Shortly after birth, as cardiomyocytes mature, they switch from glycolytic to oxidative metabolism, which affects mitochondrial homeostasis, cellular architecture and function, withdraws cardiomyocytes from the cell cycle and prevents them from cell division, and increases oxidative stress and DNA damage. Reversing the metabolic switch of mature cardiomyocytes, from oxidative to glycolytic metabolism, could re-establish some of the proliferative potential of cardiomyocytes. However, the mechanism that couples the metabolic switchback of mature cardiomyocytes to alterations in the transcriptome is unknown. In a recent study, Li et al. show that reduced fatty acid oxidation causes a reverse metabolic switch in cardiomyocytes, which increases the amount of α-ketoglutarate, activates the KDM5 demethylase, and contributes to the immaturity of cardiomyocytes and cardiac regeneration.
First, the researchers analyzed publicly available RNA-sequencing data of cardiomyocytes isolated from neonatal mice and found upregulation of genes associated with the Krebs cycle and fatty acid oxidation, including the muscle-specific Cpt1b gene. Cpt1b activates fatty acids, enabling them to pass through the mitochondrial membrane and contribute to fatty acid oxidation. The authors genetically inactivated Cpt1b specifically in cardiomyocytes during mouse embryonic development (Cpt1bcKO) and observed a distinct increase in the numbers of smaller (<100 μm2) and larger (>300 μm2) cardiomyocytes, an increase in heart weight, and a modest increase in cardiomyocyte surface area, without any pathological alterations in the heart. Similarly, Cpt1b ablation in the cardiomyocytes of adult mice (Cpt1biKO) resulted in an increased number of cardiomyocytes, and increased cardiomyocyte surface area and cardiomegaly, which suggests increased cardiomyocyte proliferation and hyperplasia in Cpt1b-null hearts.
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