deficient mice. Proceedings of the National Academy of Sciences of the United States of America, 2016, 113 (50), pp.14432-14437. ⟨10.1073/pnas.1604099113⟩. ⟨hal-04481617⟩
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