The adult mammalian heart was traditionally viewed as a post-mitotic organ. Increased cardiac mass and contractility following exercise training was thought to occur solely through physiological hypertrophy of existing myocytes. The adult mammalian heart harbors stem-progenitor cells which participate in adaptations to myocardial stress. Here, we sought to determine the role of the c-kitpos endogenous cardiac stem cells (eCSCs) and new cardiomyocyte formation in the physiological cardiac adaptation to exercise stress.Methods
42 male Wistar rats (∼220g) were exercised on motorized treadmills for 30 min/day, 4 days/wk for up to 4 wks at a low (LI; 55-60% VO2 max) or high (HI; 85-90% VO2 max) intensity. 25 untrained rats acted as age-matched sedentary controls (CTRL). To track myocardial cell generation, BrdU was administered (i.p.) twice daily. New cardiomyocyte formation, c-kitpos eCSC number and differentiation were assessed by immunohistochemistry. Growth factor gene array was determined in isolated cardiomyocytes from exercised and CTRL hearts.Results
Immunohistochemical and confocal microscopy analysis of the left ventricle (LV) showed an increase (P < 0.05) in average cardiomyocyte diameter and volume in exercised animals. In addition to larger (hypertrophied) cardiomyocytes, 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 cardiomyocytes were observed in exercised animals indicative of new cardiomyocyte formation. Capillary density in LI (2866 ± 48/mm2) and HI (4158 ± 47/mm2) animals was significantly (P < 0.05) greater than CTRL (2105 ± 51) and many of these capillaries were BrdU positive. c-kitpos eCSC number increased (P < 0.05) in exercising vs. CTRL rats and many eCSCs expressed transcription factors indicative of their commitment to the cardiomyocyte (Nkx2.5) or capillary (Ets-1) lineages. Gene array analyses revealed the up-regulation of IGF-1, TGF-β1, Neuregulin-1, BMP-10 and Periostin in cardiomyocytes isolated from exercised animals. In vitro, these factors differentially determined c-kitpos eCSC proliferation, clonogenicity and differentiation.Conclusion
Treadmill exercise training induces myocardial remodeling initiated by increased growth factor expression, leading to activation and ensuing differentiation of c-kitpos eCSCs. These effects are followed by cardiomyocyte hypertrophy along with new capillary and cardiomyocyte formation, which were dependent on exercise training intensity. These findings highlight for the first time the role of the endogenous regenerative capacity of the adult heart in the physiological adaptation to exercise stress.