Structural variability of dyads relates to calcium release in rat ventricular myocytes

Novotová, Marta; Zahradníková, Alexandra; Nichtová, Zuzana; Kováč, Radoslav; Kráľová, Eva; Stankovičová, T; Zahradnı́k, Ivan

doi:10.1038/s41598-020-64840-5

Cited by 16 publications

(18 citation statements)

References 46 publications

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“…Because JPH2 is thought to improve coupling between LTCC and RyRs ( 1 – 4 ), it is likely that the integrity of EC coupling junctions ameliorated secondary to increased JPH2 expression, even though there was no t-system recovery ( Figure 7 ). This would fit to observations of high plasticity of junctophilin-2 and ryanodine receptors ( 4 ) and to the observation that Ca 2+ release is more rapid and more efficient in compact dyads, i.e., EC coupling junctions of high integrity ( 58 ). Investigating this idea in more detail and finding ways to induce reverse remodeling of EC coupling junctions could be promising targets of future studies.…”

Section: Discussionsupporting

confidence: 67%

Severe T-System Remodeling in Pediatric Viral Myocarditis

Fiegle

Schöber

Dittrich

et al. 2021

Front. Cardiovasc. Med.

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Chronic heart failure (HF) in adults causes remodeling of the cardiomyocyte transverse tubular system (t-system), which contributes to disease progression by impairing excitation-contraction (EC) coupling. However, it is unknown if t-system remodeling occurs in pediatric heart failure. This study investigated the t-system in pediatric viral myocarditis. The t-system and integrity of EC coupling junctions (co-localization of L-type Ca2+ channels with ryanodine receptors and junctophilin-2) were analyzed by 3D confocal microscopy in left-ventricular (LV) samples from 5 children with myocarditis (age 14 ± 3 months), undergoing ventricular assist device (VAD) implantation, and 5 children with atrioventricular septum defect (AVSD, age 17 ± 3 months), undergoing corrective surgery. LV ejection fraction (EF) was 58.4 ± 2.3% in AVSD and 12.2 ± 2.4% in acute myocarditis. Cardiomyocytes from myocarditis samples showed increased t-tubule distance (1.27 ± 0.05 μm, n = 34 cells) and dilation of t-tubules (volume-length ratio: 0.64 ± 0.02 μm2) when compared with AVSD (0.90 ± 0.02 μm, p < 0.001; 0.52 ± 0.02 μm2, n = 61, p < 0.01). Intriguingly, 4 out of 5 myocarditis samples exhibited sheet-like t-tubules (t-sheets), a characteristic feature of adult chronic heart failure. The fraction of extracellular matrix was slightly higher in myocarditis (26.6 ± 1.4%) than in AVSD samples (24.4 ± 0.8%, p < 0.05). In one case of myocarditis, a second biopsy was taken and analyzed at VAD explantation after extensive cardiac recovery (EF from 7 to 56%) and clinical remission. When compared with pre-VAD, t-tubule distance and density were unchanged, as well as volume-length ratio (0.67 ± 0.04 μm2 vs. 0.72 ± 0.05 μm2, p = 0.5), reflecting extant t-sheets. However, junctophilin-2 cluster density was considerably higher (0.12 ± 0.02 μm−3 vs. 0.05 ± 0.01 μm−3, n = 9/10, p < 0.001), approaching values of AVSD (0.13 ± 0.05 μm−3, n = 56), and the measure of intact EC coupling junctions showed a distinct increase (20.2 ± 5.0% vs. 6.8 ± 2.2%, p < 0.001). Severe t-system loss and remodeling to t-sheets can occur in acute HF in young children, resembling the structural changes of chronically failing adult hearts. T-system remodeling might contribute to cardiac dysfunction in viral myocarditis. Although t-system recovery remains elusive, recovery of EC coupling junctions may be possible and deserves further investigation.

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Section: Discussionsupporting

confidence: 67%

Severe T-System Remodeling in Pediatric Viral Myocarditis

Fiegle

Schöber

Dittrich

et al. 2021

Front. Cardiovasc. Med.

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“…Recent experimental and theoretical studies established the importance of dyad structure and RyR clustering on spontaneous calcium spark formation (Cannell et al, 2013;Walker et al, 2014;Walker et al, 2015;Kolstad et al, 2018;Cosi et al, 2019) as well as on triggered calcium release (Zahradnik et al, 2013;Cosi et al, 2019;Novotova et al, 2020). In this study we used a large set of CRS geometries that approximated the structural data by constrained random distribution of RyRs in CRS (Iaparov et al, 2017;Iaparov et al, 2019).…”

Section: Discussionmentioning

confidence: 99%

“…The structure of dyads studied by electron microscopy revealed common features in their construction (Franzini-Armstrong et al, 1999;Hayashi et al, 2009) as well as substantial structural variability (Novotova et al, 2009;Novotova et al, 2013;Novotova et al, 2020). Super-resolution localization studies revealed tendency of RyRs to form irregular clusters of variable size and surface density (Baddeley et al, 2009;Hou et al, 2015;Macquaide et al, 2015;Galice et al, 2018;Jayasinghe et al, 2018;Kolstad et al, 2018;Asghari et al, 2020).…”

