Cardiac Transverse Tubules in Physiology and Heart Failure

Dibb, Katharine M.; Louch, William E.; Trafford, Andrew W.

doi:10.1146/annurev-physiol-061121-040148

Cited by 20 publications

(24 citation statements)

References 161 publications

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“…Notably, some T-tubules located away from Z-lines could be newly developed axial tubules, which form couplons. That said, the consistent finding is that a net loss of T-tubules, and hence a decreased number of couplons, is a general feature of ventricular myocytes during the development of hypertrophy and heart failure (recently reviewed by Dibb et al [2021] ).…”

Section: Noise Increases Cardiac Arrhythmogenesis In Diseasementioning

confidence: 90%

Biological noise is a key determinant of the reproducibility and adaptability of cardiac pacemaking and EC coupling

Guarina

Moghbel

Pourhosseinzadeh

et al. 2022

Journal of General Physiology

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Each heartbeat begins with the generation of an action potential in pacemaking cells in the sinoatrial node. This signal triggers contraction of cardiac muscle through a process termed excitation–contraction (EC) coupling. EC coupling is initiated in dyadic structures of cardiac myocytes, where ryanodine receptors in the junctional sarcoplasmic reticulum come into close apposition with clusters of CaV1.2 channels in invaginations of the sarcolemma. Cooperative activation of CaV1.2 channels within these clusters causes a local increase in intracellular Ca2+ that activates the juxtaposed ryanodine receptors. A salient feature of healthy cardiac function is the reliable and precise beat-to-beat pacemaking and amplitude of Ca2+ transients during EC coupling. In this review, we discuss recent discoveries suggesting that the exquisite reproducibility of this system emerges, paradoxically, from high variability at subcellular, cellular, and network levels. This variability is attributable to stochastic fluctuations in ion channel trafficking, clustering, and gating, as well as dyadic structure, which increase intracellular Ca2+ variance during EC coupling. Although the effects of these large, local fluctuations in function and organization are sometimes negligible at the macroscopic level owing to spatial–temporal summation within and across cells in the tissue, recent work suggests that the “noisiness” of these intracellular Ca2+ events may either enhance or counterintuitively reduce variability in a context-dependent manner. Indeed, these noisy events may represent distinct regulatory features in the tuning of cardiac contractility. Collectively, these observations support the importance of incorporating experimentally determined values of Ca2+ variance in all EC coupling models. The high reproducibility of cardiac contraction is a paradoxical outcome of high Ca2+ signaling variability at subcellular, cellular, and network levels caused by stochastic fluctuations in multiple processes in time and space. This underlying stochasticity, which counterintuitively manifests as reliable, consistent Ca2+ transients during EC coupling, also allows for rapid changes in cardiac rhythmicity and contractility in health and disease.

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Section: Noise Increases Cardiac Arrhythmogenesis In Diseasementioning

confidence: 90%

Biological noise is a key determinant of the reproducibility and adaptability of cardiac pacemaking and EC coupling

Guarina

Moghbel

Pourhosseinzadeh

et al. 2022

Journal of General Physiology

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“…Rather than being a whole-cell, homogeneous event, the CaT is the summation of many thousands of locally controlled Ca 2+ sparks, conferred in the specialized nanodomains called dyads or couplons which co-localize the RyRs on the SR membrane with the LTCCs on the sarcolemma membrane. Cardiomyocytes therefore feature an intracellular structure which facilitates whole-cell contraction mediated by this local control of CICR: the SR forms a cell-wide network coupling the spatially distributed dyads throughout the intracellular volume; the surface sarcolemma (SL) membrane contains multiple invaginations into the cell interior, consisting of the transverse-tubule (TT) and axial-tubule (AT) system (T-system), harboring LTCCs, NCX, and other ion channels ( Dibb et al, 2022 ) which enables dyads to be formed throughout the cellular volume. The reader is referred to the previous works and reviews by Cannell and Kong (2012 , 2017) and Laver et al (2013) for discussion about the importance of local control to explain the properties of CICR in the heart.…”

