Repression of and by prevents cardiomyocyte dedifferentiation and cell cycle entry in the adult heart.

Dedifferentiation of cardiomyocytes is part of the survival program in the remodeling myocardium and may be essential for enabling cardiomyocyte proliferation. In addition to transcriptional processes, non-coding RNAs play important functions for the control of cell cycle regulation in cardiomyocytes and cardiac regeneration. Here, we demonstrate that suppression of and by is instrumental to prevent cardiomyocyte dedifferentiation and cell cycle entry in the adult heart. Concomitant inactivation of both clusters in adult cardiomyocytes activates expression of cell cycle regulators, induces a switch from fatty acid to glycolytic metabolism, and changes expression of extracellular matrix genes. Inhibition of FGFR and OSMR pathways prevents most effects of inactivation. Short-term depletion protects cardiomyocytes against ischemia, while extended loss of causes heart failure. Our results demonstrate a crucial role of –mediated suppression of and in maintaining the postmitotic differentiated state of cardiomyocytes.