Thyroxine Alleviates Energy Failure, Prevents Myocardial Cell Apoptosis, and Protects against Doxorubicin-Induced Cardiac Injury and Cardiac Dysfunction via the LKB1/AMPK/mTOR Axis in Mice

Abstract

Background Previous studies have demonstrated that energy failure is closely associated with cardiac injury. Doxorubicin (DOX) is a commonly used clinical chemotherapy drug that can mediate cardiac injury through a variety of mechanisms. Thyroxine is well known to play a critical role in energy generation; thus, this study is aimed at investigating whether thyroxine can attenuate DOX-induced cardiac injury by regulating energy generation. Methods First, the effect of DOX on adenosine diphosphate (ADP) and adenosine triphosphate (ATP) ratios in mice was assessed. In addition, thyroxine was given to mice before they were treated with DOX to investigate the effects of thyroxine on DOX-induced cardiac injury. Furthermore, to determine whether the liver kinase b1 (LKB1)/adenosine 5′-monophosphate-activated protein kinase (AMPK)/mammalian target of rapamycin (mTOR) axis mediated the effect of thyroxine on DOX-induced cardiac injury, thyroxine was given to DOX-treated LKB1 knockout (KO) mice. Results DOX treatment time- and dose-dependently increased the ADP/ATP ratio. Thyroxine treatment also reduced lactate dehydrogenase (LDH) and creatine kinase myocardial band (CK-MB) levels in both serum and heart tissue and alleviated cardiac dysfunction in DOX-treated mice. Furthermore, thyroxine reversed DOX-induced reductions in LKB1 and AMPK phosphorylation; mitochondrial complex I, III, and IV activity; and mitochondrial swelling and reversed DOX-induced increases in mTOR pathway phosphorylation and myocardial cell apoptosis. These effects of thyroxine on DOX-treated mice were significantly attenuated by LKB1 KO. Conclusions Thyroxine alleviates energy failure, reduces myocardial cell apoptosis, and protects against DOX-induced cardiac injury via the LKB1/AMPK/mTOR axis in mice. Thyroxine may be a new agent for the clinical prevention of cardiac injury in tumor patients undergoing chemotherapy with DOX.