Abstract Body: BACKGROUND:
Cardiomyocytes (CMs) possess a limited capacity for renewal. Neonatal rodent and porcine models possess the ability to regenerate CMs following injury; however, CM regeneration rapidly declines with CM maturation, suggesting an inhibitory network between cellular maturation and proliferation in CMs. During this maturation process, CMs undergo a metabolic shift from predominantly glycolysis in the neonatal state towards increased reliance on fatty acid oxidation (FAO) in the mature state. While such metabolic state is required to meet the increased energetic demands of the growing heart, it also establishes a barrier to CM proliferation.
HYPOTHESIS:
We hypothesis that YAP induces the metabolic remodeling to overcome the CM proliferation barrier, enabling cardiac regeneration after heart injury.
METHODS:
We explored how YAP induces metabolic remodeling through transcriptomic (snRNA-seq) and metabolomic analyses in mice. By 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 stimulates fatty acid oxidation (FAO) and activates a maturation program in neonatal CMs to counteract YAP-mediated metabolic de-maturation effect. Following ATAC-seq, DNA footprinting, and transcriptional profiling (RNA-seq), we want to find the key transcription factors that YAP interrupts to reprogram the CM metabolic states.
RESULTS:
In this study, we found that YAP directs metabolic remodeling from mature CM to neonatal-like CM metabolic state and illustrate how fatty acid metabolism functions in proliferating CMs. We found that YAP reduced CM fatty acid utilization, driving fatty acid anabolism and phospholipid biosynthesis. We identified that YAP transcriptional activity inhibits the cardiac maturation transcription factor MEF2A genome wide, resulting in decreased CM maturity. 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 CM maturation program and restore regenerative capacity of the heart.
CONCLUSIONS:
Our research endeavors to provide a comprehensive understanding about how YAP balances CM metabolic maturation and proliferation to overcome the barriers for heart regeneration, offering novel insights into the potential for therapeutic intervention in heart failure.