Dihydromyricetin ameliorates myocardial glucose absorption and glycolysis in mice with diabetic cardiomyopathy

Abstract

Objective To observe the ameliorative efficacy of dihydromyricetin (DHM) on diabetic cardiomyopathy (DCM), and reveal its effect and underlying mechanism of improving myocardial glucose metabolism. Methods DCM model was established in C57BL/6J male mice by high-fat diet combined with intraperitoneal injection of streptozotocin (STZ). The mice were subsequently divided into control group (CON, normal diet), DCM group (high-fat diet), and DCM+DHM group (high-fat diet and DHM), with 15 animals in each group. After 13 weeks of intervention, echocardiography and glucose tolerance test were performed before sacrifiction. After execution, the myocardial morphology was observed with HE, Masson, and Sirius Red staining, and serum biochemical indexes were detected. The expression levels of genes and proteins related to glucose absorption and glycolysis in myocardial tissue were determined by immunofluorescence assay and qRT-PCR. The differentially expressed genes and their enriched signal pathways were analyzed with RNA-Seq technique. Results Both the cardiac systolic and diastolic functions were significantly impaired in the DCM group, accompanied with obvious inflammatory cell infiltration and increased levels of serum myocardial injury markers, such as CK, CK-MB and LDH (P < 0.01) when compared with the conditions in the CON group. Obvious myocardial fibrosis was observed in the myocardial tissue of DCM group, and elevated mRNA levels of fibrosis related molecules, TGF-β1, α-SMA and Timp (P < 0.05, P < 0.01), as well as abnormal glycolipid metabolism indexes, including glucose tolerance, blood glucose, TC, TG, LDL-C and HDL-C (P < 0.05, P < 0.01) were found. The levels of glucose absorption related genes GLUT1 and GLUT4, as well as glycolysis related genes HK1, HK2, PFK, LDH and PKM were all remarkably decreased in the myocardium (P < 0.05). However, DHM intervention greatly improved the impaired cardiac functions, ameliorated myocardial fibrosis and injury, and corrected abnormal glycolipid metabolism in the DCM mice. DHM also promoted the expression of the genes related to glucose absorption and glycolysis at mRNA and protein levels. The results of RNA-seq showed that the expression of several genes related to metabolic regulation was significantly changed after DHM intervention, among which NR4A1 might be a potential target of DHM. Conclusion DHM ameliorates the cardiac function of DCM mice, which may be closely associated with the improvement of glucose absorption and glycolysis of cardiomyocytes.

Keywords

• diabetic cardiomyopathy
• dihydromyricetin
• glucose metabolism
• glucose absorption
• glycolysis