Uncoupling protein 2-mediated metabolic adaptations define cardiac cell function in the heart during transition from young to old age. (10th September 2020) - Kurian, Justin
Abstract: Cellular replacement in the heart is restricted to postnatal stages with the adult heart largely postmitotic. Studies show that loss of regenerative properties in cardiac cells seems to coincide with alterations in metabolism during postnatal development and maturation. Nevertheless, whether changes in cellular metabolism are linked to functional alternations in cardiac cells is not well studied. We report here a novel role for uncoupling protein 2 (UCP2) in regulation of functional properties in cardiac tissue derived stem-like cells (CTSCs). CTSC were isolated from C57BL/6 mice aged 2 days (nCTSC), 2 month (CTSC), and 2 years old (aCTSC), subjected to bulk-RNA sequencing that identifies unique transcriptome significantly different between CTSC populations from young and old heart. Moreover, results show that UCP2 is highly expressed in CTSCs from the neonatal heart and is linked to maintenance of glycolysis, proliferation, and survival. With age, UCP2 is reduced shifting energy metabolism to oxidative phosphorylation inversely affecting cellular proliferation and survival in aged CTSCs. Loss of UCP2 in neonatal CTSCs reduces extracellular acidification rate and glycolysis together with reduced cellular proliferation and survival. Mechanistically, UCP2 silencing is linked to significant alteration of mitochondrial genes together with cell cycle and survival signaling pathways as identified by RNA-sequencing and STRING bioinformatic analysis. Hence, our study shows UCP2-mediated metabolic profile regulates functional properties of cardiac cells during transition from neonatal to aging cardiac states. Abstract : Loss in cardiac regeneration coincides with metabolic alterations. Whether cellular metabolism regulates cardiac cells function from young to old age remains unknown. Here we demonstrate that uncoupling protein 2 (UCP2) promotes increased glycolysis, proliferation, and survival in cardiac tissue derived stem-like cells in neonatal heart. In aging, UCP2 is reduced increasing oxidative phosphorylation, reducing glycolysis parallel with reduced proliferation and survival.