Section: Introductionmentioning

confidence: 99%

Multi-Scale Computational Modeling of Spatial Calcium Handling From Nanodomain to Whole-Heart: Overview and Perspectives

et al. 2022

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Regulation of intracellular calcium is a critical component of cardiac electrophysiology and excitation-contraction coupling. The calcium spark, the fundamental element of the intracellular calcium transient, is initiated in specialized nanodomains which co-locate the ryanodine receptors and L-type calcium channels. However, calcium homeostasis is ultimately regulated at the cellular scale, by the interaction of spatially separated but diffusively coupled nanodomains with other sub-cellular and surface-membrane calcium transport channels with strong non-linear interactions; and cardiac electrophysiology and arrhythmia mechanisms are ultimately tissue-scale phenomena, regulated by the interaction of a heterogeneous population of coupled myocytes. Recent advances in imaging modalities and image-analysis are enabling the super-resolution reconstruction of the structures responsible for regulating calcium homeostasis, including the internal structure of nanodomains themselves. Extrapolating functional and imaging data from the nanodomain to the whole-heart is non-trivial, yet essential for translational insight into disease mechanisms. Computational modeling has important roles to play in relating structural and functional data at the sub-cellular scale and translating data across the scales. This review covers recent methodological advances that enable image-based modeling of the single nanodomain and whole cardiomyocyte, as well as the development of multi-scale simulation approaches to integrate data from nanometer to whole-heart. Firstly, methods to overcome the computational challenges of simulating spatial calcium dynamics in the nanodomain are discussed, including image-based modeling at this scale. Then, recent whole-cell models, capable of capturing a range of different structures (such as the T-system and mitochondria) and cellular heterogeneity/variability are discussed at two different levels of discretization. Novel methods to integrate the models and data across the scales and simulate stochastic dynamics in tissue-scale models are then discussed, enabling elucidation of the mechanisms by which nanodomain remodeling underlies arrhythmia and contractile dysfunction. Perspectives on model differences and future directions are provided throughout.

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“…The contribution of the t-tubules to cardiac cell function is crucially dependent on their characteristics, both structural and functional ( Orchard et al, 2009 ; Pásek et al, 2012 ; Hrabcová et al, 2013 ; Hong and Shaw 2017 ; Smith et al, 2018 ). The t-tubular network is extremely dynamic and its remodelling, i.e., disruption or even loss of the t-tubules, has been demonstrated in a variety of cardiac diseases including ischemia, heart failure, and hypertension (e.g., Louch et al,2004 ; Heinzel et al, 2008 ; Dibb et al, 2009 ; Ibrahim et al, 2011 ; Crossman et al, 2011 ; Wagner et al, 2012 ; Guo et al, 2013 ; Bryant et al, 2015 ; Crossman et al, 2017 ; Dibb et al, 2021 ). These changes in the t-tubules considerably affect the electrical and mechanical function of cardiomyocytes and contribute to further progression of the cardiac pathology.…”

Section: Introductionmentioning

confidence: 99%

Fraction of the T-Tubular Membrane as an Important Parameter in Cardiac Cellular Electrophysiology: A New Way of Estimation

et al. 2022

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The transverse-axial tubular system (t-tubules) plays an essential role in excitation-contraction coupling in cardiomyocytes. Its remodelling is associated with various cardiac diseases. Numerous attempts were made to analyse characteristics essential for proper understanding of the t-tubules and their impact on cardiac cell function in health and disease. The currently available methodical approaches related to the fraction of the t-tubular membrane area produce diverse data. The widely used detubulation techniques cause irreversible cell impairment, thus, distinct cell samples have to be used for estimation of t-tubular parameters in untreated and detubulated cells. Our proposed alternative method is reversible and allows repetitive estimation of the fraction of t-tubular membrane (ft) in cardiomyocytes using short-term perfusion of the measured cell with a low-conductive isotonic sucrose solution. It results in a substantial increase in the electrical resistance of t-tubular lumen, thus, electrically separating the surface and t-tubular membranes. Using the whole-cell patch-clamp measurement and the new approach in enzymatically isolated rat atrial and ventricular myocytes, a set of data was measured and evaluated. The analysis of the electrical equivalent circuit resulted in the establishment of criteria for excluding measurements in which perfusion with a low conductivity solution did not affect the entire cell surface. As expected, the final average ft in ventricular myocytes (0.337 ± 0.017) was significantly higher than that in atrial myocytes (0.144 ± 0.015). The parameter ft could be estimated repetitively in a particular cell (0.345 ± 0.021 and 0.347 ± 0.023 in ventricular myocytes during the first and second sucrose perfusion, respectively). The new method is fast, simple, and leaves the measured cell intact. It can be applied in the course of experiments for which it is useful to estimate both the surface and t-tubular capacitance/area in a particular cell.

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Cardiac Transverse Tubules in Physiology and Heart Failure

Cited by 20 publications

References 161 publications

Biological noise is a key determinant of the reproducibility and adaptability of cardiac pacemaking and EC coupling

Biological noise is a key determinant of the reproducibility and adaptability of cardiac pacemaking and EC coupling

Multi-Scale Computational Modeling of Spatial Calcium Handling From Nanodomain to Whole-Heart: Overview and Perspectives

Fraction of the T-Tubular Membrane as an Important Parameter in Cardiac Cellular Electrophysiology: A New Way of Estimation

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