Exercise-induced cellular changes promote improved function in ischemic hearts

Ischemic heart disease (IHD) remains a leading cause of mortality worldwide, often culminating in myocardial infarction (MI) and subsequent heart failure due to adverse fibrotic remodeling of the myocardium. Despite the lack of effective treatments, exercise has emerged as a promising strategy to reduce mortality risk and improve cardiac function post-MI. This study investigates the molecular mechanisms underlying exercise-induced cardioprotection by analyzing changes in several key cardiac cell populations after MI in a murine model. We assessed the effect of exercise preconditioning in mouse MI model through echocardiography, followed by single nuclei RNA-seq of cardiac cells, and validation by microscopy and flow cytometry. Our findings demonstrate that exercise significantly enhances cardiac function post-MI, as evidenced by improved ejection fraction and stroke volume in exercised mice. These improvements are linked to adaptive changes across multiple cardiac cell types. Notably, in infarcted mice, exercise caused a downregulation of cardiomyopathy-associated pathways, accompanied by changes in ECs, macrophages, fibroblasts and cardiomyocytes. Exercise stimulated formation of new capillaries which post-MI resulted in a more vascularized infarct border zone. Additionally, exercised hearts displayed a shift in macrophage populations towards a pro-regenerative phenotype, marked by an increase in resident CCR2- macrophages and a reduction in pro-inflammatory M1-gene expression. In cardiomyocytes, exercise enhanced pathways related to endothelial support and ATP biosynthesis, mitigating the upregulation of cardiomyopathy-associated pathways observed post-MI. Importantly, exercise also restored calcium signaling and reversed pathological potassium signaling, thereby preserving contractile function. Fibroblast analysis revealed that exercise stimulated activation of these cells to participate in scar formation. In conclusion, this study provides new insights into the cellular and molecular mechanisms through which exercise enhances cardiac function and provides cardio-protection post-MI, offering potential avenues for targeted therapies in patients with IHD.