Exercise protects mouse hearts from chemotherapy toxicity by suppressing cellular senescence

In a preprint study using p16-3MR transgenic mice, researchers evaluated whether exercise prevents heart damage caused by doxorubicin. Mice treated with the chemotherapy drug developed reduced cardiac function alongside elevated p16INK4a and beta-galactosidase markers of senescent cells in the heart. Doxorubicin also triggered endothelial cell senescence, reduced axonal density, decreased HMGB1 and calreticulin expression, and disrupted the cytoskeleton through Semaphorin3A and phosphorylated cofilin. Concurrent exercise completely prevented these detrimental changes and maintained cardiac levels of FNDC5. In cell culture experiments, treating human cardiomyocytes and endothelial cells with irisin directly attenuated doxorubicin-induced senescence. The findings show that exercise mitigates cardiotoxicity by curbing cardiovascular senescence via FNDC5 and irisin signaling pathways.