title: Phosphatidylinositol 3-kinase inhibition restores Ca2+ release defects and prolongs survival in myotubularin-deficient mice.
abstract: 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.
authors.affiliation: Institut NeuroMyoGène, CNRS UMR 5310, INSERM U1217, Université Claude Bernard Lyon 1, F69622 Villeurbanne, France.
authors.forename: Candice
authors.initials: C
authors.lastname: Kutchukian
authors.affiliation: Généthon, 91002 Evry, France.|INSERM UMR_S951, 91002 Evry, France.
authors.forename: Mirella
authors.initials: M
authors.lastname: Lo Scrudato
authors.affiliation: Faculté de Médecine Lyon Sud, Cardiovasculaire, Métabolisme, Diabétologie et Nutrition, INSERM U1060, 69921 Oullins, France.|Universidade Federal de Pernambuco, Dept Nutrição, Cidade Universitária, 50670-901, Recife, Brazil.
authors.forename: Yves
authors.initials: Y
authors.lastname: Tourneur
authors.affiliation: Généthon, 91002 Evry, France.|INSERM UMR_S951, 91002 Evry, France.
authors.forename: Karine
authors.initials: K
authors.lastname: Poulard
authors.affiliation: Généthon, 91002 Evry, France.
authors.forename: Alban
authors.initials: A
authors.lastname: Vignaud
authors.affiliation: Institut NeuroMyoGène, CNRS UMR 5310, INSERM U1217, Université Claude Bernard Lyon 1, F69622 Villeurbanne, France.
authors.forename: Christine
authors.initials: C
authors.lastname: Berthier
authors.affiliation: Institut NeuroMyoGène, CNRS UMR 5310, INSERM U1217, Université Claude Bernard Lyon 1, F69622 Villeurbanne, France.
authors.forename: Bruno
authors.initials: B
authors.lastname: Allard
authors.affiliation: Division of Pediatric Pathology, Department of Pathology and Laboratory Medicine, Medical College of Wisconsin, Milwaukee, WI 53226.
authors.forename: Michael W
authors.initials: MW
authors.lastname: Lawlor
authors.affiliation: Généthon, 91002 Evry, France.|INSERM UMR_S951, 91002 Evry, France.
authors.forename: Ana
authors.initials: A
authors.lastname: Buj-Bello
authors.affiliation: Institut NeuroMyoGène, CNRS UMR 5310, INSERM U1217, Université Claude Bernard Lyon 1, F69622 Villeurbanne, France; vincent.jacquemond@univ-lyon1.fr.
authors.forename: Vincent
authors.initials: V
authors.lastname: Jacquemond
mesh_terms: D000730:Androstadienes / Q000494:pharmacology; D000818:Animals; D020013:Calcium Signaling / Q000187:drug effects / Q000502:physiology*; D004195:Disease Models, Animal; D004791:Enzyme Inhibitors / Q000494:pharmacology; D056966:Excitation Contraction Coupling / Q000187:drug effects / Q000502:physiology; D066298:In Vitro Techniques; D008297:Male; D051379:Mice; D057507:Mice, 129 Strain; D018345:Mice, Knockout; D018485:Muscle Fibers, Skeletal / Q000187:drug effects / Q000502:physiology; D020914:Myopathies, Structural, Congenital / Q000188:drug therapy / Q000235:genetics / Q000503:physiopathology; D018408:Patch-Clamp Techniques; D000081082:Phosphoinositide-3 Kinase Inhibitors; D054558:Protein Tyrosine Phosphatases, Non-Receptor / Q000172:deficiency* / Q000235:genetics; D000077191:Wortmannin
chemical_list: D000730:Androstadienes; D004791:Enzyme Inhibitors; D000081082:Phosphoinositide-3 Kinase Inhibitors; D054558:Protein Tyrosine Phosphatases, Non-Receptor; C099588:myotubularin; D000077191:Wortmannin
keywords: excitation–contraction coupling; myotubularin; ryanodine receptor; sarcoplasmic reticulum Ca2+ release; skeletal muscle