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

Background Adult mammalian cardiomyocytes are terminally differentiated and possess minimal capacity for cell cycle re-entry. However, recent studies have shown that a rare population of cycling cardiomyocytes may confer cardioprotective effects following myocardial infarction (MI). The Myc family—Myc, Mycl, and Mycn—plays central roles in regulating cell cycle progression and cellular plasticity. This raises the possibility that specific Myc isoforms could reactivate the cardiomyocyte cell cycle and promote cardioprotective responses in the ischemic heart. This study aimed to systematically evaluate the effects of Myc, Mycl, and Mycn on cardiomyocyte cell cycle activation and cardiac outcomes following MI. Methods Cardiomyocyte-specific overexpression of Myc , Mycl , or Mycn was achieved in adult mice via adeno-associated virus 9 vectors driven by the cardiac troponin T promoter. Cardiomyocyte cell cycle activity, structural remodeling, and functional outcomes were assessed using RNA sequencing, immunohistochemistry, and transthoracic echocardiography. Cardioprotective effects were evaluated in MI model mice. Results While all three Myc family members activated cell cycle-related gene expression to varying degrees, Mycn elicited the most robust response. Mycn overexpression significantly enhanced cardiomyocyte cell cycle re-entry, as demonstrated by increased 5-bromo-2’-deoxyuridine incorporation and phosphorylation of histone H3. Mycn also induced hypertrophic growth, reflected by increased cardiomyocyte size and heart mass. Transcriptomic analyses revealed that Mycn uniquely upregulated genes associated with extracellular matrix remodeling and paracrine signaling, typically enriched in neonatal cardiomyocytes and previously linked to cardioprotection. Functionally, Mycn expression preserved cardiac contractility after MI, reduced infarct size, and increased capillary density in peri-infarct regions. Conclusions These findings identify Mycn as a functionally distinct member of the Myc family in the adult heart, capable of reactivating the cardiomyocyte cell cycle and promoting cardiac protection after ischemic injury. The cardioprotective effects appear to be mediated, in part, by the induction of a neonatal-like gene expression program supporting a stress-adaptive cardiac microenvironment.