Abstract Body: Adult mammalian cardiomyocytes (CMs) are among the least able to renew of all cell types. CMs exit the cell cycle soon after birth and remain cell cycle arrested by unknown mechanisms. We previously found that in adult CMs, the active form of the Hippo signaling pathway effector YAP, YAP5SA, induces cell division in vivo. Here, we analyze the mechanism by which YAP5SA regulates the cell cycle in adult CMs. YAP5SA-expressing adult CMs reenter the cell cycle at the G1/S transition and have a prolonged S-phase lasting approximately 48 hours. Molecular and functional analysis revealed that progression from S to G2 phase, and the induction of mitotic rounding, requires sarcomere disassembly. Transition from G2 to M phase requires overcoming DNA damage checkpoint facilitated by the activation of the P21 degradation pathway. Clonal analysis showed that approximately 20% of CMs progress through cytokinesis.
Our results show that multiple barriers are involved in suppressing the adult CM cell cycle. These include the structural block caused by the highly structured CM cytoskeleton and the P21 regulated DNA damage checkpoint.