The Physiology and Pathophysiology of T-Tubules in the Heart

Abstract

In cardiomyocytes, invaginations of the sarcolemmal membrane called t-tubules are critically important for triggering contraction by excitation-contraction (EC) coupling. These structures form functional junctions with the sarcoplasmic reticulum (SR), and thereby enable close contact between L-type Ca2+ channels (LTCCs) and Ryanodine Receptors (RyRs). This arrangement in turn ensures efficient triggering of Ca2+ release, and contraction. While new data indicate that t-tubules are capable of exhibiting compensatory remodeling, they are also widely reported to be structurally and functionally compromised during disease, resulting in disrupted Ca2+ homeostasis, impaired systolic and/or diastolic function, and arrhythmogenesis. This review summarizes these findings, while highlighting an emerging appreciation of the distinct roles of t-tubules in the pathophysiology of heart failure with reduced and preserved ejection fraction (HFrEF and HFpEF). In this context, we review current understanding of the processes underlying t-tubule growth, maintenance, and degradation, underscoring the involvement of a variety of regulatory proteins, including junctophilin-2 (JPH2), amphiphysin-2 (BIN1), caveolin-3 (Cav3), and newer candidate proteins. Upstream regulation of t-tubule structure/function by cardiac workload and specifically ventricular wall stress is also discussed, alongside perspectives for novel strategies which may therapeutically target these mechanisms.

A Stochastic Spatiotemporal Model of Rat Ventricular Myocyte Calcium Dynamics Demonstrated Necessary Features for Calcium Wave Propagation

“…The T-tubule structure is complex with recent studies showing it varies for different myocytes in the heart [110]. Atrial myocytes have a lower T-tubule density than ventricular myocytes [111].…”

From Millimeters to Micrometers; Re-introducing Myocytes in Models of Cardiac Electrophysiology

“…In particular, we believe the EMI model can yield important new insights into mechanism of action of cardiac drugs, how early after depolarizations (EADs) and delayed after depolarizations (DADs) are generated in collections of myocytes, how deterioration of gap-junction coupling can modulate cardiac conduction, how reentry can be generated in very small collections of myocytes, and whether ephaptic coupling can maintain conduction in diseased tissue. Furthermore, we believe that a more complete understanding of the role of T-tubules in ventricular myocytes can be achieved if the EMI model is applied along with improved spatial modeling of ionic concentration changes in the associated restricted extracellular spaces (see Ellingsrud et al, 2020 ; Setterberg et al, 2021 ).…”

Nanoscale Organization, Regulation, and Dynamic Reorganization of Cardiac Calcium Channels

“…Dyads are predominantly found at interfaces between the jSR and the t-tubule membrane, but there are a significant number of functional dyads on the axial/longitudinal tubule interfaces and at the sarcolemmal crest interface ( Asghari et al, 2009 ). It should be noted that despite the continued use of t-tubules as the standard nomenclature for the non-surface, tubular network of sarcolemma, a convention we maintain herein, around 40% of the network is not transverse at all but rather lies longitudinally or axially along the length of the cell between the z-lines in rat ventricular myocytes ( Soeller and Cannell, 1999 ), although the proportion of longitudinally-orientated tubules varies between species ( Setterberg et al, 2021 ).…”

“…The effects of HF and myocardial infarction (MI) on the t-tubule network, dyad integrity, and SR positioning has been previously ( Guo et al, 2013 ) and very recently reviewed ( Setterberg et al, 2021 ). We refer the reader there for a detailed discussion of the architectural changes in myocytes during cardiac pathologies.…”