Exercise inhibits doxorubicin-induced cardiotoxicity by preventing cardiac and endothelial cell senescence by activating FNDC5/Irisin signaling

Exercise’s effect on Dox-induced cardiac senescence in the heart was investigated using p16-3MR transgenic mice. Mice treated with doxorubicin (Dox) had decreased cardiac function, increased p16INK4a + and b-Galactosidase+ senescent cells in the heart, decreased HMGB1 and calreticulin expression, endothelial cell senescence, and decreased TUJ1 expression (indicating reduced axonal density), increased expression of Semaphorin3A and p-cofilin with impaired F-actin depolarization and cytoskeleton disorganization. None of these changes were seen in mice treated with Dox + Exercise. Exercise sustained the levels of FNDC5 in the heart compared with the Dox-treated hearts suggesting a link between exercise, decreased senescence, and the FNDC5/ irisin pathway. In vitro studies using human cardiomyocytes and endothelial cells confirmed that irisin attenuated Dox-induced senescence. Taken together, these data provide evidence that exercise mitigates Dox-induced cardiotoxicity by suppressing cardiovascular senescence via a mechanism involving the exercise-induced myosin irisin, and that exercise is a potential intervention for preventing Dox-induced cardiotoxicity.