Cardiomyocyte mechanical activity counteracts intraluminal calcium depletion in the transverse-axial tubular system during fast electrical stimulation

Abstract The transverse-axial tubular system (TATS) enables close structural and functional coupling between plasma membrane and sarcoplasmic reticulum of cardiomyocytes. It supports fast and efficient Ca2+-induced Ca2+ release upon cell depolarisation, crucial for excitation–contraction coupling in the heart. Due to the small diameter and tortuosity of individual tubules, the TATS forms a domain of restricted diffusive transport. It has previously been suggested that, as a consequence of an uneven distribution of Ca2+ influx and efflux pathways in TATS compared to outer surface plasma membrane domains of cardiomyocytes, cyclic electrical activity may lead to a gradual depletion of Ca2+ in the TATS. Here, we show experimentally that in mechanically uncoupled rabbit ventricular cardiomyocytes, electrical stimulation does indeed lead to an L-type Ca2+ channel-dependent gradual depletion of Ca2+ inside TATS, an effect that scales with pacing frequency. Ca2+ depletion was absent in freely contracting cardiomyocytes, presumably as a result of cyclic TATS deformation during cell shortening. This squeezes transverse TATS tubules and adds an advective contribution to, and thereby accelerates the, intra-TATS content exchange with bulk extracellular fluid. Our results reveal a novel mechanism of cardiac mechano-dependent auto-regulation, where the increased propensity for development of intra-TATS Ca2+ gradients at high electrical stimulation rates is mitigated by the coinciding mechanically induced TATS deformation, twice on each cycle in the heart (during diastolic stretch and systolic shortening), which accelerates luminal content exchange. Our study provides first insight into a novel facet of cardiac mechano-biology, whose auto-regulatory benefit may be reduced by TATS remodelling in disease. Competing Interest Statement The authors have declared no competing interest.