Comparative Single-Nucleus Transcriptomic Analysis of the Intact Left Ventricle in Acomys cahirinus and Mus musculus

Background/Objectives: Acomys cahirinus exhibits more favorable cardiac remodeling after ischemic injury than Mus musculus, yet the molecular organization of the intact myocardium remains poorly characterized. This study aimed to identify baseline interspecies differences in the adult left ventricle, with particular emphasis on ventricular cardiomyocyte transcriptional states. Methods: Intact left ventricles from adult male A. cahirinus and M. musculus were analyzed by single-nucleus RNA sequencing using three biological samples per species. Cross-species integration was followed by cell type annotation, pseudobulk differential expression analysis, Augur-based assessment of interspecies separability, coexpression module analysis, and focused reintegration analysis of ventricular cardiomyocytes. Cardiomyocyte profiles were further compared with published embryonic and early postnatal M. musculus heart datasets. Results: Both species contained comparable major myocardial cell populations, whereas marked interspecies transcriptional differences persisted within individual cell types. Ventricular cardiomyocytes exhibited the largest number of differentially expressed genes and were classified into three transcriptional states: contractile, matrix-associated, and alternative. Adult A. cahirinus cardiomyocytes retained a mature cardiomyocyte phenotype but showed greater enrichment of developmental, morphogenetic, and Hippo-associated gene programs than adult M. musculus cardiomyocytes. Their transcriptional profile did not correspond to embryonic or early postnatal mouse states. The integrated atlas further identified interspecies differences in fibroblast-associated and extracellular matrix-related programs. Conclusions: The intact myocardium of A. cahirinus exhibits cell type-specific transcriptional differences relative to M. musculus. Ventricular cardiomyocytes display a distinct mature transcriptional configuration rather than a direct immature state, which may contribute to the favorable response of A. cahirinus to myocardial injury.