Regulation of Cardiomyocyte T-Tubular Structure: Opportunities for Therapy

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 a Confocal images of the t-tubule network in tissue sections from human ventricle (top left, unpublished) and rat ventricle (top right, modified from [3]), labeled with wheat germ agglutinin (WGA) and lipophilic membrane indicator FM4-64, respectively.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of single cardiomyocytes from human and rat ventricle are shown in the lower panels (WGA labeling, human cell unpublished, rat cell reproduced from [4]) b Confocal images of the t-tubule network in tissue sections from human and pig atria (upper panels, WGA labeling; [4, 5]), and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 [3–5], 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 [63•]). All images reproduced with permission. [39] Copyright (2006) National Academy of Sciences