The structure and function of cardiac t-tubules in health and disease

Abstract

The transverse tubules (t-tubules) are invaginations of the cell membrane rich in several ion channels and other proteins devoted to the critical task of excitation-contraction coupling in cardiac muscle cells (cardiomyocytes). They are thought to promote the synchronous activation of the whole depth of the cell despite the fact that the signal to contract is relayed across the external membrane. However, recent work has shown that t-tubule structure and function are complex and tightly regulated in healthy cardiomyocytes. In this review, we outline the rapidly accumulating knowledge of its novel roles and discuss the emerging evidence of t-tubule dysfunction in cardiac disease, especially heart failure. Controversy surrounds the t-tubules' regulatory elements, and we draw attention to work that is defining these elements from the genetic and the physiological levels. More generally, this field illustrates the challenges in the dissection of the complex relationship between cellular structure and function.

Figure 1.

Two-photon imaging of the t-tubule network in rat ventricular cardiomyocytes. From Soeller & Cannell [1]. Scale bar = 5 µm.

Figure 2.

The dyad and Ca²⁺-induced Ca²⁺ release (CICR). LTCCs (red) closely associate with the RyR2 (green).

Figure 3.

Ca²⁺ channels are concentrated at the t-tubule. (a) Variation of the density of chloride and LTCCs at different positions on the cell surface. (b) Functional schematic of the sarcomeric unit showing clustering and co-localization of chloride and Ca²⁺ channels on the cell surface [29].

Figure 4.

Beta-adrenergic receptor distribution is altered in heart failure. (a) Normally, β₂-adrenoceptors (ARs) are concentrated in the t-tubules, whereas β₁-ARs are spread across both membrane fractions. (b) In heart failure, t-tubule abnormalities are associated with a reversal of the normal β₂-AR distribution. Scanning ion conductance microscopy (SICM) images from Nikolaev et al. [40].^.

Figure 5.

Heart failure, regardless of the aetiology, disrupts the t-tubule network. SICM images from the surface of cardiomyocytes from (a) non-failing and (b) failing human hearts. The black line is a one-dimensional surface map from (c) non-failing and (e) failing human cardiomyocytes. Confocal images after staining with di-8-ANNEPPS in (d) non-failing and (f) failing cardiomyocytes. (g) T-tubule and (h) Z-groove ratios in cardiomyocytes isolated from patients with DCM (dilated cardiomyopathy), HF secondary to ischaemic heart disease (IHD) or HOCM. NF, non-failing. (i) Prolonged TTP and relaxation times (R50 and R90) in human failing cardiomyocytes (black bars, n = 12) compared with non-failing human cardiomyocytes (white bars, n = 6). **p < 0.01 versus non-failing. From Lyon et al. [73].

Figure 6.

Mechanical load alters t-tubule structure. Both mechanical overload and unloading impair CICR and alter t-tubule structure. We have shown that t-tubular abnormalities in heart failure are reversible by mechanical unloading [85]. We propose that the t-tubule system is sensitive to the degree of chronic load, and that normal t-tubule structure depends on normal myocardial load.