Multiomic analyses reveal enriched glycolytic processes in β-myosin heavy chain-expressed cardiomyocytes in early cardiac hypertrophy.

Background: Cardiac pressure overload induces cardiac hypertrophy and eventually leads to heart failure. One distinct feature of pathological cardiac hypertrophy is fetal-gene re-expression, but not every cardiomyocyte exhibits fetal gene re-expression in the diseased heart. Adult cardiomyocytes are terminally differentiated cells, so we do not know how the heterogeneity is determined and whether the differential fetal-gene reprogramming indicates a different degree of remodeling among cardiomyocytes. We hypothesized that fetal gene-expressed cardiomyocytes show more pathological features in the pressure-overloaded heart.

Results: We induced pressure overload in mice by transverse aortic constriction (TAC) and observed a cardiomyocyte population with expression of β-myosin heavy chain (βMHC, a fetal gene encoded by ) after TAC for 3 days. On transcriptomic and proteomic analyses, βMHC-expressed cardiomyocytes of 3-day TAC hearts were enriched in genes in cardiomyopathy-associated pathways and glycolytic processes. Moreover, results of immunoblotting and enzyme activity assay suggested higher glycolytic activity in βMHC-expressed than non-expressed cardiomyocytes. When we inhibited the glycolytic flux by 2-deoxy-d-glucose, a widely used glycolysis inhibitor, the number of βMHC-expressed cardiomyocytes was reduced, and the level of TEA domain family member 1 (TEAD1), a transcriptional enhancer, was decreased. Also, our spatial transcriptomic results demonstrated that naïve and 3-day TAC hearts had fetal-gene-rich tissue domains that were enriched in pathways in extracellular matrix organization and tissue remodeling. As well, gene levels of glycolytic enzymes were higher in -positive than -negative domains.

Conclusions: Our data suggest that βMHC-expressed cardiomyocytes progress to pathological remodeling in the early stages of cardiac hypertrophy. In addition, the diverse glycolytic activity among cardiomyocytes might play a role in regulating gene expression via TEAD1 signaling.