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

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.

Activation or inhibition of PPARα-mediated fatty acid β-oxidation does not active cardiomyocyte proliferation in normal or infarcted adult mice

“…Heart ventricles were harvested 24 hours after the last injection. Previous studies demonstrated the expression of fatty acid metabolismassociated genes (Acaca, Acacb, Acadl, Acadm, Cpt1b) as indicators of PPARα biological activity in vivo [21]. Consistent with these previous studies, GW7647 treatment resulted in a significant increase in the mRNA level of these genes ( Figure 1B).…”

“…However, ETO treatment led to significant lower levels of EF and FS compared with the saline treatment ( Figure 2D). Our previous studies have suggested that ETO treatment prevented cardiomyocyte maturation in early postnatal mouse hearts [21].…”

“…Whether cardiac metabolism contributes to cardiomyocyte proliferation in physiological and pathological settings remains unanswered. Our previous studies have suggested that activation of PPARα-mediated fatty acid β -oxidation promoted cardiomyocyte proliferation rate in infant mouse hearts during early postnatal life [21]. However, it is unclear whether PPARα activation has impact on adult cardiomyocyte proliferation.…”

“…This ability to regeneration in response to injury ends by 7 days after birth in mice, corresponding to the exit of cardiomyocyte from the cell cycle. Notably, those changes coincide with the metabolic shift toward fatty acid β -oxidation [21]. Whether cardiac metabolism contributes to cardiomyocyte proliferation in physiological and pathological settings remains unanswered.…”

“…Our previous studies from infant mice have indicated that GW7647 treatment or cardiacrestricted activation of PPARα enhanced fatty acid β -oxidation and promoted cardiomyocyte proliferation rate in the postnatal day 4 mouse heart [21]. Interestingly, recent studies of PPARβ/δ, the closely related family member to PPARα, have suggested that enhanced PPARδ activation promoted cardiomyocyte proliferation and cardiac repair after injury in adult mice [22].…”