Contractile function maintains cardiomyocyte differentiation and inhibits cell cycle activity

This is suggested to underlie the restricted proliferative potential of cardiomyocytes. Whether the strong cardiovascular function required for the mammalian heart directly contributes to the cell cycle blockade remains to be explored.

Here, we use human cardiac organoids combined with direct targeting of contraction using mavacamten and aficamten to enable exquisite control of active contraction over brief time windows. We show that transient inhibition of contraction reactivates the cell cycle. Multi-omics analyses demonstrated the cell cycle response to be mediated through a dedifferentiation-like process involving rapid sarcomere remodeling and metabolic adaptations including AKT1 and PDK mediated cell cycle activation.