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J Appl Physiol (November 22, 2006). doi:10.1152/japplphysiol.00937.2006
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Submitted on August 23, 2006
Accepted on November 16, 2006

Myocyte Enlargement, Differentiation, And Proliferation Kinetics In the Fetal Sheep Heart

Sonnet S Jonker1*, Lubo Zhang2, Samantha Louey3, George D Giraud4, Kent L. Thornburg5, and J Job Faber6

1 Heart Research Center, OHSU, Portland, Oregon, United States; Physiol/Pharmacol, OHSU, United States
2 Department of Pharmacology, Center for Perinatal, Loma Linda University School of Medicine, Loma Linda, California, United States
3 Heart Research Center, Oregon Health Sciences University, Portland, Oregon, United States
4 Heart Research Center, OHSU, Portland, Oregon, United States; Physiol/Pharmacol, OHSU, United States; School of Medicine (Cardiovascular Medicine), OHSU, Portland, Oregon, United States; Portland VA Medical Center, United States
5 Heart Research Center, OHSU, Portland, Oregon, United States; Physiol/Pharmacol, OHSU, United States; School of Medicine (Cardiovascular Medicine), OHSU, Portland, Oregon, United States
6 Physiol/Pharmacol, OHSU, Portland, Oregon, United States; Heart Research Center, OHSU, Portland, Oregon, United States

* To whom correspondence should be addressed. E-mail: ssj{at}efn.org.

The generation of new myocytes is an essential process of in utero heart growth. Most, or all, cardiac myocytes lose their capacity for proliferation during the perinatal period through the process of terminal differentiation. An increasing number of studies focus on how experimental interventions affect cardiac myocyte growth in the fetal sheep. Nevertheless, fundamental questions about normal growth of the fetal heart remain unanswered. In this study we determined that during the last third of gestation the hearts of fetal sheep grew primarily by four processes: (1) Myocyte proliferation contributed substantially to daily cardiac mass gain, and the number of cardiac myocytes continued to increase to term. (2) The (hitherto unrecognized) contribution to cardiac growth by the increase in myocyte size associated with the transition from mononucleation to binucleation (terminal differentiation) became considerable from ~115 days of gestation (dGA) until term (145dGA). As binucleation became the more frequent outcome of myocyte cell cycle activity following ~115dGA, the number of binucleated myocytes increased at the expense of the number of mononucleated myocytes. Both the interval between nuclear divisions and the duration of cell cycle activity in myocytes decreased substantially during this same period. Finally, cardiac growth was in part due to enlargement of (3) mononucleated and (4) binucleated myocytes, which grew in cross-sectional diameter but not length during the last third of gestation. These data on normal cardiac growth may enable a more detailed understanding of the consequences of experimental and pathological interventions in prenatal life.




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