The Physiology and Pathophysiology of T-Tubules in the Heart

Figures

• 

  FIGURE 1. T-tubule structure and key proteins involved in excitation-contraction (EC) coupling in the cardiomyocyte. A schematic overview of the t-tubule network is provided in the upper panel, while an enlargement of the indicated region is provided below to illustrate positioning of EC coupling proteins. EC coupling is initiated as Na+ channels are opened, and the cell membrane depolarizes during the action potential. This depolarization triggers the opening of voltage-gated L-type Ca2+-channels (LTCCs) in the t-tubules, and subsequent Ca2+-induced Ca2+ release from the SR through the opening of Ryanodine Receptors (RyRs). This process occurs at specialized junctions called dyads, where LTCCs and RyRs are in close proximity. After released Ca2+ binds to the myofilaments to trigger contraction, Ca2+ is recycled into the SR by the sarco-endoplasmic reticulum ATPase (SERCA), and removed from the cell by the Na+-Ca2+ exchanger (NCX) and the plasma-membrane Ca2+ ATPase. NCX activity is critically regulated by Na+ levels, set by the Na+ channel and the Na+-K+ ATPase within t-tubules. Created with BioRender.com.

• 

  FIGURE 2. Changes in cardiomyocyte surface topography and dyadic organization in the developing and HFrEF rat heart. (A) Left panels: Scanning electron micrographs show the appearance of Z-spines (arrowheads) from an early time point during development and their re-appearance during post-infarction HFrEF. Z-grooves (dashed lines) and t-tubule openings (arrows) appear gradually during development and are lost in HFrEF. Right panels: temporally matched confocal captures of internal t-tubules (di-8-ANEPPS staining). (B) Quantification of these t-tubule signals illustrates an organizational shift from a predominantly longitudinal to largely transverse orientation during maturation, but reversion to an immature phenotype during HFrEF. (C) Structural parallels between developing and failing myocytes include not only t-tubule structure, but also similarly sparse arrangements of RyRs that exhibit low co-localization with LTCCs. d.o., days old. *P < 0.05 vs. adult in same category, †P < 0.05 vs. SHAM in same category. Reproduced from Lipsett et al. (2019) with permission.

• 

  FIGURE 3. Alterations in cardiomyocyte t-tubule structure and Ca2+ release in different HF entities. (A) Left panels: 3D reconstructions and 2D zoom-ins of t-tubules imaged in human cardiac biopsies (wheat germ agglutinin staining). Healthy individuals are compared with HFpEF patients, with and without diabetes mellitus, and HFrEF patients. As illustrated in the schematics (right panels), t-tubule density is unchanged in diabetic HFpEF, increased in non-diabetic HFpEF, and decreased in HFrEF. In all HF entities, t-tubules dilate. However, whereas t-tubule remodeling is accompanied by increased NCX and SERCA function in non-diabetic HFpEF, Ca2+ removal by these proteins is decreased in diabetic HFpEF and HFrEF. (B) T-tubule disruption promotes dyssynchronous and slowed Ca2+ release in rats with HFrEF but not HFpEF, while slowed Ca2+ removal promotes diastolic dysfunction in diabetic HFpEF and HFrEF. For each disease state, representative Ca2+ transients (right panels) are presented with comparison to a control cardiomyocyte (green) for the individual rat models. Micrographs and Ca2+ transients are reproduced from Frisk et al. (2021) with permission.

• 

  FIGURE 4. Key regulators of t-tubule structure during development, adulthood, and heart failure of various etiologies. HFpEF, heart failure with preserved ejection fraction; HFrEF, heart failure with reduced ejection fraction; Dnm2, dynamin-2; Mtm1, myotubularin-1; JPH2, junctophilin-2; Cav3, caveolin-3.

• 

  FIGURE 5. Proposed proteins and pathways involved in dyadic biogenesis, maintenance, and disruption. Created with BioRender.com.