Melatonin attenuates an impairment of metabolic reprogramming in doxorubicin-induced cardiotoxicity: insights from metabolomics study in rats

Abstract

Abstract Background Doxorubicin is an effective chemotherapeutic agent. Unfortunately, the clinical utilization of doxorubicin is limited due to cardiotoxicity. It was previously shown that doxorubicin caused the changes in glycolysis metabolome levels, fatty acid levels, and genes involving lipid metabolism in the heart. However, the pattern of metabolic reprogramming in doxorubicin-induced heart failure remains unknown. Moreover, the benefit of melatonin in attenuating doxorubicin-induced heart failure was previously revealed. Nonetheless, the potential benefits of melatonin on metabolic reprogramming in doxorubicin-induced heart failure has never been determined. Purposes Using liquid chromatography coupled with mass spectrometry-based targeted metabolomics, we identified the pattern of metabolic reprogramming in rats with doxorubicin-induced heart failure. In addition, the effects of melatonin on metabolic reprogramming in doxorubicin-induced heart failure were investigated. Methods Male Wistar rats (n=18) were divided into 3 groups (n=6/group) to receive either 1) normal saline solution as a vehicle, 2) 3 mg/kg/day of doxorubicin at days 0, 4, 8, 15, 22, and 29, and 3) 3 mg/kg/day of doxorubicin at days 0, 4, 8, 15, 22, and 29 plus 10 mg/kg/day of melatonin at days 0-29. At day 30, echocardiography and heart rate variability were done for an evaluation of cardiac function. The rats were then euthanized to collect ventricular cardiac tissues for metabolomics study. Results Comparing to vehicle-treated rats, the heart of rats treated with doxorubicin alone exhibited cardiac dysfunction, increased glucose and ketone body utilization, decreased fat utilization, decreased succinate oxidation, and decreased adenosine triphosphate (ATP) production. The co-treatment with melatonin effectively restored cardiac function, glucose and ketone body utilization, and ATP production in the heart. Interestingly, the co-treatment with melatonin also increased cardiac fatty acid oxidation, branched-chain amino acid catabolism, and anaplerosis (Figure). Conclusions Our findings highlighted the potential benefits of melatonin on cardiac metabolic reprogramming impaired by doxorubicin. These findings also suggested that melatonin could be considered as an adjunctive treatment for doxorubicin-induced heart failure in clinical settings.