Fatty Acid Oxidation Promotes Cardiomyocyte Proliferation Rate but Does Not Change Cardiomyocyte Number in Infant Mice.

Tongtong Cao,Brian N Finck,Rong Lu,Xiaoying Zhang,Ying Tian,Ryan Lacanna,Konstantinos Drosatos,Daniela Liccardo,Xiongwen Chen,Tani Leigh

doi:10.3389/fcell.2019.00042

Abstract

Cardiomyocyte proliferation accounts for the increase of cardiac muscle during fetal mammalian heart development. Shortly after birth, cardiomyocyte transits from hyperplasia to hypertrophic growth. Here, we have investigated the role of fatty acid β-oxidation in cardiomyocyte proliferation and hypertrophic growth during early postnatal life in mice. A transient wave of increased cell cycle activity of cardiomyocyte was observed between postnatal day 3 and 5, that proceeded as cardiomyocyte hypertrophic growth and maturation. Assessment of cardiomyocyte metabolism in neonatal mouse heart revealed a myocardial metabolic shift from glycolysis to fatty acid β-oxidation that coincided with the burst of cardiomyocyte cell cycle reactivation and hypertrophic growth. Inhibition of fatty acid β-oxidation metabolism in infant mouse heart delayed cardiomyocyte cell cycle exit, hypertrophic growth and maturation. By contrast, pharmacologic and genetic activation of PPARα, a major regulator of cardiac fatty acid metabolism, induced fatty acid β-oxidation and initially promoted cardiomyocyte proliferation rate in infant mice. As the cell cycle proceeded, activation of PPARα-mediated fatty acid β-oxidation promoted cardiomyocytes hypertrophic growth and maturation, which led to cell cycle exit. As a consequence, activation of PPARα-mediated fatty acid β-oxidation did not alter the total number of cardiomyocytes in infant mice. These findings indicate a unique role of fatty acid β-oxidation in regulating cardiomyocyte proliferation and hypertrophic growth in infant mice.

Highlights

Cardiac myocytes constitute the most fundamental functional units of the heart
Over the FAO Regulates Cardiomyocyte Proliferation Rate first week of postnatal life in mice, cardiomyocytes exhibit a transient wave of increased cell cycle activity (Lopaschuk et al, 1991; Soonpaa et al, 1996; Li et al, 1997a,b), that proceeds as cardiomyocyte binucleation, cell size enlargement and a metabolic switch from glycolysis to fatty acid β-oxidation (Lopaschuk and Spafford, 1990; Li et al, 1997a; Makinde et al, 1998; Ahuja et al, 2007; Naqvi et al, 2009; Lopaschuk and Jaswal, 2010; Zebrowski and Engel, 2013)
To determine whether cell division changes during postnatal life, we calculated the number of mono, and bi-nuclear cardiomyocytes added to the ventricles by multiplying the average cardiomyocyte numbers by the percentages of cardiomyocyte that were mononucleate, or binucleate at these time points

Summary

Introduction

Cardiac myocytes constitute the most fundamental functional units of the heart. Mammalian cardiomyocytes proliferate rapidly and use glycolysis as the main source of energy during fetal life (Lopaschuk et al, 1991; Soonpaa et al, 1996; Li et al, 1997b). Over the FAO Regulates Cardiomyocyte Proliferation Rate first week of postnatal life in mice, cardiomyocytes exhibit a transient wave of increased cell cycle activity (Lopaschuk et al, 1991; Soonpaa et al, 1996; Li et al, 1997a,b), that proceeds as cardiomyocyte binucleation, cell size enlargement and a metabolic switch from glycolysis to fatty acid β-oxidation (Lopaschuk and Spafford, 1990; Li et al, 1997a; Makinde et al, 1998; Ahuja et al, 2007; Naqvi et al, 2009; Lopaschuk and Jaswal, 2010; Zebrowski and Engel, 2013) It remains unknown whether the switch in metabolic pathways controls cardiomyocyte proliferation and hypertrophic growth. Relevant studies, using interventions that alter nutrient utilization, show that oscillating metabolism of budding yeast determines the timing of the cell-cycle phases and sets the pace of cell division (Papagiannakis et al, 2017)

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Conclusion