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Elife. 2018 Oct 30;7. pii: e39427. doi: 10.7554/eLife.39427.

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

Author information

1
Institute for Experimental Medical Research, Oslo University Hospital and University of Oslo, Oslo, Norway.
2
KG Jebsen Center for Cardiac Research, University of Oslo, Oslo, Norway.
3
Simula Research Laboratory, Fornebu, Norway.
4
Institute of Cardiovascular Sciences, University of Glasgow, Glasgow, Great Britain.
5
Bjørknes College, Oslo, 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.

KEYWORDS:

Ca2+ spark; cardiomyocyte; cell biology; dSTORM; heart failure; human biology; medicine; rat; ryanodine receptor

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