Treadmill exercise activates mechanosensitive Piezo1 to inhibit cardiomyocyte apoptosis and improve cardiac function after myocardial infarction in mice.

Abstract

The cardioprotective mechanisms through which the heart directly senses exercise remain incompletely defined. In this study, wild-type C57BL/6J and cardiomyocyte-specific Piezo1 knockdown mice were subjected to myocardial infarction (MI) and moderate treadmill exercise. We found that treadmill exercise significantly increased myocardial Piezo1 and SERCA2 expression and improved ejection fraction and short-axis shortening fraction in MI mice through echocardiography, histological staining, and molecular biology analysis. In contrast, Piezo1 knockdown impaired exercise-induced reductions in cardiomyocyte apoptosis, survival benefits, and attenuation of fibrosis. In HL-1 cells, mechanical stretch upregulated Piezo1 and suppressed HO-induced apoptosis via the p38MAPK-YAP1 pathway, while Piezo1 deficiency abolished this protective signaling. In addition, Piezo1 mediates the expression of FSTL1 and GDF5, which are key molecules of exercise-induced cardioprotection. These findings identify Piezo1 as a mechanosensor essential for exercise-triggered myocardial protection and highlight its potential therapeutic relevance for MI patients' recovery.