Ryanodine receptor dispersion disrupts Ca 2+ release in failing cardiac myocytes

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

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • 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*

Substances

  • Cations, Divalent
  • Ryanodine Receptor Calcium Release Channel
  • Calcium