Metabolic determinants in cardiomyocyte function and heart regenerative strategies

Heart disease is the leading cause of mortality in developed countries. The associated pathology is characterized by a loss of cardiomyocytes that leads, eventually, to heart failure. In this context, several cardiac regenerative strategies have been developed, but they still lack clinical effectiveness. The mammalian neonatal heart is capable of substantial regeneration following injury, but this capacity is lost at postnatal stages when cardiomyocytes become terminally differentiated and transit to the fetal metabolic switch. Cardiomyocytes are metabolically versatile cells capable of using an array of fuel sources, and the metabolism of cardiomyocytes suffers extended reprogramming after injury. Apart from energetic sources, metabolites are emerging regulators of epigenetic programs driving cell pluripotency and differentiation. Thus, understanding the metabolic determinants that regulate cardiomyocyte maturation and function is key for unlocking future metabolic interventions for cardiac regeneration. In this review, we will discuss the emerging role of metabolism and nutrient signaling in cardiomyocyte function and repair, as well as whether exploiting this axis could potentiate current cellular regenerative strategies for the mammalian heart.

This research was funded by Fundação para a Ciência e Tecnologia (FCT), grant number ERA-CVD/0001/2018-INNOVATION, EXPL/BIA-CEL/0358/2021 and LISBOA-01-0145-FEDER028534. The MC and FS were funded by FCT individual scholarships (UI/BD/151373/2021 and SFRH/BD/146204/2019, respectively).

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