Regulation of Cardiomyocyte T-Tubular Structure: Opportunities for Therapy

Abstract

Purpose of review: Membrane invaginations called t-tubules play an integral role in triggering cardiomyocyte contraction, and their disruption during diseases such as heart failure critically impairs cardiac performance. In this review, we outline the growing understanding of the malleability of t-tubule structure and function, and highlight emerging t-tubule regulators which may be exploited for novel therapies.

Recent findings: New technologies are revealing the nanometer scale organization of t-tubules, and their functional junctions with the sarcoplasmic reticulum called dyads, which generate Ca²⁺ sparks. Recent data have indicated that the dyadic anchoring protein junctophilin-2, and the membrane-bending protein BIN1 are key regulators of dyadic formation and maintenance. While the underlying signals which control expression and localization of these proteins remain unclear, accumulating data support an important role of myocardial workload. Although t-tubule alterations are believed to be a key cause of heart failure, the plasticity of these structures also creates an opportunity for therapy. Promising recent data suggest that such therapies may specifically target junctophilin-2, BIN1, and/or mechanotransduction.

Keywords: Bridging integrator-1; Calcium homeostasis; Cardiomyocytes; Heart failure; Junctophilin-2; T-tubules.

Fig. 1

T-tubule organization in ventricular and atrial cardiac myocytes. a Confocal images of the t-tubule network in tissue sections from human ventricle (top left, unpublished) and rat ventricle (top right, modified from [3]), labeled with wheat germ agglutinin (WGA) and lipophilic membrane indicator FM4-64, respectively. Three-dimensional reconstructions of single cardiomyocytes from human and rat ventricle are shown in the lower panels (WGA labeling, human cell unpublished, rat cell reproduced from [4]) b Confocal images of the t-tubule network in tissue sections from human and pig atria (upper panels, WGA labeling; [4, 5]), and isolated rat atrial myocytes (lower panel, di-8-ANEPPS staining; [4]). Variable t-tubule organization was observed across the atria in all three species. Images from [–5], reproduced with permissions

Fig. 2

T-tubule structure in normal and failing cardiac myocytes. a In healthy cardiomyocytes, L-type Ca²⁺ channels in the t-tubules are apposed from ryanodine receptors (RyRs) in the sarcoplasmic reticulum (SR). Excitation-contraction coupling occurs at these dyadic junctions, which are maintained by Junctophilin-2 (JPH2) and BIN1, and dynamically regulated by workload. b Elevated workload during heart failure has been linked to downregulation of JPH2 and BIN1, and disorganization/loss of t-tubules. Such remodeling results in the formation of orphaned RyRs, which are uncoupled from Ca²⁺channels, reduced efficiency of Ca²⁺-induced Ca²⁺release, and impaired contractility in this condition. Novel opportunities for cellular-level heart failure therapies include mitigation of workload/mechanotransduction and strategies for elevating JPH2 and BIN1 expression

Fig. 3

Structural and functional alterations in t-tubules during heart failure. a–c Confocal images of t-tubular structure (di-8-ANEPPS staining) in healthy and diseased ventricular cardiomyocytes. The well-organized t-tubule network observed in myocytes from wild-type and sham-operated hearts is lost and disorganized during heart failure resulting from myocardial infarction, hypertension, and diabetes. This structural remodeling results in de-synchronized Ca²⁺ release across the cell, as indicated by confocal line-scan images. Images are modified from a: [38]; b: [39]; c: [62]. d Elevated ventricular wall stress leads to t-tubule disruption. In the post-infarction failing rat heart, high wall stress proximal to the infarct is associated with regional reduction of JPH2 expression, t-tubule loss and dyssynchrony of Ca² release (modified from [•]). All images reproduced with permission. [39] Copyright (2006) National Academy of Sciences