YAP Induces a Pro-Renewal Metabolic State in Cardiomyocytes: Cardiomyocyte-enriched Datasets

Cardiomyocyte (CM) maturation is characterized by a change in energy metabolism from glucose to fatty acid catabolism, which poses a barrier to CM proliferation and cardiac regenerative repair. YAP, a transcriptional cofactor that is regulated by the Hippo signaling pathway, induces cardiac regenerative repair. We investigated YAP function in postnatal metabolic maturation and remodeling and found that YAP inhibits fatty acid catabolism and shifts fatty acid catabolism to anabolism with phospholipid biosynthesis. Moreover, YAP induced metabolic remodeling enhances CM carbohydrate utilization. Functional experiments using maternal dietary fat challenge, which stimulates fatty acid oxidation (FAO) and induces CM maturation, counteracts YAP-induced metabolic remodeling. Mechanistically, we discover that YAP inhibits the MEF2A directed maturation program leading to a neonatal-like CM metabolic state. We provide a transcriptional framework by which YAP induces neonatal CM metabolic remodeling to reverse CM metabolic maturation, thereby promoting heart regeneration.