Key result
YAP overexpression promotes cardiac regeneration by driving neonatal-like metabolic reprogramming in mature cardiomyocytes.
Why the study?
To understand the balance of cardiomyocyte metabolic maturation and proliferation to overcome barriers to heart regeneration.
Key Points
- To investigate how YAP-driven metabolic remodeling overcomes the cardiomyocyte proliferation barrier and facilitates regenerative repair in the injured heart.
- Analyzed adult and postnatal day 7 mice expressing YAP5SA using single-nucleus RNA sequencing, metabolomics, and lipidomic assays.
- Assessed metabolic fuel usage with Seahorse fatty acid oxidation and glucose utilization stress tests, as well as ATAC-seq chromatin accessibility and DNA footprinting.
- Employed a maternal high-fat diet model to activate fatty acid oxidation and evaluate its ability to counteract YAP-mediated metabolic reprogramming.
- YAP5SA expression suppressed fatty acid utilization genes (Ppargc1a, Ppara, Cd36, and Cpt1b) and shifted cellular metabolism to glucose catabolism, elevating pyruvate and citrate levels while reducing acyl-carnitines.
- Lipidomic profiling revealed a selective conversion of 18-carbon fatty acids from triglycerides into phospholipids, marked by reduced saturated and unsaturated triglycerides and elevated glycerophospholipids.
- Genomic analyses showed YAP represses the transcription factor MEF2A and downregulates RXR/PPAR activity, an effect antagonized by maternal high-fat diet or γ-linolenic acid supplementation.
Structured PICO
P
Population
Mouse models (neonatal and adult) used to investigate the role of YAP and MEF2A in cardiomyocyte metabolic remodeling and cardiac regenerative repair.
I
Intervention
YAP activation (via transgenic overexpression, AAV-delivery of YAP5SA, or Sav1 deletion) and metabolic modulation (e.g., maternal high-fat diet, PDK inhibitors, etomoxir).
C
Comparator
Littermate controls, normal-fat diet, or untreated controls.
O
Outcome
Cardiomyocyte metabolic remodeling (shift between glycolysis and fatty acid oxidation) and cardiac regenerative capacity.surrogate
YAP induces a pro-renewal, neonatal-like metabolic state in mature cardiomyocytes by suppressing fatty acid oxidation and the MEF2A maturation program, highlighting a potential strategy to restore regenerative capacity in heart failure.
Limitations
- Study does not rule out off-target or cell-nonspecific effects of pharmacological inhibitors like etomoxir or dichloroacetate.
- Further studies using isoform-selective inhibitors or genetic models may be needed to dissect specific roles of CPT1b or PDK4 in YAP-mediated cardiac effects.
Discussion
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Key expert perspectives
Captured external expert commentary on this paper, strongest first. Original sources are linked where available.
“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.”
“Induction of endogenous regeneration of human heart muscle is the holy grail of modern medicine. YAP101 is designed to unlock the heart's own repair mechanism by transiently lifting the Hippo pathway 'brake' and activating YAP via shRNAs delivered directly to cardiomyocytes. We successfully regenerated cardiomyocytes in preclinical studies, and we are excited about the next step—healing the hearts of patients with limited treatment options.”
“Until now, there has not been a way to regenerate human heart tissue. YAP101 offers new hope for patients with heart failure. Our aim is to enable the heart to repair itself and reverse heart failure through a brief cardiac catheterization procedure.”
Implication
YAP metabolic reprogramming may guide future regeneration strategies; leaves open whether this axis can be safely targeted in patients.
Abstract
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.
Cite This Study
Liu et al. (2026) studied Cardiomyocyte renewal and cardiac regenerative repair. YAP5SA overexpression vs. Control littermates was evaluated. YAP overexpression directs metabolic remodeling of mature cardiomyocytes toward a neonatal-like state by reducing fatty acid utilization and driving glucose utilization, enhancing cardiac regeneration.