Section: Introductionmentioning

confidence: 99%

“…Super-resolution localization studies revealed tendency of RyRs to form irregular clusters of variable size and surface density (Baddeley et al, 2009;Hou et al, 2015;Macquaide et al, 2015;Galice et al, 2018;Jayasinghe et al, 2018;Kolstad et al, 2018;Asghari et al, 2020). Moreover, the composition of CRSs may change in parallel with changes in the structure of dyads (Asghari et al, 2020;Drum et al, 2020;Novotova et al, 2020). Thus, the understanding of the dyad as the source of local CREs became ambiguous for the difficulty to define explicitly the common source structure.…”

Section: Introductionmentioning

confidence: 99%

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Synergy of calcium release site determinants in control of calcium release events in cardiac myocytes

Iaparov

Zahradník

Moskvin

et al. 2020

Preprint

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Recent data on structure of dyads in cardiac myocytes indicate variable clustering of RyR calcium release channels. The question arises as to how geometric factors of RyR arrangement translate to their role in formation of calcium release events (CRE). Since this question is not experimentally testable in situ, we performed in silico experiments on a large set of calcium release site (CRS) models. The models covered the range of RyR spatial distributions observed in dyads, and included gating of RyRs with open probability dependent on Ca2+ and Mg2+ concentration. The RyR single-channel calcium current, varied in the range of previously reported values, was set constant in the course of CRE simulations. Other known features of dyads were omitted in the model formulation for clarity. CRE simulations initiated by a single random opening of one of the RyRs in a CRS produced spark-like responses with characteristics that varied with RyR vicinity, a newly defined parameter quantifying spatial distribution of RyRs in the CRSs, and with the RyR single-channel calcium current. The CRE characteristics followed the law of mass action with respect to a CRS state variable, defined as a weighed product of RyR vicinity and RyR single-channel calcium current. The results explained the structure-function relations among determinants of cardiac dyads on synergy principles and thus allowed to evolve the concept of CRS as a dynamic unit of cardiac dyad.

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“…The structure of terminal cisternae studied by EM revealed common features in their construction ( Franzini-Armstrong et al, 1999 ; Hayashi et al, 2009 ) as well as their substantial structural variability ( Novotova et al, 2009 ; Novotova et al, 2013 ; Novotová et al, 2020 ). Super-resolution localization studies revealed a tendency of RYRs to form irregular clusters of variable size and surface density ( Baddeley et al, 2009 ; Hou et al, 2015 ; Macquaide et al, 2015 ; Galice et al, 2018 ; Jayasinghe et al, 2018 ; Kolstad et al, 2018 ; Asghari et al, 2020 ).…”

Section: Introductionmentioning

confidence: 99%

In silico simulations reveal that RYR distribution affects the dynamics of calcium release in cardiac myocytes

Iaparov

Zahradnı́k

Moskvin

et al. 2021

Journal of General Physiology

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The dyads of cardiac myocytes contain ryanodine receptors (RYRs) that generate calcium sparks upon activation. To test how geometric factors of RYR distribution contribute to the formation of calcium sparks, which cannot be addressed experimentally, we performed in silico simulations on a large set of models of calcium release sites (CRSs). Our models covered the observed range of RYR number, density, and spatial arrangement. The calcium release function of CRSs was modeled by RYR openings, with an open probability dependent on concentrations of free Ca2+ and Mg2+ ions, in a rapidly buffered system, with a constant open RYR calcium current. We found that simulations of spontaneous sparks by repeatedly opening one of the RYRs in a CRS produced three different types of calcium release events (CREs) in any of the models. Transformation of simulated CREs into fluorescence signals yielded calcium sparks with characteristics close to the observed ones. CRE occurrence varied broadly with the spatial distribution of RYRs in the CRS but did not consistently correlate with RYR number, surface density, or calcium current. However, it correlated with RYR coupling strength, defined as the weighted product of RYR vicinity and calcium current, so that CRE characteristics of all models followed the same state-response function. This finding revealed the synergy between structure and function of CRSs in shaping dyad function. Lastly, rearrangements of RYRs simulating hypothetical experiments on splitting and compaction of a dyad revealed an increased propensity to generate spontaneous sparks and an overall increase in calcium release in smaller and more compact dyads, thus underlying the importance and physiological role of RYR arrangement in cardiac myocytes.

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Structural variability of dyads relates to calcium release in rat ventricular myocytes

Cited by 16 publications

References 46 publications

Severe T-System Remodeling in Pediatric Viral Myocarditis

Severe T-System Remodeling in Pediatric Viral Myocarditis

Synergy of calcium release site determinants in control of calcium release events in cardiac myocytes

In silico simulations reveal that RYR distribution affects the dynamics of calcium release in cardiac myocytes

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