Electrical defects of the transverse‐axial tubular system in cardiac diseases

Crocini, Claudia; Ferrantini, Cecilia; Coppini, Raffaele; Sacconi, Leonardo

doi:10.1113/jp273042

Cited by 13 publications

(10 citation statements)

References 59 publications

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“…Finally, in view of the formal analogy that exists between diffusion and electrical conduction, the apparent diffusion coefficient is linked to the effective electrical conductivity of the network. The methodology is first validated using an acutely detubulated cellular model (8,9) and then applied to assessing the effective electrical conductivity in diseased cardiomyocytes where structural (10) and functional (11)(12)(13)(14)(15) defects of the TATS have been described.…”

Section: Significancementioning

confidence: 99%

Quantitative assessment of passive electrical properties of the cardiac T-tubular system by FRAP microscopy

Scardigli

Crocini

Ferrantini

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

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Well-coordinated activation of all cardiomyocytes must occur on every heartbeat. At the cell level, a complex network of sarcolemmal invaginations, called the transverse-axial tubular system (TATS), propagates membrane potential changes to the cell core, ensuring synchronous and uniform excitation-contraction coupling. Although myocardial conduction of excitation has been widely described, the electrical properties of the TATS remain mostly unknown. Here, we exploit the formal analogy between diffusion and electrical conductivity to link the latter with the diffusional properties of TATS. Fluorescence recovery after photobleaching (FRAP) microscopy is used to probe the diffusion properties of TATS in isolated rat cardiomyocytes: A fluorescent dextran inside TATS lumen is photobleached, and signal recovery by diffusion of unbleached dextran from the extracellular space is monitored. We designed a mathematical model to correlate the time constant of fluorescence recovery with the apparent diffusion coefficient of the fluorescent molecules. Then, apparent diffusion is linked to electrical conductivity and used to evaluate the efficiency of the passive spread of membrane depolarization along TATS. The method is first validated in cells where most TATS elements are acutely detached by osmotic shock and then applied to probe TATS electrical conductivity in failing heart cells. We find that acute and pathological tubular remodeling significantly affect TATS electrical conductivity. This may explain the occurrence of defects in action potential propagation at the level of single T-tubules, recently observed in diseased cardiomyocytes.cardiac disease | transverse-axial tubular system | diffusion | electrical conductivity | porous rock T he sequential and coherent recruitment of all cardiomyocytes that occurs on every heartbeat is fundamental for proper contraction of the heart. Every heartbeat is triggered by a depolarizing event, the action potential (AP), spontaneously generated in cardiac pacemaker cells, which propagates through the conductive tissue and the working myocardium. The well-coordinated activation of all cardiomyocytes involves a spreading AP wave, conducted from cell to cell throughout the lattice of interconnections called gap junctions. The 3D electrical network of cardiomyocytes includes a finer order of complexity that involves a system of deep sarcolemmal membrane invaginations within each cell. As a network within a network, these sarcolemmal invaginations occur transversely with a periodicity roughly corresponding to that of sarcomere z-lines (transverse tubules, or T-tubules) and branch in the longitudinal direction (axial tubules) to form a complex system in atrial and ventricular cells, named the transverse-axial tubular system (TATS) (1, 2). The TATS allows membrane potential changes to propagate rapidly into the cardiomyocyte core and is considered an ultimate structural player for excitation-contraction coupling. During rapid depolarization, such as seen during the AP, Ca 2+ enters the cytos...

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Section: Significancementioning

confidence: 99%

Quantitative assessment of passive electrical properties of the cardiac T-tubular system by FRAP microscopy

Scardigli

Crocini

Ferrantini

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

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“…Consequently, T-tubules function as a platform for excitation-contraction coupling and signaling, which is essential for the initiation and regulation of muscle contraction (Hong and Shaw, 2017). Importantly, T-tubular remodeling has been reported for several cardiac diseases (Crocini et al, 2017;Crossman et al, 2017a). In particular, T-tubules widen (Wagner et al, 2012;Pinali et al, 2017;Seidel et al, 2017).…”

Section: Introductionmentioning

confidence: 99%

Modeling Depolarization Delay, Sodium Currents, and Electrical Potentials in Cardiac Transverse Tubules

2019

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T-tubules are invaginations of the lateral membrane of striated muscle cells that provide a large surface for ion channels and signaling proteins, thereby supporting excitationcontraction coupling. T-tubules are often remodeled in heart failure. To better understand the electrical behavior of T-tubules of cardiac cells in health and disease, this study addresses two largely unanswered questions regarding their electrical properties: (1) the delay of T-tubular membrane depolarization and (2) the effects of T-tubular sodium current on T-tubular potentials. Here, we present an elementary computational model to determine the delay in depolarization of deep T-tubular membrane segments as the narrow T-tubular lumen provides resistance against the extracellular current. We compare healthy tubules to tubules with constrictions and diseased tubules from mouse and human, and conclude that constrictions greatly delay T-tubular depolarization, while diseased T-tubules depolarize faster than healthy ones due to tubule widening. Increasing the tubule length non-linearly delays the depolarization. We moreover model the effect of T-tubular sodium current on intraluminal T-tubular potentials. We observe that extracellular potentials become negative during the sodium current transient (up to −40 mV in constricted T-tubules), which feedbacks on sodium channel function (self-attenuation) in a manner resembling ephaptic effects that have been described for intercalated discs where opposing membranes are very close together. The intraluminal potential and sodium current self-attenuation however greatly depend on sodium current conductance. These results show that (1) the changes in passive electrical properties of remodeled T-tubules cannot explain the excitation-contraction coupling defects in diseased cells; and (2) the sodium current may modulate intraluminal potentials. Such extracellular potentials might also affect excitation-contraction coupling and macroscopic conduction.

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“…Passive responses are only limited by the voltage drop of the current flowing from the surface sarcolemma along the t‐tubule with a characteristic space constant (Crocini et al . ). The space constant of t‐tubules has been determined theoretically and experimentally to be of the order of 200 μm (Pásek et al .…”

mentioning

confidence: 97%

“…A local drop in voltage could instead be explained by ultrastructural alterations that increase the resistivity of t‐tubules (Crocini et al . ; Scardigli et al . ; Uchida & Lopatin, ) and could represent an additional pathological feature of HF cardiomyocytes.…”

mentioning

confidence: 99%