Cardiac T-Tubule Microanatomy and Function

Abstract

Unique to striated muscle cells, transverse tubules (t-tubules) are membrane organelles that consist of sarcolemma penetrating into the myocyte interior, forming a highly branched and interconnected network. Mature t-tubule networks are found in mammalian ventricular cardiomyocytes, with the transverse components of t-tubules occurring near sarcomeric z-discs. Cardiac t-tubules contain membrane microdomains enriched with ion channels and signaling molecules. The microdomains serve as key signaling hubs in regulation of cardiomyocyte function. Dyad microdomains formed at the junctional contact between t-tubule membrane and neighboring sarcoplasmic reticulum are critical in calcium signaling and excitation-contraction coupling necessary for beat-to-beat heart contraction. In this review, we provide an overview of the current knowledge in gross morphology and structure, membrane and protein composition, and function of the cardiac t-tubule network. We also review in detail current knowledge on the formation of functional membrane subdomains within t-tubules, with a particular focus on the cardiac dyad microdomain. Lastly, we discuss the dynamic nature of t-tubules including membrane turnover, trafficking of transmembrane proteins, and the life cycles of membrane subdomains such as the cardiac BIN1-microdomain, as well as t-tubule remodeling and alteration in diseased hearts. Understanding cardiac t-tubule biology in normal and failing hearts is providing novel diagnostic and therapeutic opportunities to better treat patients with failing hearts.

Plasma cBIN1 Score (CS) Identifies HFrEF and Can Predict Cardiac Hospitalization in Stable Ambulatory Patients

“…There is currently no invasive or noninvasive tool that measures intrinsic cardiomyocyte health. cBIN1 is an integral protein in cardiomyocyte t-tubule biology [20,21] and beat-to-beat calcium transients [29][30][31]. Previously, our group found that BIN1 is transcriptionally decreased in HF and is also detectable in blood [22,23].…”

“…A generic BIN1 ELISA measured plasma BIN1 levels correlated with cardiac health in patients with arrhythmogenic right ventricular cardiomyopathy [23]. More recently, we cloned the cardiac specific t-tubule isoform cBIN1 [20], which is enclosed in microparticles and released into blood [23,24,31]. In the present study, we introduce CS, which is derived from the inverse of plasma cBIN1 concentration measured by a specific ELISA.…”

Plasma cBIN1 Score (CS) Identifies HFpEF and Can Predict Cardiac Hospitalization in Stable Ambulatory Patients

“…T-tubule remodeling and the resultant abnormal calcium transients are central to the pathophysiology of HF [13,17,[37][38][39][40][41][42][43][44][45]. Our groups and others have identified that t-tubule remodeling can be a consequence of reduced cBIN1 [9,10].…”

“…cBIN1 is a ventricular cardiomyocyte t-tubule membrane scaffolding protein, which organizes membrane microdomains that regulate calcium transients and its levels are decreased in failing cardiomyocytes [13,18]. A known pathophysiological hallmark of HF is the development of LV hypertrophy [15,24,25].…”

“…In this single-center study, we explore a novel biomarker of myocardial health, the cardiac isoform of bridging integrator 1 (cBIN1). cBIN1 is a t-tubule membrane scaffolding protein in cardiomyocytes, which organizes the cardiac dyad-containing microdomains responsible for the initiation and regulation of myocardial calcium transients [9][10][11][12][13]. Loss of regulation in calcium signaling is a well described phenomenon in HF [14][15][16].…”