title: The adult heart responds to increased workload with physiologic hypertrophy, cardiac stem cell activation, and new myocyte formation.
abstract: OBJECTIVE
  It is a dogma of cardiovascular pathophysiology that the increased cardiac mass in response to increased workload is produced by the hypertrophy of the pre-existing myocytes. The role, if any, of adult-resident endogenous cardiac stem/progenitor cells (eCSCs) and new cardiomyocyte formation in physiological cardiac remodelling remains unexplored.
  
  
  RESULTS
  In response to regular, intensity-controlled exercise training, adult rats respond with hypertrophy of the pre-existing myocytes. In addition, a significant number (∼7%) of smaller newly formed BrdU-positive cardiomyocytes are produced by the exercised animals. Capillary density significantly increased in exercised animals, balancing cardiomyogenesis with neo-angiogenesis. c-kit(pos) eCSCs increased their number and activated state in exercising vs. sedentary animals. c-kit(pos) eCSCs in exercised hearts showed an increased expression of transcription factors, indicative of their commitment to either the cardiomyocyte (Nkx2.5(pos)) or capillary (Ets-1(pos)) lineages. These adaptations were dependent on exercise duration and intensity. Insulin-like growth factor-1, transforming growth factor-β1, neuregulin-1, bone morphogenetic protein-10, and periostin were significantly up-regulated in cardiomyocytes of exercised vs. sedentary animals. These factors differentially stimulated c-kit(pos) eCSC proliferation and commitment in vitro, pointing to a similar role in vivo.
  
  
  CONCLUSIONS
  Intensity-controlled exercise training initiates myocardial remodelling through increased cardiomyocyte growth factor expression leading to cardiomyocyte hypertrophy and to activation and ensuing differentiation of c-kit(pos) eCSCs. This leads to the generation of new myocardial cells. These findings highlight the endogenous regenerative capacity of the adult heart, represented by the eCSCs, and the fact that the physiological cardiac adaptation to exercise stress is a combination of cardiomyocyte hypertrophy and hyperplasia (cardiomyocytes and capillaries).
authors.affiliation: Stem Cell and Regenerative Biology Unit (BioStem), Research Institute for Sport and Exercise Sciences, Liverpool John Moores University, Tom Reilly Building, Byrom Street, Liverpool L3 3AF, UK.
authors.forename: Cheryl D
authors.initials: CD
authors.lastname: Waring
authors.affiliation: Stem Cell and Regenerative Biology Unit (BioStem), Research Institute for Sport and Exercise Sciences, Liverpool John Moores University, Tom Reilly Building, Byrom Street, Liverpool L3 3AF, UK Laboratory of Molecular and Cellular Cardiology, Department of Medical and Surgical Sciences, Magna Graecia University, Viale Europa, Catanzaro 88100, Italy.
authors.forename: Carla
authors.initials: C
authors.lastname: Vicinanza
authors.affiliation: Stem Cell and Regenerative Biology Unit (BioStem), Research Institute for Sport and Exercise Sciences, Liverpool John Moores University, Tom Reilly Building, Byrom Street, Liverpool L3 3AF, UK.
authors.forename: Angela
authors.initials: A
authors.lastname: Papalamprou
authors.affiliation: Stem Cell and Regenerative Biology Unit (BioStem), Research Institute for Sport and Exercise Sciences, Liverpool John Moores University, Tom Reilly Building, Byrom Street, Liverpool L3 3AF, UK.
authors.forename: Andrew J
authors.initials: AJ
authors.lastname: Smith
authors.affiliation: Stem Cell and Regenerative Biology Unit (BioStem), Research Institute for Sport and Exercise Sciences, Liverpool John Moores University, Tom Reilly Building, Byrom Street, Liverpool L3 3AF, UK.
authors.forename: Saranya
authors.initials: S
authors.lastname: Purushothaman
authors.affiliation: Stem Cell and Regenerative Biology Unit (BioStem), Research Institute for Sport and Exercise Sciences, Liverpool John Moores University, Tom Reilly Building, Byrom Street, Liverpool L3 3AF, UK.
authors.forename: David F
authors.initials: DF
authors.lastname: Goldspink
authors.affiliation: Stem Cell and Regenerative Biology Unit (BioStem), Research Institute for Sport and Exercise Sciences, Liverpool John Moores University, Tom Reilly Building, Byrom Street, Liverpool L3 3AF, UK.
authors.forename: Bernardo
authors.initials: B
authors.lastname: Nadal-Ginard
authors.affiliation: Stem Cell and Regenerative Biology Unit (BioStem), Research Institute for Sport and Exercise Sciences, Liverpool John Moores University, Tom Reilly Building, Byrom Street, Liverpool L3 3AF, UK Laboratory of Molecular and Cellular Cardiology, Department of Medical and Surgical Sciences, Magna Graecia University, Viale Europa, Catanzaro 88100, Italy g.m.ellison@ljmu.ac.uk torella@ljmu.ac.uk.
authors.forename: Daniele
authors.initials: D
authors.lastname: Torella
authors.affiliation: Stem Cell and Regenerative Biology Unit (BioStem), Research Institute for Sport and Exercise Sciences, Liverpool John Moores University, Tom Reilly Building, Byrom Street, Liverpool L3 3AF, UK Laboratory of Molecular and Cellular Cardiology, Department of Medical and Surgical Sciences, Magna Graecia University, Viale Europa, Catanzaro 88100, Italy g.m.ellison@ljmu.ac.uk torella@ljmu.ac.uk.
authors.forename: Georgina M
authors.initials: GM
authors.lastname: Ellison
mesh_terms: D000818:Animals; D002196:Capillaries / Q000166:cytology; D006332:Cardiomegaly / Q000503:physiopathology*; D002454:Cell Differentiation / Q000502:physiology; D036341:Intercellular Signaling Peptides and Proteins / Q000378:metabolism; D008297:Male; D009206:Myocardium / Q000166:cytology; D032383:Myocytes, Cardiac / Q000502:physiology*; D018919:Neovascularization, Physiologic / Q000502:physiology; D010101:Oxygen Consumption / Q000502:physiology; D005082:Physical Exertion / Q000502:physiology*; D019009:Proto-Oncogene Proteins c-kit / Q000378:metabolism; D017208:Rats, Wistar; D013234:Stem Cells / Q000502:physiology*; D015854:Up-Regulation; D066253:Vascular Remodeling / Q000502:physiology
chemical_list: D036341:Intercellular Signaling Peptides and Proteins; D019009:Proto-Oncogene Proteins c-kit
keywords: Cardiac stem cells; Cardiomyogenesis; Exercise; Growth factors; Myocyte hyperplasia; Physiological remodelling