Ryanodine receptor dispersion disrupts Ca 2+ 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

Research output: Contribution to journalArticle

17 Scopus citations

Abstract

Reduced cardiac contractility during heart failure (HF) is linked to impaired Ca 2+ 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 Ca 2+ sparks (Ca 2+ release units, CRUs) also became less solid. An increased fraction of small CRUs in HF was linked to augmented ‘silent’ Ca 2+ 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 Ca 2+ spread across dispersed CRUs. During the action potential, these slow sparks protracted and desynchronized the overall Ca 2+ transient. Thus, nanoscale RyR reorganization during HF augments Ca 2+ leak and slows Ca 2+ release kinetics, leading to weakened contraction in this disease.

Original languageEnglish (US)
Article numbere39427
JournaleLife
Volume7
DOIs
StatePublished - Oct 2018
Externally publishedYes

ASJC Scopus subject areas

  • Neuroscience(all)
  • Biochemistry, Genetics and Molecular Biology(all)
  • Immunology and Microbiology(all)

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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 Ca 2+ release in failing cardiac myocytes eLife, 7, [e39427]. https://doi.org/10.7554/eLife.39427