Proposed model. At P1, a proportion of CMs presents long telomeres, giving them potential to proliferate during postnatal development and in response to cardiac injury. However, during the first two postnatal weeks, most CMs inactivate telomerase and shorten their telomeres. Telomere shortening leads to the appearance of dysfunctional damaged telomeres, chromosome fusions, micronuclei, and binucleation and at the same time activates p21, ultimately leading to CM cell-cycle arrest. CMs with premature telomere shortening (P1 G3 Terc^−/− CMs) precociously activate the DNA damage response at telomeres, form anaphase bridges, up-regulate p21, and binucleate, outcomes that reinforce the role of telomere shortening in the withdrawal of CMs from the cell cycle.