Telomeres come up short in heart regeneration

Telomeres come up shor t in hear t regeneration During embryogenesis, and for about a week after birth, mouse cardiomyocytes can proliferate and replace damaged heart tissue, but this regenerative capacity is lost as the mice grow older (1, 2). Newborn humans, too, can repair injured myo-cardium (3), but, in adults, heart attacks cause permanent damage, often leading to heart failure and death. Aix et al. reveal that mouse cardiomyocytes lose their pro-liferative and regenerative capacity due to a dramatic shortening of their telomeres in the fi rst week after birth (4). Most mouse cardiomyocytes withdraw from the cell cycle and become binucle-ated in the first week after birth (5, 6). " We wanted to understand the mechanism behind this process, " explains Ignacio Flores, from the Spanish National Center for Cardiovascular Research in Madrid. " Why do cardiomyocytes arrest their cell cycle, and what drives their binucleation? " Flores and colleagues wondered whether the mechanism might involve telomeres, repetitive DNA sequences that protect the ends of chromosomes. If telomeres grow too short—due, for example, to a loss of the telomere-extending telom-erase enzyme—cells can mistake chromosome ends for DNA double strand breaks, leading to checkpoint activation and cell cycle arrest. Moreover, chromosomes without telomeres can fuse to form anaphase bridges that may interfere with cytokinesis and cause binucleation. Flores and colleagues previously found that telomerase is essential for heart regen-eration in zebrafi sh (7), but these animals, unlike mammals, retain their regenerative capacity into adulthood. Postdoc Esther Aix therefore examined the length of telomeres in newborn mouse cardiomyocytes (4). " And we found that the telomeres rapidly erode in the fi rst week after birth, " says Flores. This erosion coincided with a decrease in telomerase expression and was accompanied by the activation of the DNA damage response and an increase in anaphase bridge formation. To investigate whether telomere erosion was the cause of cardiomyocyte binucleation and arrest, the researchers examined telomerase-deficient mice. These animals already had short telo-meres on the first day after birth and, accordingly, many of their cardiomyo-cytes already showed DNA damage markers and ana-phase bridges. Moreover, compared with one-day-old wild-type mice, the number of proliferative cardiomyo-cytes was reduced, whereas the number of binucleated cardiomyocytes was increased. " So telomere shortening contributes to binucleation, " Flores says. When Aix et al. injured the hearts of one-day-old mice, wild-type cardiomyocytes were able to proliferate and replace the damaged …