The young mouse heart is composed of myocytes heterogeneous in age and function.
The recognition that the adult heart continuously renews its myocyte compartment raises the possibility that the age and lifespan of myocytes does not coincide with the age and lifespan of the organ and organism. If this were the case, myocyte turnover would result at any age in a myocardium composed by a heterogeneous population of parenchymal cells which are structurally integrated but may contribute differently to myocardial performance. To test this hypothesis, left ventricular myocytes were isolated from mice at 3 months of age and the contractile, electrical, and calcium cycling characteristics of these cells were determined together with the expression of the senescence-associated protein p16(INK4a) and telomere length. The heart was characterized by the coexistence of young, aged, and senescent myocytes. Old nonreplicating, p16(INK4a)-positive, hypertrophied myocytes with severe telomeric shortening were present together with young, dividing, p16(INK4a)-negative, small myocytes with long telomeres. A class of myocytes with intermediate properties was also found. Physiologically, evidence was obtained in favor of the critical role that action potential (AP) duration and I(CaL) play in potentiating Ca(2+) cycling and the mechanical behavior of young myocytes or in decreasing Ca(2+) transients and the performance of senescent hypertrophied cells. The characteristics of the AP appeared to be modulated by the transient outward K(+) current I(to) which was influenced by the different expression of the K(+) channels subunits. Collectively, these observations at the physiological and structural cellular level document that by necessity the heart has to constantly repopulate its myocyte compartment to replace senescent poorly contracting myocytes with younger more efficient cells. Thus, cardiac homeostasis and myocyte turnover regulate cardiac function.
Rota
Marcello
M
Cardiovascular Research Institute, Department of Medicine, New York Medical College, Valhalla, New York 10595, USA. marcello_rota@nymc.edu
Hosoda
Toru
T
De Angelis
Antonella
A
Arcarese
Michael L
ML
Esposito
Grazia
G
Rizzi
Roberto
R
Tillmanns
Jochen
J
Tugal
Derin
D
Musso
Ezio
E
Rimoldi
Ornella
O
Bearzi
Claudia
C
Urbanek
Konrad
K
Anversa
Piero
P
Leri
Annarosa
A
Kajstura
Jan
J
D000200:Action Potentials / Q000502:physiology; D000375:Aging / Q000502:physiology*; D000818:Animals; D002118:Calcium / Q000378:metabolism; D019070:Cell Lineage / Q000502:physiology; D048429:Cell Size; D016922:Cellular Senescence / Q000502:physiology*; D019941:Cyclin-Dependent Kinase Inhibitor p16 / Q000235:genetics / Q000378:metabolism; D006321:Heart / Q000502:physiology*; D006706:Homeostasis / Q000502:physiology; D051379:Mice; D008810:Mice, Inbred C57BL; D009200:Myocardial Contraction / Q000502:physiology; D032383:Myocytes, Cardiac / Q000166:cytology* / Q000502:physiology*; D011188:Potassium / Q000378:metabolism; D013234:Stem Cells / Q000166:cytology / Q000502:physiology; D016615:Telomere / Q000502:physiology
D019941:Cyclin-Dependent Kinase Inhibitor p16; D011188:Potassium; D002118:Calcium