Architecture of the cardiac transverse-axial tubular system across different mammalian species.

Cardiac excitation-contraction coupling relies on a pancellular network of regular cardiomyocyte surface membrane invaginations, termed the transverse-axial tubular system (TATS). The TATS is ubiquitously present in adult mammalian cardiomyocytes, enabling efficient structural and functional coupling of sarcolemma and intracellular Ca2+ stores. However TATS ultrastructural characteristics across species, and their relation to cardiomyocyte morphology and physiological parameters such as heart rate, remain largely unexplored. Here we quantified TATS and cardiomyocyte features in a confocal microscopy dataset (91 three-dimensional image volumes) obtained from tissue slices across eight species (mouse, rat, rabbit, pig, horse, elephant, whale, and humans). We applied a semi-automated image analysis pipeline to quantify mean cytosolic distances to the nearest TATS element (Cyto-TATSmin), transverse tubule fraction, and cardiomyocyte dimensions. Cyto-TATSmin and transverse tubule fraction differed substantially between species, with the lowest Cyto-TATSmin in mouse and highest in humans. No significant within-species associations between Cyto-TATSmin and cardiomyocyte size were detected in six of eight species. Associations were limited to pig (cross-sectional area and width) and elephant (area, depth, and width), although elephant was represented by a single subject. Across all species, Cyto-TATSmin positively correlated with species' lifespan and body mass, and was inversely correlated with resting heart rate. Our findings reveal structural scaling principles in cardiac cellular ultrastructure and provide a resource for studying TATS organisation in health and disease. As TATS remodelling is a common hallmark of cardiac pathology, awareness of species differences in reference states and remodelling dynamics is needed to guide the design and interpretation of translational research. KEY POINTS: The transverse-axial tubular system (TATS) is essential for efficient excitation-contraction coupling in cardiomyocytes and, consequently, normal cardiac function. However systematic comparisons of TATS architecture across mammalian species remain limited. We analysed 91 three-dimensional (3D) image volumes, obtained using confocal microscopy, from eight mammalian species (mouse, rat, rabbit, pig, horse, humans, elephant, whale) using a unified image analysis pipeline. We quantified mean cytosolic distance to the nearest TATS element (Cyto-TATSmin), transverse tubule percentage, and 3D cardiomyocyte morphology. Cyto-TATSmin and transverse tubule percentage showed species-dependent patterns, with Cyto-TATSmin being lowest in mouse and highest in human. Across species, Cyto-TATSmin covaries with organismal physiology (lifespan, body mass, and resting heart rate). Our quantitative data provide a cross-species reference framework for interpreting physiological adaptations and pathological remodelling of the cardiac TATS.