Mechanical loading induces distinct and shared responses in endothelial and muscle cells and reveals exercise-like molecular profiles

Skeletal muscles and blood vessels are continuously exposed to mechanical forces, particularly during exercise. We subjected human endothelial and skeletal muscle cells to cyclic mechanical stretch and investigated acute molecular responses. Mechanical loading elicited both shared and cell type-specific alterations in transcriptomic and metabolomic profiles, several of which mirror changes observed in vivo following exercise. Notably, both cell types released acetate in response to mechanical loading, however, many of the changes occurred in opposite directions. For example, genes associated with the electron transport chain were repressed in endothelial cells but upregulated in skeletal muscle cells. Furthermore, mechanical loading promoted a transcriptomic shift in endothelial cells indicative of maturation, and reduced their proliferation. Metabolic changes were more pronounced in endothelial cells, which exhibited increased serine biosynthesis from glucose, as demonstrated by ¹³ C-(U)-glucose tracing. Further experiments targeting phosphoglycerate dehydrogenase (PHGDH), a key enzyme in the serine synthesis pathway, underscored its role in endothelial cell anabolism. These findings suggest that mechanical loading alone can recapitulate several exercise-induced effects in endothelial and muscle cells, and highlight a potential link between mechanical stimuli, serine synthesis, and endothelial cell maturation.