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.
Highlights
The basic processes for cardiac excitation-contraction coupling are well described
This estimation is in close agreement with previous estimates made at the cell surface (14 Ryanodine Receptors (RyRs)/cluster) (Baddeley et al, 2009), but considerably lower than estimates made deep within the cell interior (Hou et al, 2015), a discrepancy which may reflect regional differences in RyR organization across the cell
Assuming that RyR clusters located within 150 nm cooperatively form a Ca2+ Release Units (CRUs) (Macquaide et al, 2015), we calculated that average CRUs contain roughly 3 – 4 clusters, and a total of » 30 RyRs
Summary
Depolarization of the sarcolemma triggers the opening of voltage-gated L-Type Ca2+ channels (LTCCs), and the resulting Ca2+ influx elicits additional Ca2+ release via Ryanodine Receptors (RyRs) in the sarcoplasmic reticulum (SR). This process of Ca2+-induced Ca2+ release leads to a sharp increase in cytosolic Ca2+ concentration which initiates cardiomyocyte contraction. The RyRs themselves are organized into clusters; an arrangement that couples their gating, promoting synchronized opening and closing of neighbouring channels (Marx et al, 2001; Sobie et al, 2006). While Ca2+ sparks are an important source of RyR-mediated Ca2+ leak from the SR, ‘silent’ or ‘non-spark’ events occur, and involve the opening of a subset of RyRs within a CRU; so-called ‘quarky’ release (Brochet et al, 2011)
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