Sequential changes in calcium transients during M phase regulate cardiomyocyte proliferation

Heart muscle growth and regeneration require the proliferation of cardiomyocytes. Rapid pulsatile increases in cytosolic Ca(2+) concentration, called calcium transients (CaTs), trigger cardiomyocyte contractions, but how cardiomyocytes adapt Ca(2+) signaling during proliferation is largely unknown. Here, we show that cardiomyocyte proliferation requires changes in Ca(2+) signaling. Cardiomyocytes undergo a sequence of CaT changes during M phase: CaT amplitudes begin to decline in prometaphase, reach a minimum in metaphase, rise during anaphase, and return to the original state in daughter cardiomyocytes. Spindle poles show decreased Ca(2+) levels during prometaphase and metaphase. Localized reduction of Ca(2+) levels at spindle poles is mediated by dynein 1-dependent SERCA2a accumulation. Active cyclin-dependent kinase 1 (CDK1) induces both the decrease in CaT amplitudes and the accumulation of SERCA2a at the spindle poles, whereas CDK1 inhibition reverses these effects. Forcing an increase in cytosolic Ca(2+) levels by blocking SERCA2a during prometaphase and metaphase disrupts mitosis and produces binucleated cardiomyocytes, underscoring the essential role of Ca(2+) signaling changes for cardiomyocyte proliferation.