Ontogeny of cardiomyocytes: ultrastructure optimization to meet the demand for tight communication in excitation-contraction coupling and energy transfer

Abstract

The ontogeny of the heart describes its development from the fetal to the adult stage. In newborn mammals, blood pressure and thus cardiac performance are relatively low. The cardiomyocytes are thin, and with a central core of mitochondria surrounded by a ring of myofilaments, while the sarcoplasmic reticulum (SR) is sparse. During development, as blood pressure and performance increase, the cardiomyocytes become more packed with structures involved in excitation-contraction (e-c) coupling (SR and myofilaments) and the generation of ATP (mitochondria) to fuel the contraction. In parallel, the e-c coupling relies increasingly on calcium fluxes through the SR, while metabolism relies increasingly on fatty acid oxidation. The development of transverse tubules and SR brings channels and transporters interacting via calcium closer to each other and is crucial for e-c coupling. However, for energy transfer, it may seem counterintuitive that the increased structural density restricts the overall ATP/ADP diffusion. In this review, we discuss how this is because of the organization of all these structures forming modules. Although the overall diffusion across modules is more restricted, the energy transfer within modules is fast. A few studies suggest that in failing hearts this modular design is disrupted, and this may compromise intracellular energy transfer. This article is part of the theme issue 'The cardiomyocyte: new revelations on the interplay between architecture and function in growth, health, and disease'.

Keywords: cardiomyocytes; energy transfer; excitation–contraction coupling; heart; intracellular diffusion; ontogeny.

Figure 1.

Schematic of (a) fish cardiomyocyte, (b) neonatal mammalian cardiomyocyte, and (c) adult mammalian cardiomyocyte drawn on the basis of the references in table 1. The sarcolemma is shown in green, the myofilaments in grey, the SR in blue, and mitochondria in red. Neonatal mammalian and fish cardiomyocytes have a smooth sarcolemma, which is shown on the top and bottom, because their diameter is relatively small. The myofilaments are situated peripherally, as a ring surrounding the central core of mitochondria. The SR is more irregular in fish cardiomyocytes, where it has no specific relation to the myofibrillar bands, whereas in neonatal cardiomyocytes, the SR is peripheral with the periodicity corresponding to the z-lines and m-band. Adult mammalian cardiomyocytes are thicker and with more internal membrane structures. The sarcolemma invaginates to form transverse tubules (t-tubules). It is only shown on the top side of the figure, because the cell is four to five times wider than fish and neonatal cardiomyocytes. There are multiple, parallel, interchanging rows of myofilaments and mitochondria. The SR wraps around t-tubules, myofilaments and mitochondria.

Figure 2.

Organization of mitochondria and t-tubules in adult rat cardiomyocytes. (a) Overall confocal image of a live cardiomyocyte. Mitochondria (red) were labelled for 10 min with 250 nM MitoTracker® Deep Red FM (ThermoFisher). The sarcolemma (green), including t-tubules, was labelled with 500 nM CellMask™ Orange (ThermoFisher). (b–d) Zoom of the white rectangle in panel (a), showing the t-tubules (b), the mitochondria (c) and the merged image (d). Note the regular pattern of mitochondria, the highly organized network of t-tubules, and how densely these structures are packed.

Figure 3.

Schematic illustration of a section of an adult mammalian cardiomyocyte. On the left, the cell is shown in full width, but not full length, with sarcolemma (green) on the top and bottom invaginating to form t-tubules. The many parallel rows of mitochondria (red) and myofilaments (grey) in contact with t-tubules as well as the SR (blue) form modules within the cell. Whereas the diffusion coefficient in solution is 200 µm² s⁻¹, the overall diffusion coefficient across several modules is 80–90% lower (24 and 35 µm² s⁻¹ in the transversal and longitudinal direction, respectively). On the right is shown an enlargement of the black square illustrating a single module, i.e. a sarcomere surrounded by mitochondria, t-tubules and SR. Within each module, the diffusion coefficient is estimated to be 80% of the coefficient in solution, i.e. 160 µm² s⁻¹. Diffusion coefficients are from Illaste et al. [112].