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Phosphoinositide substrates of myotubularin affect voltage-activated Ca2+ release in skeletal muscle

  • Muscle physiology
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Pflügers Archiv - European Journal of Physiology Aims and scope Submit manuscript

Abstract

Skeletal muscle excitation–contraction (E–C) coupling is altered in several models of phosphatidylinositol phosphate (PtdInsP) phosphatase deficiency and ryanodine receptor activity measured in vitro was reported to be affected by certain PtdInsPs, thus prompting investigation of the physiological role of PtdInsPs in E–C coupling. We measured intracellular Ca2+ transients in voltage-clamped mouse muscle fibres microinjected with a solution containing a PtdInsP substrate (PtdIns(3,5)P 2 or PtdIns(3)P) or product (PtdIns(5)P or PtdIns) of the myotubularin phosphatase MTM1. No significant change was observed in the presence of either PtdIns(5)P or PtdIns but peak SR Ca2+ release was depressed by ~30% and 50% in fibres injected with PtdIns(3,5)P 2 and PtdIns(3)P, respectively, with no concurrent alteration in the membrane current signals associated with the DHPR function as well as in the voltage dependence of Ca2+ release inactivation. In permeabilized muscle fibres, the frequency of spontaneous Ca2+ release events was depressed in the presence of the three tested phosphorylated forms of PtdInsP with PtdIns(3,5)P 2 being the most effective, leading to an almost complete disappearance of Ca2+ release events. Results support the possibility that pathological accumulation of MTM1 substrates may acutely depress ryanodine receptor-mediated Ca2+ release. Overexpression of a mCherry-tagged form of MTM1 in muscle fibres revealed a striated pattern consistent with the triadic area. Ca2+ release remained although unaffected by MTM1 overexpression and was also unaffected by the PtdIns-3-kinase inhibitor LY2940002, suggesting that the 3-phosphorylated PtdIns lipids active on voltage-activated Ca2+ release are inherently maintained at a low level, inefficient on Ca2+ release in normal conditions.

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Acknowledgements

This work was supported by grants from Centre National de la Recherche Scientifique (CNRS), Université Lyon 1, Association Française contre les Myopathies (AFM), Hubert Curien Partnership Balaton (TeT_10-1-2011-0723) and OTKA K107765. E.G.R. was a recipient of a fellowship from the Spanish Ministry of Education and Science (MEC, José Castillejo Program). We thank Bruno Allard for critical comments on the manuscript and helpful discussion.

Ethical standards

All experiments comply with the current laws of the two countries (France and Hungary) in which they were performed.

Conflict of interest

The authors declare that they have no conflict of interest.

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Authors and Affiliations

  1. Departamento de Fisiología, Genética y Microbiología, Universidad de Alicante, Alicante, Spain

    Estela González Rodríguez

  2. Centre de Génétique et de Physiologie Moléculaire et Cellulaire, Université Lyon 1, UMR CNRS 5534, Bât. Raphaël Dubois, 43 boulevard du 11 novembre 1918, F69622, Villeurbanne, France

    Romain Lefebvre, Claude Legrand & Vincent Jacquemond

  3. Department of Physiology, University of Debrecen, Debrecen, Hungary

    Dóra Bodnár, Peter Szentesi, János Vincze & Laszlo Csernoch

  4. Department of Research and Development, Généthon, INSERM, Evry, France

    Karine Poulard & Anna Buj-Bello

  5. Lipidomic Core Facility, Metatoul Platform, INSERM U1048, Université de Toulouse, Université Paul Sabatier, Toulouse, France

    Justine Bertrand-Michel

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  1. Estela González Rodríguez
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Correspondence to Vincent Jacquemond.

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González Rodríguez, E., Lefebvre, R., Bodnár, D. et al. Phosphoinositide substrates of myotubularin affect voltage-activated Ca2+ release in skeletal muscle. Pflugers Arch - Eur J Physiol 466, 973–985 (2014). https://doi.org/10.1007/s00424-013-1346-5

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  • DOI: https://doi.org/10.1007/s00424-013-1346-5

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