1. Cell Biology
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Ryanodine receptor dispersion disrupts Ca2+ release in failing cardiac myocytes

  1. Terje R Kolstad
  2. Jonas van den Brink
  3. Niall MacQuaide
  4. Per Kristian Lunde
  5. Michael Frisk
  6. Jan Magnus Aronsen
  7. Einar Sjaastad Norden
  8. Alessandro Cataliotti
  9. Ivar Sjaastad
  10. Ole Mathias Sejersted
  11. Andrew G Edwards
  12. Glenn Terje Lines
  13. William Edward Louch  Is a corresponding author
  1. Oslo University Hospital, Norway
  2. Simula Reseach Laboratory, Norway
  3. University of Glasgow, United Kingdom
  4. Simula Research Laboratory, Norway
Research Article
  • Cited 21
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Cite this article as: eLife 2018;7:e39427 doi: 10.7554/eLife.39427

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.

Article and author information

Author details

  1. Terje R Kolstad

    Insitute for Experimental Medical Research, Oslo University Hospital, Oslo, Norway
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-0589-5689
  2. Jonas van den Brink

    Simula Reseach Laboratory, Fornebu, Norway
    Competing interests
    The authors declare that no competing interests exist.
  3. Niall MacQuaide

    Institute of Cardiovascular Sciences, University of Glasgow, Glasgow, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.
  4. Per Kristian Lunde

    Institute for Experimental Medical Research, Oslo University Hospital, Oslo, Norway
    Competing interests
    The authors declare that no competing interests exist.
  5. Michael Frisk

    Institute for Experimental Medical Research, Oslo University Hospital, Oslo, Norway
    Competing interests
    The authors declare that no competing interests exist.
  6. Jan Magnus Aronsen

    Institute for Experimental Medical Research, Oslo University Hospital, Oslo, Norway
    Competing interests
    The authors declare that no competing interests exist.
  7. Einar Sjaastad Norden

    Institute for Experimental Medical Research, Oslo University Hospital, Oslo, Norway
    Competing interests
    The authors declare that no competing interests exist.
  8. Alessandro Cataliotti

    Institute for Experimental Medical Research, Oslo University Hospital, Oslo, Norway
    Competing interests
    The authors declare that no competing interests exist.
  9. Ivar Sjaastad

    Institute for Experimental Medical Research, Oslo University Hospital, Oslo, Norway
    Competing interests
    The authors declare that no competing interests exist.
  10. Ole Mathias Sejersted

    Institute for Experimental Medical Research, Oslo University Hospital, Oslo, Norway
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0001-8817-3296
  11. Andrew G Edwards

    Simula Research Laboratory, Fornebu, Norway
    Competing interests
    The authors declare that no competing interests exist.
  12. Glenn Terje Lines

    Simula Research Laboratory, Fornebu, Norway
    Competing interests
    The authors declare that no competing interests exist.
  13. William Edward Louch

    Institute for Experimental Medical Research, Oslo University Hospital, Oslo, Norway
    For correspondence
    w.e.louch@medisin.uio.no
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-0511-6112

Funding

Horizon 2020 Framework Programme (Consolidator grant for WEL 647714)

  • Terje R Kolstad
  • William Edward Louch

The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.

Ethics

Animal experimentation: All experiments were approved by the Norwegian National Animal Research Authority (project license no. FOTS 5982, 7786), and were performed in accordance with the National Institute of Health guidelines (NIH publication No. 85-23, revised 2011) and European Directive 2010/63/EU.

Reviewing Editor

  1. Gordana Vunjak-Novakovic, Columbia University, United States

Publication history

  1. Received: June 21, 2018
  2. Accepted: October 24, 2018
  3. Accepted Manuscript published: October 30, 2018 (version 1)
  4. Version of Record published: November 20, 2018 (version 2)
  5. Version of Record updated: June 26, 2019 (version 3)

Copyright

© 2018, Kolstad et al.

This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.

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