Local Ca2+ releases enable rapid heart rates in developing cardiomyocytes

Abstract

The ability to generate homogeneous intracellular Ca(2+) oscillations at high frequency is the basis of the rhythmic contractions of mammalian cardiac myocytes. While the specific mechanisms and structures enabling homogeneous high-frequency Ca(2+) signals in adult cardiomyocytes are well characterized, it is not known how these kind of Ca(2+) signals are produced in developing cardiomyocytes. Here we investigated the mechanisms reducing spatial and temporal heterogeneity of cytosolic Ca(2+) signals in mouse embryonic ventricular cardiomyocytes. We show that in developing cardiomyocytes the propagating Ca(2+) signals are amplified in cytosol by local Ca(2+) releases. Local releases are based on regular 3-D sarcoplasmic reticulum (SR) structures containing SR Ca(2+) uptake ATPases (SERCA) and Ca(2+) release channels (ryanodine receptors, RyRs) at regular intervals throughout the cytosol. By evoking [Ca(2+)](i)-induced Ca(2+) sparks, the local release sites promote a 3-fold increase in the cytosolic Ca(2+) propagation speed. We further demonstrate by mathematical modelling that without these local release sites the developing cardiomyocytes lose their ability to generate homogeneous global Ca(2+) signals at a sufficiently high frequency. The mechanism described here is robust and indispensable for normal mammalian cardiomyocyte function from the first heartbeats during the early embryonic phase till terminal differentiation after birth. These results suggest that local cytosolic Ca(2+) releases are indispensable for normal cardiomyocyte development and function of developing heart.