Abstract 10234: HMGCS2-Mediated Ketogenesis Induces Adult Cardiomyocyte Dedifferentiation and Enables Cardiac Regeneration

Introduction: Human cardiac regeneration after injury is limited by the low proliferative capacity of adult mammalian cardiomyocytes (CMs). However, some animals readily regenerate lost myocardium via a process involving CM dedifferentiation, which unlocks their proliferative capacity. Methods: Inspired by this concept, we generated mice with inducible, CM-specific expression of the Yamanaka factors (OSKM), enabling adult CM dedifferentiation in vivo . We profiled changes in CM gene expression by microarray, measured metabolite production by LC-MS and 13 C NMR, and used adeno-associated virus (AAV) to over-express target genes. Cardiac function was measured by echocardiography and intraventricular catheterization. Results: Two days following OSKM induction, adult CMs exhibited a dedifferentiated phenotype and increased proliferation in vivo . Microarray analysis revealed alterations of metabolism-related pathways, particularly an increase of the ketogenic enzyme HMGCS2. Analysis of metabolites confirmed that HMGCS2-induced ketogenesis in adult CMs allowed a metabolic switch from fatty acid oxidation towards ketone utilization. AAV-driven overexpression of HMGCS2 in OSKM mice induced more adult CM dedifferentiation and increased the proliferation rate by two-fold compared to controls. The same phenomenon was observed after myocardial infarction, specifically in the border zone. On the contrary, CM-specific HMGCS2 knockout mice showed poorer baseline cardiac function and impaired recovery following injury. Forced expression of HMGCS2 rescued cardiac function in these mice, thus demonstrating a role of ketogenesis in CM dedifferentiation and proliferation. Conclusions: These data demonstrate the importance of HMGCS2-induced ketogenesis as a means to regulate metabolic response to mammalian cardiac injury, allowing cell dedifferentiation and proliferation as a regenerative response.