CA2+ Tides in Cardiomyocytes Under Mechanical Loading

AbstractCa2+ signaling is central to cardiac excitation-contraction coupling and extensive studies have revealed various Ca2+ signaling events in ventricular myocytes. In systole, the action potential opens L-type Ca2+ channels and triggers a synchronous release of Ca2+ from SR, which causes a global Ca2+ transient and whole cell contraction. During diastole, Ca2+ is sequestered back into SR and the cytosolic Ca2 concentration is kept low. However, pathological conditions can cause localized and spontaneous Ca2+ release from SR seen as Ca2+ sparks, puffs, embers, and waves. Spontaneous Ca2+ waves can drive Na+/Ca2+ exchange current to depolarize the membrane potential, manifesting as delayed afterdepolarizations and triggered action potentials that are arrhythmogenic. Here we report a new type of Ca2+ release event that is distinct from the previously known forms, named Ca2+ tide. A Ca2+ tide contains many discernable Ca2+ sparks that occur near synchronously, but does not show a propagating wave front. Ca2+ tides spontaneously arise after the systolic Ca2+ transient in a contracting myocyte and can happen several times during diastole. Interestingly and importantly, the Ca2+ tides are induced by mechanical loading of cardiomyocytes (by embedding cells in our Cell-in-Gel elastic matrix). Moreover, the cardiomyocytes isolated from TAC pressure-overload mouse model exhibited pronounced Ca2+ tides under mechanical loading. In contrast, cardiomyocytes under load-free conditions did not show any Ca2+ tides. The mechanisms and conditions that give rise to the ‘new kid on the block’ – Ca2+ tides – will be discussed.