Mycn Reactivates the Cell Cycle in Adult Cardiomyocytes and Promotes Cardioprotection in Myocardial Infarction

Background: Adult cardiomyocytes are terminally differentiated with limited capacity for cell cycle re‐entry. However, recent studies have shown that cycling cardiomyocytes may exert cardioprotective effects after myocardial infarction (MI). The Myc family— Myc , Mycl , and Mycn —regulates cell cycle progression and plasticity, raising the possibility that specific isoforms could reactivate cardiomyocyte cycling and therefore enhance cardiac repair in MI. This study evaluated the effects of Myc isoforms on cardiomyocyte cell cycle activation and cardiac outcomes after MI. Methods: Cardiomyocyte‐specific overexpression of Myc , Mycl , or Mycn was induced in adult mice using adeno‐associated virus 9 vectors driven by the cardiac troponin T promoter. Cell cycle activity, remodeling, and function were assessed by RNA sequencing, immunohistochemistry, and echocardiography. Cardioprotection was evaluated in MI models. Results: Mycn elicited the most robust cell cycle gene expression among the Myc isoforms. Mycn overexpression markedly enhanced cardiomyocyte re‐entry—evidenced by increased 5‐bromo‐2′‐deoxyuridine incorporation and histone H3 phosphorylation—and induced hypertrophic growth. Transcriptomic profiling revealed Mycn ‐specific upregulation of extracellular matrix and paracrine signaling genes, which are typically enriched in neonatal cardiomyocytes and also linked to cardioprotection. In MI models, Mycn preserved cardiac contractility, reduced infarct size, and increased capillary density in peri‐infarct regions. Conclusions: Mycn exerts robust biological effects in the adult heart, including reactivation of the cardiomyocyte cell cycle and promotion of cardioprotection following ischemic injury. Its effects likely involve induction of a neonatal‐like transcriptional program that fosters a stress‐adaptive microenvironment.