Serial block face scanning electron microscopy reveals region-dependent remodelling of transverse tubules post-myocardial infarction

Abstract

The highly organized transverse tubule (t-tubule) network facilitates cardiac excitation–contraction coupling and synchronous cardiac myocyte contraction. In cardiac failure secondary to myocardial infarction (MI), changes in the structure and organization of t-tubules result in impaired cardiac contractility. However, there is still little knowledge on the regional variation of t-tubule remodelling in cardiac failure post-MI. Here, we investigate post-MI t-tubule remodelling in infarct border and remote regions, using serial block face scanning electron microscopy (SBF-SEM) applied to a translationally relevant sheep ischaemia reperfusion MI model and matched controls. We performed minimally invasive coronary angioplasty of the left anterior descending artery, followed by reperfusion after 90 min to establish the MI model. Left ventricular tissues obtained from control and MI hearts eight weeks post-MI were imaged using SBF-SEM. Image analysis generated three-dimensional reconstructions of the t-tubular network in control, MI border and remote regions. Quantitative analysis revealed that the MI border region was characterized by t-tubule depletion and fragmentation, dilation of surviving t-tubules and t-tubule elongation. This study highlights region-dependent remodelling of the tubular network post-MI and may provide novel localized therapeutic targets aimed at preservation or restoration of the t-tubules to manage cardiac contractility post-MI. This article is part of the theme issue ‘The cardiomyocyte: new revelations on the interplay between architecture and function in growth, health, and disease’.

Volume overload impedes the maturation of sarcomeres and T-tubules in the right atria: a potential cause of atrial arrhythmia following delayed atrial septal defect closure

“…T-tubules are characteristic markers that distinguish mature from immature cardiomyocytes. They are formed by the invagination of the myocardial cell membrane and serve as the structural basis for the coupling of excitation and contraction of cardiomyocytes ( Perera et al, 2022 ; Tarasov et al, 2023 ). We then determined whether VO affected the T-tubule maturation of RA cardiomyocytes.…”

“…During the postnatal cardiac developmental process, cardiomyocytes undergo a maturation transformation to meet the physiological needs of the systemic circulation, which mainly includes the following: 1) sarcomere maturation, in which the sarcomere components change from MYH7 to MYH6, from TNNI1 to TNNI3, and from a disordered and irregular sarcomere arrangement to a rod-like and ordered sarcomere arrangement ( Schiaffino et al, 1993 ; Opitz et al, 2004 ; Bray et al, 2008 ); 2) electrophysiological maturation, in which the transverse tubules (T-tubules) gradually increase in density and integrity, with an increased calcium-handling ability ( Perera et al, 2022 ; Smith et al, 2022 ; Zhang et al, 2022 ; Tarasov et al, 2023 ). Cardiomyocyte maturation failure may lead to a range of clinical symptoms, including arrhythmias and heart failure ( Campostrini et al, 2021 ; Funakoshi et al, 2021 ; Dimasi et al, 2023 ; Lou et al, 2023 ).…”

Correlative super-resolution analysis of cardiac calcium sparks and their molecular origins in health and disease

“…Increasing structural heterogeneity, including local t-tubule remodelling [45][46][47], local regions of RyR2 fragmentation [17,38,48] and diminishing regularity of the expression patterns Ca 2+ handling proteins over nanometre/micron length-scales [49], are now understood to be hallmarks of wide-ranging cardiac pathologies. In MCT-RV, we have previously observed evidence of heterogeneous RyR2 cluster fragmentation [31] and the receding sub-domains of RyR2modulators and molecular tethers, junctophilin-2 (JPH2) [32] and BIN-1 from some clusters [18].…”

Correlative super-resolution analysis of cardiac calcium sparks and their molecular origins in health and disease

“…Increasing structural heterogeneity, including local t-tubule remodelling [45][46][47] , local regions of RyR fragmentation 17,38,48 , diminishing regularity of the expression patterns Ca 2+ handling proteins over nanometre/micron length-scales 49 , is now understood to be a hallmark of wide-ranging cardiac pathologies. In MCT-RV, we have previously observed evidence of heterogeneous RyR cluster fragmentation 31 and the receding subdomains of RyR-modulators and molecular tethers, junctophilin-2 (JPH2) 32 and BIN-1 from some clusters 18 .…”