Transverse tubule remodelling: a cellular pathology driven by both sides of the plasmalemma?

Crossman, DC; Jayasinghe, Izzy; Soeller, Christian

doi:10.1007/s12551-017-0273-7

Cited by 14 publications

(10 citation statements)

References 112 publications

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“…A stream of evidence from human [1][2][3][4] and animal [5][6][7][8][9] studies has led to the prevailing recognition that the disorganization of the network of the transverse tubules (t-tubules) is a major contributor to many forms of heart failure. [10][11][12] In healthy myocardium, t-tubules are a highly organized network of invaginations of the cell surface membrane. They harbour ion channels, transporters and ATPases essential to the cellular excitation-contraction coupling process.…”

Section: Introductionmentioning

confidence: 99%

“…Such pathological remodelling of the t-tubular network, including the reduction in density or loss of t-tubules, is closely associated with defective excitation-contraction coupling in heart failure. [10][11][12] It is recognized that t-tubular remodelling establishes prior to the onset of heart failure, early in the disease progression, and represents one of the causal events that drives the transition from compensated hypertrophy to heart failure. [14][15][16] The contribution of t-tubular remodelling to heart failure is boosted by evidence from experiments where the t-tubules are artificially, and acutely, disrupted.…”

Section: Introductionmentioning

confidence: 99%

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Disruption of transverse‐tubular network reduces energy efficiency in cardiac muscle contraction

et al. 2020

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Aim Altered organization of the transverse‐tubular network is an early pathological event occurring even prior to the onset of heart failure. Such t‐tubular remodelling disturbs the synchrony and signalling between membranous and intracellular ion channels, exchangers, receptors and ATPases essential in the dynamics of excitation‐contraction coupling, leading to ionic abnormality and mechanical dysfunction in heart disease progression. In this study, we investigated whether a disrupted t‐tubular network has a direct effect on cardiac mechano‐energetics. Our aim was to understand the fundamental link between t‐tubular remodelling and impaired energy metabolism, both of which are characteristics of heart failure. We thus studied healthy tissue preparations in which cellular processes are not altered by any disease event. Methods We exploited the “formamide‐detubulation” technique to acutely disrupt the t‐tubular network in rat left‐ventricular trabeculae. We assessed the energy utilization by cellular Ca2+ cycling and by crossbridge cycling, and quantified the change of energy efficiency following detubulation. For these measurements, trabeculae were mounted in a microcalorimeter where force and heat output were simultaneously measured. Results Following structural disorganization from detubulation, muscle heat output associated with Ca2+ cycling was reduced, indicating impaired intracellular Ca2+ homeostasis. This led to reduced force production and heat output by crossbridge cycling. The reduction in force‐length work was not paralleled by proportionate reduction in the heat output and, as such, energy efficiency was reduced. Conclusions These results reveal the direct energetic consequences of disrupted t‐tubular network, linking the energy disturbance and the t‐tubular remodelling typically observed in heart failure.

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Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Disruption of transverse‐tubular network reduces energy efficiency in cardiac muscle contraction

et al. 2020

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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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“…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 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%

Modelling depolarization delay, sodium currents, and electrical potentials in cardiac transverse tubules

Vermij

Abriel

Kučera

2019

Preprint

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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 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, and diseased T-tubules depolarize faster than healthy ones due to tubule widening. 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 -50 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.These results show that (1) the excitation-contraction coupling defects seen in diseased cells cannot be explained by T-tubular remodeling alone; and (2) the sodium current may modulate intraluminal potentials. Such extracellular potentials might also affect excitation-contraction coupling.

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Transverse tubule remodelling: a cellular pathology driven by both sides of the plasmalemma?

Cited by 14 publications

References 112 publications

Disruption of transverse‐tubular network reduces energy efficiency in cardiac muscle contraction

Disruption of transverse‐tubular network reduces energy efficiency in cardiac muscle contraction

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

Modelling depolarization delay, sodium currents, and electrical potentials in cardiac transverse tubules

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