Published online before print June 29, 2007, doi: 10.1161/CIRCRESAHA.107.151449
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Submitted on February 28, 2007
Revised on June 13, 2007
Accepted on June 20, 2007
The Young Mouse Heart Is Composed of Myocytes Heterogeneous in Age and Function
Marcello Rota *;
From the Cardiovascular Research Institute (M.R., T.H., A.D.A., M.L.A., G.E., R.R., J.T., D.T., E.M., C.B., K.U., P.A., A.L., J.K.), Department of Medicine, New York Medical College, Valhalla; and the MRC Clinical Sciences Centre (O.R.), Faculty of Medicine, Imperial College School of Medicine, London, UK.
* To whom correspondence should be addressed. E-mail: marcello_rota{at}nymc.edu.
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 p16INK4a and telomere length. The heart was characterized by the coexistence of young, aged, and senescent myocytes. Old nonreplicating, p16INK4a-positive, hypertrophied myocytes with severe telomeric shortening were present together with young, dividing, p16INK4a-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 ICaL play in potentiating Ca2+ cycling and the mechanical behavior of young myocytes or in decreasing Ca2+ transients and the performance of senescent hypertrophied cells. The characteristics of the AP appeared to be modulated by the transient outward K+ current Ito 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.
Key words: action potential profile • excitation-contraction coupling • myocyte volume • telomere length • senescence-associated proteins
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