An attempt to reverse cardiac lipotoxicity by aerobic interval training in a high-fat diet- and streptozotocin-induced type 2 diabetes rat model

Jingqin Liu,Shuchun Chen,Huan Cai,Yuxiu He

doi:10.1186/s13098-019-0436-8

Abstract

BackgroundDiabetes mellitus (DM) is an important risk factor for cardiovascular disease. Aerobic interval training (AIT) has been recommended to patients as a non-pharmacological strategy to manage DM. However, little is known about whether AIT intervention at the onset of DM will reverse the process of diabetic cardiomyopathy (DCM). In this study, we sought to evaluate whether AIT can reverse the process of DCM and explore the underlying mechanisms.MethodsFifty Wistar rats were randomly divided into a control group (CON), DCM group (DCM) and AIT intervention group (AIT). A high-fat diet and streptozotocin (STZ) were used to induce diabetes in rats in the DCM group and AIT group. Rats in the AIT group were subjected to an 8-week AIT intervention. Fasting blood glucose (FBG), lipid profiles and insulin levels were measured. Haematoxylin and eosin (HE) staining and oil red O staining were used to identify cardiac morphology and lipid accumulation, respectively. Serum BNP levels and cardiac BNP mRNA expression were measured to ensure the safety of the AIT intervention. Free fatty acid (FFA) and diacylglycerol (DAG) concentrations were analysed by enzymatic methods. AMPK, p-AMPK, FOXO1, CD36 and PPARα gene and protein expression were detected by RT-PCR and Western blotting.ResultsAIT intervention significantly reduced rat serum cardiovascular disease risk factors in DCM rats (P < 0.05). The safety of AIT intervention was illustrated by reduced serum BNP levels and cardiac BNP mRNA expression (P < 0.05) after AIT intervention in DCM rats histological analysis and FFA and DAG concentrations revealed that AIT intervention reduced the accumulation of lipid droplets within cardiomyocytes and alleviated cardiac lipotoxicity (P < 0.05). CD36 and PPARα gene and protein expression were elevated in the DCM group, and these increases were reduced by AIT intervention (P < 0.01). The normalized myocardial lipotoxicity was due to increased expression of phosphorylated AMPK and reduced FOXO1 expression after AIT intervention.ConclusionAIT intervention may alleviate cardiac lipotoxicity and reverse the process of DCM through activation of the AMPK–FOXO1 pathway.

Highlights

Diabetic cardiomyopathy (DCM) is primarily caused by diabetes and is independent of coronary artery disease and hypertension, leading to cardiac diastolic dysfunction during the initial stage and systolic dysfunction at later stages [1]
Aerobic interval training (AIT) is beneficial to diabetic cardiomyopathy (DCM), and previous studies pointed out that it may reduce sarcoplasmic reticulum (SR) Ca2+ leak [11] and improve cardiac function [12], but few studies have directly explored the effect of AIT on cardiac steatosis
This study aimed to investigate the effects of an 8-week AIT intervention on reducing cardiac steatosis and to further explore the underlying mechanisms involved in the reversal of DCM progression after AIT intervention

Summary

Introduction

Diabetic cardiomyopathy (DCM) is primarily caused by diabetes and is independent of coronary artery disease and hypertension, leading to cardiac diastolic dysfunction during the initial stage and systolic dysfunction at later stages [1]. Because no significant clinical symptoms are observed in the early stage of DCM, it is hard to identify until patients present with heart failure. Pharmacological treatment may reverse DCM in the early stage; pharmacological intervention will cause substantial economic pressure on the family and society [6]. Exercise intervention is attracting the attention of medical and sports scientists for treating diabetes mellitus patients with heart failure [8]. Aerobic interval training (AIT) consists of 1–4 min of high-intensity exercise (≥ 70% maximal aerobic capacity) with active low intensity exercise, which has been proved to improve fasting and postprandial blood glucose levels, improve VO2max, and speed up rehabilitation progress [10]. Little is known about whether AIT intervention at the onset of DM will reverse the process of diabetic cardiomyopathy (DCM). We sought to evaluate whether AIT can reverse the process of DCM and explore the underlying mechanisms

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