Axial Tubule Junctions Activate Atrial Ca2+ Release Across Species

Brandenburg, Sören; Pawlowitz, Jan; Fakuade, Funsho E; Kownatzki-Danger, Daniel; Kohl, Tobias; Mitronova, Gyuzel Yu.; Scardigli, Marina; Neef, Jakob; Schmidt, Constanze; Wiedmann, Felix; Pavone, Francesco S.; Sacconi, Leonardo; Kutschka, Ingo; Sossalla, Samuel; Moser, Tobias; Voigt, Niels; Lehnart, Stephan E.

doi:10.3389/fphys.2018.01227

Cited by 41 publications

(84 citation statements)

References 74 publications

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“…= 0.033, respectively) would be consistent with values measured experimentally, of * 0.3 for ventricular myocytes and up to * 0.1 for sheep atrial myocytes [30]. Typical branch length in atrial myocytes varies from 1.5-2μm in small mammals (rat, mouse, rabbit) to * 2μm in humans [31]. In our model this again would correspond to a F.A.…”

Section: Discussionsupporting

confidence: 89%

Influence of the tubular network on the characteristics of calcium transients in cardiac myocytes

Marchena

Echebarria

2020

PLoS ONE

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Transverse and axial tubules (TATS) are an essential ingredient of the excitation-contraction machinery that allow the effective coupling of L-type Calcium Channels (LCC) and ryanodine receptors (RyR2). They form a regular network in ventricular cells, while their presence in atrial myocytes is variable regionally and among animal species We have studied the effect of variations in the TAT network using a bidomain computational model of an atrial myocyte with variable density of tubules. At each z-line the t-tubule length is obtained from an exponential distribution, with a given mean penetration length. This gives rise to a distribution of t-tubules in the cell that is characterized by the fractional area (F.A.) occupied by the t-tubules. To obtain consistent results, we average over different realizations of the same mean penetration length. To this, in some simulations we add the effect of a network of axial tubules. Then we study global properties of calcium signaling, as well as regional heterogeneities and local properties of sparks and RyR2 openings. In agreement with recent experiments in detubulated ventricular and atrial cells, we find that detubulation reduces the calcium transient and synchronization in release. However, it does not affect sarcoplasmic reticulum (SR) load, so the decrease in SR calcium release is due to regional differences in Ca 2+ release, that is restricted to the cell periphery in detubulated cells. Despite the decrease in release, the release gain is larger in detubulated cells, due to recruitment of orphaned RyR2s, i.e, those that are not confronting a cluster of LCCs. This probably provides a safeguard mechanism, allowing physiological values to be maintained upon small changes in the t-tubule density. Finally, we do not find any relevant change in spark properties between tubulated and detubulated cells, suggesting that the differences found in experiments could be due to differential properties of the RyR2s in the membrane and in the t-tubules, not incorporated in the present model. This work will help understand the effect of detubulation, that has been shown to occur in disease conditions such as heart failure (HF) in ventricular cells, or atrial fibrillation (AF) in atrial cells.

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Section: Discussionsupporting

confidence: 89%

Influence of the tubular network on the characteristics of calcium transients in cardiac myocytes

Marchena

Echebarria

2020

PLoS ONE

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“…However, a recent study has shown transverse tubules in mammalian atrial myocytes including humans [20]. More interesting, a 50% higher density of axial-tubule junctions than of transverse tubules were identified in intact live human atrial myocytes using superresolution microscopy imaging [21]. In this study, more axial-tubules were observed in comparison to transverse-tubules, this will be quantified in future.…”

Section: Discussionmentioning

confidence: 53%

Structural Basis of Atrial Arrhythmogenesis in Metabolic Syndrome

Agrawal¹,

Ramlugun²,

Ashton³

et al. 2019

2019 Computing in Cardiology Conference (CinC)

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Individual components of metabolic syndrome (MetS) have been correlated with atrial fibrillation (AF), but as a whole, the exact mechanism underlying the increased susceptibility of AF still remains unclear. This study identifies key structural substrates in a robust obesogenic dietary model of MetS in the rabbits. The rabbit atria from both MetS and controls (N=3 each) were processed and incubated in wheat germ agglutinin (WGA) to label cell membranes and collagen. Confocal microscopy was used to image the tissue. The collagen and cell membranes were segmented using a robust machine learning architecture, V-net. Quantification of fibrosis was done by calculating the ratio of total pixels of collagen to those of atrial tissue in each of the segmented images. Cell hypertrophy measurements were calculated by measuring means of individual cell diameters. We discovered atrial dilation, increased collagen, cell hypertrophy and reduction in axial-tubules in MetS atria. These are established arrhythmogenic phenotypes which might lead to increased AF susceptibility.

