Ryanodine receptor dispersion disrupts Ca2+ release in failing cardiac myocytes

Terje R. Kolstad, Jonas van den Brink, Niall MacQuaide, Per Kristian Lunde, Michael Frisk, Jan Magnus Aronsen, Einar S. Norden, Alessandro Cataliotti, Ivar Sjaastad, Ole M. Sejersted, Andrew G. Edwards, Glenn Terje Lines, William E. Louch*

*Corresponding author for this work

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Abstract

Reduced cardiac contractility during heart failure (HF) is linked to impaired Ca2+ release from Ryanodine Receptors (RyRs). We investigated whether this deficit can be traced to nanoscale RyR reorganization. Using super-resolution imaging, we observed dispersion of RyR clusters in cardiomyocytes from post-infarction HF rats, resulting in more numerous, smaller clusters. Functional groupings of RyR clusters which produce Ca2+ sparks (Ca2+ release units, CRUs) also became less solid. An increased fraction of small CRUs in HF was linked to augmented 'silent' Ca2+ leak, not visible as sparks. Larger multi-cluster CRUs common in HF also exhibited low fidelity spark generation. When successfully triggered, sparks in failing cells displayed slow kinetics as Ca2+ spread across dispersed CRUs. During the action potential, these slow sparks protracted and desynchronized the overall Ca2+ transient. Thus, nanoscale RyR reorganization during HF augments Ca2+ leak and slows Ca2+ release kinetics, leading to weakened contraction in this disease.

Original languageEnglish
Article numbere39427
Number of pages24
JournaleLife
Volume7
DOIs
Publication statusPublished - 30 Oct 2018

Keywords

  • Action Potentials
  • Animals
  • Calcium/metabolism
  • Cations, Divalent/metabolism
  • Disease Models, Animal
  • Heart Failure/pathology
  • Microscopy, Fluorescence
  • Myocardial Infarction/pathology
  • Myocytes, Cardiac/pathology
  • Rats
  • Ryanodine Receptor Calcium Release Channel/metabolism

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    Kolstad, T. R., van den Brink, J., MacQuaide, N., Lunde, P. K., Frisk, M., Aronsen, J. M., Norden, E. S., Cataliotti, A., Sjaastad, I., Sejersted, O. M., Edwards, A. G., Lines, G. T., & Louch, W. E. (2018). Ryanodine receptor dispersion disrupts Ca2+ release in failing cardiac myocytes. eLife, 7, [e39427]. https://doi.org/10.7554/eLife.39427