In mammals, myocardial infarction (MI) leads to the formation of diseased heart tissue – however, the heart lacks the ability to replace this myocardium with newly divided cardiomyocytes because adult cardiomyocytes do not undergo cell division. Little has been known about the mechanisms regulating cell-cycle exit in cardiomyocytes but, as Kishore Pasumarthi and colleagues () now show, a splice variant of cyclin D2 (D2SV) might have an important role. The authors first demonstrate that endogenous D2SV is highly expressed in embryonic myocardium – where it localises to micro-aggregate structures – but not in the adult heart. Moreover, in mouse embryonic cardiomyocytes, endogenous D2SV expression is inversely correlated with cell-cycle activity, and enforced expression of D2SV leads to cell-cycle exit. The authors next demonstrate that D2SV aggregates are retained in the Golgi, ER and lysosomes, and that cells containing D2SV aggregates are subject to ER stress. Importantly, they show that D2SV aggregates also contain other cell-cycle proteins such as cyclins and cyclin-dependent kinases. They therefore propose that the sequestration of cell-cycle proteins is the mechanism by which D2SV induces cell-cycle exit. Their data shed light on cell-cycle control in cardiomyocytes, and hint at potential therapeutic strategies for MI.
