Heart disease continues to be the leading cause of mortality worldwide, primarily attributed to the restricted regenerative potential of the adult human heart following injury. In contrast to their adult counterparts, many neonatal mammals can spontaneously regenerate their myocardium in the first few days of life via extensive proliferation of the pre-existing cardiomyocytes. Reasons for the decline in regenerative capacity during postnatal development, and how to control it, remain largely unexplored. Accumulated evidence suggests that the preservation of regenerative potential depends on a conducive metabolic state in the embryonic and neonatal heart. Along with the postnatal increase in oxygenation and workload, the mammalian heart undergoes a metabolic transition, shifting its primary metabolic substrate from glucose to fatty acids shortly after birth for energy advantage. This metabolic switch causes cardiomyocyte cell-cycle arrest, which is widely regarded as a key mechanism for the loss of regenerative capacity. Beyond energy provision, emerging studies have suggested a link between this intracellular metabolism dynamics and postnatal epigenetic remodeling of the mammalian heart that reshapes the expression of many genes important for cardiomyocyte proliferation and cardiac regeneration, since many epigenetic enzymes utilize kinds of metabolites as obligate cofactors or substrates. This review summarizes the current state of knowledge of metabolism and metabolite-mediated epigenetic modifications in cardiomyocyte proliferation, with a particular focus on highlighting the potential therapeutic targets that hold promise to treat human heart failure via metabolic and epigenetic regulations.
Keywords: Cardiomyocyte proliferation; Epigenetic modifications; Metabolism.
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