Matrix metalloproteinase 9 deficiency promotes endogenous cardiomyocyte proliferation

Abstract

Matrix metalloproteinase 9 (MMP9) is known to modulate cardiac remodeling after myocardial infarction, but its role in cardiomyocyte proliferation remains unclear. Here, we showed that MMP9 deficiency enhanced neonatal cardiomyocyte proliferation and mononucleation following apical resection. Integrated transcriptomic and proteomic analyses revealed that MMP9 knockout induces a metabolic shift from oxidative phosphorylation to glycolysis in injured neonatal hearts, coinciding with upregulation of acyl-CoA thioesterase 1 (ACOT1). ACOT1 overexpression enhanced glycolysis and proliferation in primary rat cardiomyocytes, whereas 2-Deoxy-D-glucose inhibition blocked this effect. Collectively, our findings demonstrate that MMP9 deficiency drives a metabolic shift from oxidative phosphorylation to glycolysis via ACOT1 upregulation, thereby promoting cardiomyocyte proliferation.