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“…Atrial cells have a different t-tubule system than ventricular cells; they are termed transverse-axial tubules (TATs) and present as heterogenous sarcolemmal membrane invaginations that appear near the z-lines and assist in atrial cell contraction (Kirk et al, 2003;Hund and Mohlerp, 2016;Yue et al, 2017). When an AP is initiated, the atrial cells activate intracellular Ca 2+ release and sarcomeric contraction through the TAT junctions (Brandenburg et al, 2018). The existence of the TATs contributes to nearsynchronous Ca 2+ transients and to synchronous subcellular depolarization and intracellular Ca 2+ release.…”

Section: Electro-ca 2+ -Metabolic-mechanical Feedback In Pacemaker Anmentioning

confidence: 99%

“…The existence of the TATs contributes to nearsynchronous Ca 2+ transients and to synchronous subcellular depolarization and intracellular Ca 2+ release. TATs may lead to region-specific electro-mechanical coupling and heterogeneous atrial contraction (Hund and Mohlerp, 2016;Yue et al, 2017;Brandenburg et al, 2018). There is evidence of dense and welldeveloped TATs in both small and large animals (Kirk et al, 2003;Glukhov et al, 2015;Yue et al, 2017;Brandenburg et al, 2018).…”

Section: Electro-ca 2+ -Metabolic-mechanical Feedback In Pacemaker Anmentioning

confidence: 99%

“…TATs may lead to region-specific electro-mechanical coupling and heterogeneous atrial contraction (Hund and Mohlerp, 2016;Yue et al, 2017;Brandenburg et al, 2018). There is evidence of dense and welldeveloped TATs in both small and large animals (Kirk et al, 2003;Glukhov et al, 2015;Yue et al, 2017;Brandenburg et al, 2018). In addition, studies have shown the existence of an atrial t-tubule system in larger mammals, such as sheep and humans (Richards et al, 2011;Trafford et al, 2013).…”

Section: Electro-ca 2+ -Metabolic-mechanical Feedback In Pacemaker Anmentioning

confidence: 99%

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May the Force Not Be With You During Culture: Eliminating Mechano-Associated Feedback During Culture Preserves Cultured Atrial and Pacemaker Cell Functions

2020

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Cultured cardiomyocytes have been shown to possess significant potential as a model for characterization of mechano-Ca 2+ , mechano-electric, and mechano-metabolic feedbacks in the heart. However, the majority of cultured cardiomyocytes exhibit impaired electrical, mechanical, biochemical, and metabolic functions. More specifically, the cells do not beat spontaneously (pacemaker cells) or beat at a rate far lower than their physiological counterparts and self-oscillate (atrial and ventricular cells) in culture. Thus, efforts are being invested in ensuring that cultured cardiomyocytes maintain the shape and function of freshly isolated cells. Elimination of contraction during culture has been shown to preserve the mechano-Ca 2+ , mechano-electric, and mechanometabolic feedback loops of cultured cells. This review focuses on pacemaker cells, which reside in the sinoatrial node (SAN) and generate regular heartbeat through the initiation of the heart's electrical, metabolic, and biochemical activities. In parallel, it places emphasis on atrial cells, which are responsible for bridging the electrical conductance from the SAN to the ventricle. The review provides a summary of the main mechanisms responsible for mechano-electrical, Ca 2+ , and metabolic feedback in pacemaker and atrial cells and of culture methods existing for both cell types. The work concludes with an explanation of how the elimination of mechano-electrical, mechano-Ca 2+ , and mechano-metabolic feedbacks during culture results in sustained cultured cell function.

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Axial Tubule Junctions Activate Atrial Ca2+ Release Across Species

Cited by 41 publications

References 74 publications

Influence of the tubular network on the characteristics of calcium transients in cardiac myocytes

Influence of the tubular network on the characteristics of calcium transients in cardiac myocytes

Structural Basis of Atrial Arrhythmogenesis in Metabolic Syndrome

May the Force Not Be With You During Culture: Eliminating Mechano-Associated Feedback During Culture Preserves Cultured Atrial and Pacemaker Cell Functions

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