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Ryanodine receptor dispersion disrupts Ca 2+ release in failing cardiac myocytes
Reduced cardiac contractility during heart failure (HF) is linked to impaired Ca 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...
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Published in: | eLife 2018-10, Vol.7 |
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Main Authors: | , , , , , , , , , , , , |
Format: | Article |
Language: | English |
Subjects: | |
Online Access: | Get full text |
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Summary: | Reduced cardiac contractility during heart failure (HF) is linked to impaired Ca
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
sparks (Ca
release units, CRUs) also became less solid. An increased fraction of small CRUs in HF was linked to augmented 'silent' Ca
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
spread across dispersed CRUs. During the action potential, these slow sparks protracted and desynchronized the overall Ca
transient. Thus, nanoscale RyR reorganization during HF augments Ca
leak and slows Ca
release kinetics, leading to weakened contraction in this disease. |
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ISSN: | 2050-084X |