Ryanodine receptor dispersion disrupts Ca2+ release in failing cardiac myocytes
- Oslo University Hospital, Norway
- Simula Reseach Laboratory, Norway
- University of Glasgow, United Kingdom
- Simula Research Laboratory, Norway
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.
Data availability
Source data files have been provided for Figures 2 , 4 and 6.All raw data acquired and analyzed in this study are publicly available in the following repository: https://github.com/TerjePrivate/Ryanodine_Receptor_Dispersion_during_Heart_Failure
Article and author information
Author details
Ole Mathias Sejersted
William Edward Louch
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.
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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