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.
Original language | English |
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Article number | e39427 |
Number of pages | 24 |
Journal | eLife |
Volume | 7 |
DOIs | |
Publication status | Published - 30 Oct 2018 |
Keywords
- Action Potentials
- Animals
- Calcium/metabolism
- Cations, Divalent/metabolism
- Disease Models, Animal
- Heart Failure/pathology
- Microscopy, Fluorescence
- Myocardial Infarction/pathology
- Myocytes, Cardiac/pathology
- Rats
- Ryanodine Receptor Calcium Release Channel/metabolism
ASJC Scopus subject areas
- General Immunology and Microbiology
- General Biochemistry,Genetics and Molecular Biology
- General Neuroscience