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

C. Kutchukian
  • Fonction : Auteur
M. Lo Scrudato
  • Fonction : Auteur
K. Poulard
  • Fonction : Auteur
A. Vignaud
  • Fonction : Auteur
C. Berthier
  • Fonction : Auteur
Béatrice Allard
  • Fonction : Auteur
  • PersonId : 940849
M. W. Lawlor
  • Fonction : Auteur
A. Buj-Bello
  • Fonction : Auteur
V. Jacquemond
  • Fonction : Auteur

Résumé

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.

Dates et versions

hal-01850367 , version 1 (27-07-2018)

Identifiants

Citer

C. Kutchukian, M. Lo Scrudato, Y. Tourneur, K. Poulard, A. Vignaud, et al.. Phosphatidylinositol 3-kinase inhibition restores Ca2+ 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-01850367⟩
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