PT - JOURNAL ARTICLE AU - Rajika Roy AU - Tani Leigh AU - Erhe Gao AU - Xiaoying Zhang AU - Ying Tian TI - Activation or inhibition of PPARα-mediated fatty acid β-oxidation does not active cardiomyocyte proliferation in normal or infarcted adult mice AID - 10.1101/667964 DP - 2019 Jan 01 TA - bioRxiv PG - 667964 4099 - http://biorxiv.org/content/early/2019/06/11/667964.short 4100 - http://biorxiv.org/content/early/2019/06/11/667964.full AB - Objectives PPAR genes are known as the important regulators of fatty acid oxidation and energy homeostasis. PPARα is highly expressed in the embryonic and adult heart. Previous studies from infant mouse hearts have suggested that activation of PPARα using GW7647 treatment or cardiac-restricted activation of PPARα using αMHC-PPARα transgenic mice enhanced fatty acid β-oxidation and promoted cardiomyocyte proliferation rate in the postnatal day 4 mouse heart. Here, we further investigate the impact of PPARα-mediated fatty acid β-oxidation on cardiomyocyte proliferation in the adult mouse heart.Methods and Results Adult wild-type (C57BL/6J) mice were subjected to five injections of GW7647, a highly specific PPARα agonist, or vehicle (saline). Cardiomyocyte proliferation was analyzed by quantification of DNA synthesis via ethynyldeoxyuridine (EdU) incorporation and quantification of cells undergoing mitosis using phosphorylated histone H3 (PH3). GW7647 treatment resulted in activation of PPARα target genes associated with fatty acid metabolism and β-oxidation, validating its biological activity. However, GW7647 treatment did not active cardiomyocyte proliferation in the normal heart. In parallel, mice were subjected to myocardial infarction (MI) using permanent coronary artery occlusion. Both GW7647-treatd wild-type mice and αMHC-PPARα transgenic mice showed no significant differences in cardiomyocyte DNA synthesis and mitosis compared with vehicle-treated wild-type mice after MI. Furthermore, inhibition of PPARα-mediated fatty acid β-oxidation using etomoxir (ETO) treatment had no impact on cardiomyocyte proliferation in both normal and infarcted hearts of wild-type mice compared with vehicle treatment.Summary These findings suggest that activation or inhibition of PPARα-mediated fatty acid β-oxidation did not active cardiomyocyte proliferation in normal or infarcted hearts of adult mice. Any effects on cardiac function observed following PPARα activation treatment is independent of enhanced cardiomyocyte renewal in the adult heart.