Ryanodine receptor dispersion disrupts Ca2+ release in failing cardiac myocytes

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.