Exercise Training Upregulates Cardiac mtp Expression in Drosophila melanogaster with HFD to Improve Cardiac Dysfunction and Abnormal Lipid Metabolism

SIMPLE SUMMARY: It is well-established that the heart regulates systemic lipid metabolism, but the exact molecular mechanisms remain largely unclear. A high-fat diet (HFD) can lead to systemic lipid overload and a range of cardiac dysfunctions such as arrhythmias, fibrillation and reduced contractility. Although pharmacological treatment is often effective, there are always side effects. Accordingly, exercise training represents an effective alternative intervention to medication. In this experiment, we established a high-fat Drosophila model by HFD feeding and conducted exercise training intervention to investigate whether the exercise intervention altered the expression of the target gene (mtp), thus affecting systemic lipid metabolism and cardiac function. Our results suggest that specific knockdown of mtp mitigates HFD-induced elevation of systemic triglycerides and protects cardiac contractility to some extent. Further analysis showed that exercise training could upregulate the expression of mtp to restore dysregulated systemic lipid metabolism and cardiac function induced by HFD. Overall, we explored the important role of mtp in systemic lipid metabolism and cardiac function, providing new insights for future clinical studies related to lipotoxic cardiomyopathy and the potential use of exercise training to treat abnormal lipid metabolism and cardiac dysfunction due to HFD. ABSTRACT: Current evidence suggests that the heart plays an important role in regulating systemic lipid homeostasis, and high-fat diet (HFD)-induced obesity is a major cause of cardiovascular disease, although little is known about the specific mechanisms involved. Exercise training can reportedly improve abnormal lipid metabolism and cardiac dysfunction induced by high-fat diets; however, the molecular mechanisms are not yet understood. In the present study, to explore the relationship between exercise training and cardiac mtp in HFD flies and potential mechanisms by which exercise training affects HFD flies, Drosophila was selected as a model organism, and the GAL4/UAS system was used to specifically knock down the target gene. Experiments revealed that HFD-fed Drosophila exhibited changes in body weight, increased triglycerides (TG) and dysregulated cardiac contractility, consistent with observations in mammals. Interestingly, inhibition of cardiac mtp expression reduced HFD-induced cardiac damage and mitigated the increase in triglycerides. Further studies showed that in HFD +w(1118), HFD + Hand > w(1118), and HFD+ Hand > mtp(RNAi), cardiac mtp expression downregulation induced by HFD was treated by exercise training and mitochondrial β-oxidation capacity in cardiomyocytes was reversed. Overall, knocking down mtp in the heart prevented an increase in systemic TG levels and protected cardiac contractility from damage caused by HFD, similar to the findings observed after exercise training. Moreover, exercise training upregulated the decrease in cardiac mtp expression induced by HFD. Increased Had1 and Acox3 expression were observed, consistent with changes in cardiac mtp expression.