YAP induces a prorenewal metabolic state in cardiomyocytes, offering novel insights into balancing metabolic maturation and proliferation to overcome barriers to heart regeneration.
YAP induces a prorenewal metabolic state in cardiomyocytes, offering potential novel insights for therapeutic intervention in heart failure by overcoming barriers to heart regeneration.
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BACKGROUND: Cardiomyocytes, as highly specialized and differentiated somatic cells, possess a limited capacity for renewal. Neonatal rodents possess the ability to regenerate cardiomyocytes after injury; however, this regenerative capacity declines rapidly with cardiomyocyte maturation, suggesting an inhibitory network between cellular maturation and cardiomyocyte proliferation. Maturing cardiomyocytes undergo a metabolic shift from predominantly glycolysis in the neonatal state to increased fatty acid oxidation in the mature state, which poses a barrier to cardiomyocyte proliferation and cardiac regenerative repair. YAP, a transcriptional cofactor regulated by the Hippo signaling pathway, promotes cardiac regenerative repair. We investigated the role of YAP in mediating metabolic remodeling to overcome the cardiomyocyte proliferation barrier and enable cardiac regenerative repair after heart injury. METHODS: We explored how YAP induces metabolic remodeling through single-nucleus RNA sequencing and metabolomic analyses in mice. Using lipidomic analysis, we demonstrated how YAP remodels the balance of fatty acid catabolism and anabolism. We further used a maternal fat overloading model to stimulate fatty acid oxidation, which activates a maturation program in neonatal cardiomyocytes and counteracts YAP-mediated metabolic dematuration. Using chromatin accessibility (assay for transposase-accessible chromatin with high-throughput sequencing), DNA footprinting, and transcriptional profiling (RNA sequencing), we discovered the key transcription factors that YAP interrupts to reprogram the cardiomyocyte metabolic state. RESULTS: Our results demonstrate that YAP directs metabolic remodeling of mature cardiomyocytes toward a neonatal-like metabolic state and illustrate the role of fatty acid metabolism in proliferating cardiomyocytes. We found that YAP reduces cardiomyocyte fatty acid utilization, driving fatty acid anabolism and phospholipid biosynthesis. Genome-wide analyses revealed that YAP inhibits the cardiac maturation transcription factor MEF2A (myocyte-specific enhancer factor 2A), resulting in decreased gene expression of cardiomyocyte maturity pathways. Given the role of MEF2A in regulating contractility, energy production, and mitochondrial homeostasis, we found that perturbing MEF2A transcriptional activity can serve as a strategy to interrupt the cardiomyocyte maturation program and restore the regenerative capacity of the heart. CONCLUSIONS: Our research endeavors to provide a comprehensive understanding of the balance of cardiomyocyte metabolic maturation and proliferation to overcome barriers to heart regeneration, offering novel insights into the potential for therapeutic intervention in heart failure.
“Our goal is to better understand the fundamental biology that limits heart regeneration in adults. By identifying mechanisms that can reprogram cardiomyocytes toward a more regenerative state, we are laying the groundwork for future therapies that could help the heart repair itself after injury.”
Liu et al. (Mon,) reported a other. YAP induces a prorenewal metabolic state in cardiomyocytes, offering novel insights into balancing metabolic maturation and proliferation to overcome barriers to heart regeneration.