Abstract 19155: Cardiac Stem Cell Activation and Ensuing Myogenesis and Angiogenesis Contribute to Cardiac Adaptation following Intensity-Controlled Exercise Training
The role of cardiac stem/progenitor cells (CSCs) in the cardiac adaptation to exercise stress is undefined. We evaluated whether treadmill exercise training at different intensities can stimulate c-kit positive (c-kitpos) CSCs and their differentiation into new myocytes and microvasculature in the adult rat myocardium. To this aim, 33 male Wistar rats (∼220g) were exercised at either a low (LI; 55–60% VO2 max) or high (HI; 85–90% VO2 max) intensity for 30 min/day, 4 days/wk for up to 4 wks on motorized treadmills. Eighteen untrained rats acted as age-matched sedentary controls (CTRL). To track myocardial cell proliferation, BrdU was administered (i.p.) twice daily. Immunohistochemical and confocal microscopy analysis of the left ventricle (LV) showed an increase (P<0.05) in average myocyte diameter in exercised animals compared to CTRL. In addition to larger (hypertrophied) myocytes, smaller BrdU (3.4±0.2% LI, 7.4±0.3% HI) and Ki67 (0.8±0.1% LI, 1.0±0.1% HI) positive myocytes were observed in the LV of exercised animals indicative of myogenesis. c-kitpos CSC number increased (P<0.05) in exercising vs. CTRL rats. Many CSCs were BrdU and/or Ki67 positive and many expressed transcription factors indicative of their commitment to the cardiomyocyte (Nkx2.5) or capillary (Ets-1) lineages. Capillary number per mm2 in LI (2695±90) and HI (3977±378) exercised animals was significantly (P<0.05) greater than CTRL (1552±110). Many of these capillaries were BrdU positive showing their recent formation. Gene array analyses revealed the up-regulation of IGF-1, Neuregulin, BMP-10 and Wnt11 in myocytes isolated from exercise trained hearts. In vitro, these factors differentially stimulated c-kitpos CSC proliferation, clonogenicity and differentiation. In conclusion, intensity-controlled treadmill exercise training in adult rats results in myocardial remodeling through myocyte hypertrophy and hyperplasia along with new capillary formation. Myocyte hyperplasia and neovasculogenesis is due to exercise training intensity-dependent activation of resident CSCs and their ensuing differentiation. These results highlight the role of c-kitpos CSCs in the physiological adaptation to different conditions and workloads in the adult myocardium.
- © 2010 by American Heart Association, Inc.