Abstract
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 excitation–contraction 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.
Highlights
Transverse (T-)tubules are deep invaginations of the lateral membrane of skeletal and cardiac muscle cells
T-tubules form a complex network throughout the cell, especially in species with high heart rates such as mice (Pinali et al, 2013; Jayasinghe et al, 2015), and carry many ion channels and regulatory proteins [reviewed in Bers (2002), Hong and Shaw (2017), and Bhogal et al (2018)]
When we consider an electrophysiological experiment in which a cardiomyocyte is voltage-clamped, a voltage step at the pipette site will first induce a capacitive current into the cell membrane, which will cause depolarization (Figure 1)
Summary
Transverse (T-)tubules are deep invaginations of the lateral membrane of skeletal and cardiac muscle cells. T-tubules form a complex network throughout the cell, especially in species with high heart rates such as mice (Pinali et al, 2013; Jayasinghe et al, 2015), and carry many ion channels and regulatory proteins [reviewed in Bers (2002), Hong and Shaw (2017), and Bhogal et al (2018)]. Understanding the electrical properties of T-tubules in health and disease is paramount to understanding cardiac physiology and pathophysiology. Several questions regarding the electrical properties of T-tubules remain largely open (Vermij et al, 2019)
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