Abstract 14343: A Defective Cardiac Stem Cell Pool Leads to Impaired Cardiac Function in Aging W/Wv Mice
The adult heart contains a compartment of c-kit-positive cardiac stem cells (CSCs) which regulates cardiomyogenesis and, thereby, cardiac performance. The objective of the current study was to determine whether functionally defective CSCs progressively influence the mechanical and Ca2+ properties of myocytes compromising ventricular hemodynamics with age. For this purpose, W/Wv mice, which carry a mutated non-functional c-kit receptor, were studied together with age-matched wild-type (WT) mice. CSCs were isolated from fully mature adult W/Wv and WT and cultured. After stimulation with IGF-1 or SCF, the fraction of BrdU-labeled CSCs was 50% lower in W/Wv. The attenuated growth response of W/WV CSCs was coupled with a 4-fold increase of cell apoptosis. At 5–6 months of age, the fraction of CSCs and myocytes positive for the senescence-associated protein p16INK4a was 2-fold higher in W/Wv than in WT. Similarly, myocyte apoptosis was 2.5-fold greater in W/Wv. To establish whether W/Wv CSCs formed poorly functioning myocytes, cells from W/Wv and WT mice were electrically stimulated, and sarcomere shortening and Ca2+ transients were measured. Cell shortening was reduced 40% in W/Wv myocytes and this alteration was coupled with a slower relaxation phase. A 35% decrease in Ca2+ transient amplitude and a prolongation of SR Ca2+ re-uptake were also detected. Since the impairment in Ca2+ re-uptake may impact on SR Ca2+ load, myocytes were exposed to caffeine to assess SR Ca2+ content. Caffeine-induced Ca2+ transient in W/Wv myocytes was 35% lower than in WT, suggesting that defects in Ca2+ cycling were partly implicated in the decline in contractility of W/Wv myocytes. To establish whether depressed myocyte mechanics affected global cardiac function, echocardiography was performed. Ejection fraction was similar in W/Wv and WT mice at 5 months of age. However, at 10 and 23 months of age, W/Wv mice showed ventricular dilation and reduced ejection fraction. In conclusion, abnormalities in c-kit receptor function depress CSC growth and survival, resulting in the accumulation of senescent myocytes with altered Ca2+ cycling and contractility, which lead to a premature aging myopathy.
- © 2010 by American Heart Association, Inc.