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Cholesterol metabolism plays a crucial role in regulating cardiac repair, influencing inflammation and cell proliferation. After birth, adult cardiomyocytes undergo a rapid metabolic shift from glycolysis-dominated metabolism to fatty acid oxidation (FAO)-dominant metabolism. This transition is accompanied by the maturation of cardiomyocytes and the loss of their proliferative capacity, posing a natural barrier to cardiac regeneration. Therefore, identifying effective methods to reactivate cardiomyocyte proliferation in the adult heart is a significant scientific and clinical challenge. Inhibition of fatty acid oxidation (FAO) has been demonstrated to enhance cardiac regeneration in various heart injury models. Targeted metabolic interventions on specific lipid metabolism pathways can modulate cardiac regeneration, highlighting the therapeutic potential of metabolic reprogramming.

Recently, Li et al. explored the impact of inhibiting fatty acid oxidation (FAO) in cardiomyocytes on cardiac regeneration. Firstly, the authors used αMHC-Cre and Cpt1b fl/fl mouse models (Cpt1bcKO), as well as Tamoxifen-induced Cpt1biKO mouse models, to specifically inhibit the Cpt1b gene in cardiomyocytes. The results showed that Cpt1b gene inactivation effectively inhibited FAO, enhanced hypoxia resistance, and significantly increased cardiomyocyte proliferation. RNA-seq data analysis indicated that Cpt1b inactivation led to the accumulation of α-ketoglutarate (αKG), which activated the αKG-dependent lysine demethylase KDM5. Secondly, metabolic studies demonstrated significant changes in energy metabolism in Cpt1b mutant cardiomyocytes, with αKG accumulation leading to KDM5 activation. This activation resulted in the demethylation of genes on H3K4me3 broad domains, reducing their transcription levels and maintaining cardiomyocytes in a less mature state, thereby promoting proliferation. Further metabolic flux and Seahorse analyses indicated that Cpt1b-deficient cardiomyocytes efficiently utilized glucose and branched-chain amino acids as alternative energy sources to compensate for the loss of FAO. To verify whether Cpt1b inactivation promotes cardiac regeneration, the researchers conducted ischemia-reperfusion (I-R) injury experiments on Cpt1bcKO and Cpt1biKO mice. The results showed that Cpt1b-deficient mouse hearts formed almost no scars post I-R injury, and their cardiac function significantly recovered, indicating that FAO inhibition not only promoted cardiomyocyte proliferation but also enhanced cardiomyocyte protection. ChIP-seq analysis revealed a significant reduction in H3K4me3 levels in Cpt1b-deficient cardiomyocytes, particularly on genes involved in cardiac maturation and function. These genes included Mylk3, Cacna1g, and Myocd, where H3K4me3 demethylation resulted in decreased expression, reprogramming cardiomyocytes into a more proliferative state. Finally, to further confirm the critical role of αKG in this process, the authors treated neonatal cardiomyocytes with αKG. The results showed a significant increase in Ki67+cTnT+ and pH3(Ser10)+cTnT+ cardiomyocytes, with a concomitant decrease in H3K4me3 levels in these cells, confirming that αKG promoted cardiomyocyte proliferation through KDM5-mediated H3K4me3 demethylation. Additionally, by overexpressing Kdm5b or inhibiting KDM5 activity, the study further validated the pivotal role of KDM5 in this process.

Previous research primarily focused on enhancing anaerobic metabolism, such as expressing Pkm2 mRNA and deleting Pdk4, to promote cardiomyocyte proliferation. However, these approaches failed to systematically elucidate how metabolic reprogramming limits cardiomyocyte proliferation through transcriptional and structural changes. This study systematically inhibited FAO by specifically inhibiting Cpt1b, thereby providing a comprehensive observation of the effects of metabolic reprogramming on cardiomyocyte proliferation. This approach offers a more systematic and in-depth understanding. The study also revealed for the first time the direct link between metabolic state, chromatin structure, and gene expression. Furthermore, the research team employed innovative functional validation experiments, providing robust experimental evidence for understanding the complex relationship between metabolism and gene expression. These findings hold potential clinical applications, offering new therapeutic strategies for patients with heart disease, especially in the treatment of acute cardiac injuries such as myocardial infarction.

However, the study has certain limitations, such as the constraints of the models used, the complexity of metabolic reprogramming, and concerns regarding long-term safety. Additionally, the impact of immune responses and the microenvironment, including the extracellular matrix and signaling molecules, needs to be considered. Therefore, future research should further explore the specific mechanisms of metabolic reprogramming, assess its long-term safety and efficacy, and investigate the feasibility of personalized treatment strategies.

Reference:

Li X, Wu F, Günther S, et al. Inhibition of fatty acid oxidation enables heart regeneration in adult mice[J]. Nature, 2023, 622(7983): 619-626.