Abstract 16246: Telomeric Shortening Impairs EC-Coupling and Ventricular Function
Chromosome replication and oxidative DNA damage lead to shortening of telomeres, promoting signaling pathways culminating in replicative senescence and cell cycle arrest. But whether inherited short telomeres impact on the electromechanical properties of adult cardiomyocyte, ultimately affecting ventricular performance, remains to be clarified. For this purpose, homozygous telomerase RNA component (Terc) deficient mice (KO) were employed, because they present defective telomerase, an enzyme involved in preserving telomere integrity in dividing cells. Third generation Terc-KO mice, which exhibit critical telomere shortening, were studied and compared to age- and sex-matched WT. At 3-4 months, Terc-KO mice showed slightly depressed LV function assessed by invasive hemodynamics, in respect to WT. At ~12 months, systolic and diastolic indices of LV performance were deteriorated in KO with respect to WT, together with protraction of the electrical recovery, assessed by ECG. To establish whether defective myocyte properties contributed to the impaired cardiac function, LV isolated cell preparations from WT and KO mice at 12 months, were studied. WT and Terc-KO mice had comparable cell size, excluding the occurrence of hypertrophic remodeling. By patch-clamp, under intracellular Ca2+ buffered condition, action potential amplitude and duration were comparable in the two groups of cells. Additionally, L-type Ca2+ current, responsible for triggering cell contraction, was not affected by the shortened telomeres. In contrast, using Fluo-4 loaded cells in field stimulation, Ca2+ transient decay in Terc-KO myocytes was significantly prolonged (+20%) with respect to WT, suggesting defective clearance of this cation from the cytoplasm, which represents a typical feature of the senescent myocardium. Importantly, myocyte relaxation was slower in KO, together with weaker cell contraction. Differences in mechanical function between the two cell types were abolished following isoproterenol exposure, indicating that contractile reserve was not impaired in Terc mice. In conclusion, myocytes with shortened telomeres present abnormalities in Ca2+ cycling and mechanical function which negatively impact on cardiac performance.
- © 2013 by American Heart Association, Inc.