Faculty Collaboration Database

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

Date

12/03/2016

Pubmed ID

27911767

Pubmed Central ID

PMC5167204

DOI

10.1073/pnas.1604099113

Scopus ID

2-s2.0-85005992133 (requires institutional sign-in at Scopus site)   28 Citations

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.

Author List

Kutchukian C, Lo Scrudato M, Tourneur Y, Poulard K, Vignaud A, Berthier C, Allard B, Lawlor MW, Buj-Bello A, Jacquemond V

Author

Michael W. Lawlor MD, PhD Adjunct Professor in the Pathology department at Medical College of Wisconsin

MESH terms used to index this publication - Major topics in bold

Androstadienes
Animals
Calcium Signaling
Disease Models, Animal
Enzyme Inhibitors
Excitation Contraction Coupling
In Vitro Techniques
Male
Mice
Mice, 129 Strain
Mice, Knockout
Muscle Fibers, Skeletal
Myopathies, Structural, Congenital
Patch-Clamp Techniques
Protein Tyrosine Phosphatases, Non-Receptor