Effects of melatonin on cardiac metabolic reprogramming in doxorubicin-induced heart failure rats: A metabolomics study for potential therapeutic targets.

Using mass spectrometry-based targeted metabolomics, we aimed to determine the pattern of cardiac metabolic reprogramming and energetics in doxorubicin-induced heart failure. More importantly, we aimed to identify the potential effects of melatonin on cardiac metabolic reprogramming and energetics in doxorubicin-induced heart failure. Male Wistar rats (n = 18) were randomly divided into three groups (n = 6/group) to receive either (1) normal saline solution as a control, (2) 3 mg/kg/day of doxorubicin on Days 0, 4, 8, 15, 22, and 29, or (3) 3 mg/kg/day of doxorubicin on Days 0, 4, 8, 15, 22, and 29 plus 10 mg/kg/day of melatonin on Days 0-29. On Day 30, echocardiography was carried out and heart rate variability was analyzed for the evaluation of cardiac function. The rats were euthanized on the following day to enable the collection of ventricular cardiac tissue. Compared to the control group, the hearts of rats treated with doxorubicin alone exhibited impaired cardiac function, increased glucose and ketone body utilization, decreased fat utilization, decreased succinate oxidation, and decreased production of adenosine triphosphate. The cotreatment with melatonin could restore cardiac function, glucose and ketone body utilization, and adenosine triphosphate production in the heart. Interestingly, the cotreatment with melatonin led to an increase in cardiac fatty acid oxidation, branched-chain amino acid catabolism, and anaplerosis. All of these findings highlighted the potential efficacy of melatonin with regard to cardiac metabolic reprogramming and energetics. Our findings also suggested that melatonin could be considered as an adjunctive treatment for doxorubicin-induced heart failure in clinical practice.

Blood metabolomes as non-invasive biomarkers and targets of metabolic interventions for doxorubicin and trastuzumab-induced cardiotoxicity.

This study aimed to identify the alterations of blood metabolome levels and their association with cardiac dysfunction and cardiac injury following treatment with doxorubicin and trastuzumab. Eight-week-old male Wistar rats were divided into four groups (n = 6 per group) to receive intraperitoneal injection with either: (1) 1 mL of normal saline solution (NSS) at days 0, 4, 8, 15, 22, and 29 (control group for doxorubicin); (2) 3 mg/kg/day of doxorubicin at days 0, 4, 8, 15, 22, and 29 (doxorubicin group); (3) 1 mL of NSS at days 0-6 (control group for trastuzumab); or (4) 4 mg/kg/day of trastuzumab at days 0-6 (trastuzumab group). Four days after the last injected dose, cardiac function was determined. The rats were then euthanized to collect venous blood and the heart for the quantification of 107 serum and 100 cardiac metabolomes using mass spectrometry-based targeted metabolomics. We observed strong relationships between 72 cardiac versus 61 serum metabolomes in doxorubicin and trastuzumab groups. Moreover, significant correlations between cardiac function and the cardiac injury biomarker versus 28 and 58 serum metabolomes were revealed in doxorubicin and trastuzumab-treated rats, respectively. Interestingly, the patterns of both serum and cardiac metabolome alterations differed between doxorubicin and trastuzumab groups. Our findings emphasize the potential role of the constituents of the blood metabolome as non-invasive biomarkers to assess severity and prognosis of heart failure induced by doxorubicin and trastuzumab. These findings may contribute to the development of metabolic-targeted therapy specific for cardioprotection during different phases of cancer treatment.