Endurance exercise protects cardiac muscle against doxorubicin‐induced damage via mitochondrial adaptations (706.1)

Abstract

Doxorubicin (DOX) is an antitumor agent used in cancer treatment. Unfortunately, DOX can induce cardiotoxicity that limits its clinical use. While endurance exercise training protects against DOX‐induced cardiotoxicity, the mechanisms for this exercise‐induced cardioprotection remain elusive. Therefore, we tested the hypothesis that exercise‐induced increases in the activity of cardiac AMPK can mediate alterations to downstream pathways protecting the heart from DOX‐induced damage. Rats were assigned to sedentary or exercise groups and paired with either placebo or DOX treatment. Exercise prior to DOX administration induced significant increases in the ratio of cardiac pAMPK/AMPK resulting in increased mRNA and protein levels of PGC‐1α in the heart. Cardiac PGC‐1α levels remained elevated in exercised animals treated with DOX. Also, exercise increased expression of the PGC‐1α‐sensitive mitochondrial fusion protein Mfn2 in the heart, which remained elevated in hearts of exercised animals treated with DOX. These findings reveal that exercise‐induced protection against DOX‐induced cardiomyopathy is associated with increases in myocardial levels of PGC‐1α that regulate the expression of proteins essential for mitochondrial function.