Exercise with calorie restriction improves cardiac function via attenuating mitochondrial dysfunction in ovariectomized prediabetic rats

https://doi.org/10.1016/j.exger.2020.110940Get rights and content

Highlights

  • Estrogen deprivation aggravated metabolic disturbance in obese-insulin resistance.

  • Combined therapy exerted the highest efficacy in improving metabolic function

  • Combined therapy exerted the highest efficacy in attenuating cardiac calcium dysregulation

  • Combined therapy exerted the highest efficacy in improving mitochondrial dynamics balance

  • All of those benefits led to the greatest cardioprotection in obese-insulin resistant rats

Abstract

Obesity and menopause are known as a major risk factor in the development of left ventricular (LV) dysfunction. Calorie restriction (CR) or exercise (Ex) improved metabolic status and LV function. This study aims to investigate the combined effects of Ex and CR on the cardiometabolic status, and cardiac calcium ([Ca2+]i) regulation in estrogen-deprivation, obese prediabetic rats. Female rats were fed with either a high-fat diet (HFD) or a normal diet for 13 weeks. The HFD rats were ovariectomized (HFO), and subjected to 1) vehicle (HFOV); 2) calorie restriction (HFOCR); 3) exercise (HFOEx); 4) combined therapy (HFOCB); or 5) estrogen (HFOE2). After six weeks of interventions the cardiometabolic status, cardiac [Ca2+]i transients, mitochondrial function and dynamics were determined. HFD-fed rats developed insulin resistance as indicated by increased plasma insulin and HOMA index. Although rats in the HFOV groups had markedly reduced %LVFS which indicated impaired LV function, impaired [Ca2+]i homeostasis, cardiac mitochondrial function and their dynamics, all interventions attenuated these impairments. Interestingly, HFOCB rats were observed to have the greatest cardiometabolic improvement. The combination of calorie restriction and exercise exerted greater efficacy in attenuating LV dysfunction through an improved metabolic status, cardiac function, mitochondrial function, and cardiac [Ca2+]i homeostasis than Ex or CR monotherapy in ovariectomized obese prediabetic rats.

Introduction

Obese-insulin resistance or prediabetic conditions induced by the long-term consumption of a high-fat diet (HFD) is a major risk factor for the development of left ventricular (LV) contractile dysfunction (Pratchayasakul et al., 2011). In addition, obese-insulin resistance also causes an impairment of cardiac autonomic regulation, cardiac mitochondrial function and cardiac contractile function (Apaijai et al., 2013; Ginsberg, 2000; Maas et al., 2011; Sivasinprasasn et al., 2015).

In addition, a previous study indicated that the incidence of cardiovascular disease (CVDs) was increased in menopausal women (Pines et al., 1993). Moreover, lack of estrogen was shown to be associated with a reduction in left ventricular (LV) stroke volume, fractional shortening and cardiac contractile dysfunction (Pines et al., 1993; Scheuer et al., 1987; Sivasinprasasn et al., 2015).

The intracellular calcium (Ca2+) homeostasis relies on cyclical changes in intracellular Ca2+ concentration ([Ca2+]i transients) and mainly control cardiac contractility (Dunay et al., 2015). There are three major cardiac Ca2+ handling proteins that control cardiac contractility. These consist of sarcoplasmic reticulum Ca2+-ATPase (SERCA), ryanodine receptor Ca2+ release channel proteins (RYR) and Na+-Ca2+ exchanger proteins (NCX) (Bupha-Intr and Wattanapermpool, 2006). Our previous study demonstrated that cardiac [Ca2+]i regulation was impaired during the estrogen deprivation period (Palee et al., 2019). This is possibly due to a reduced SERCA protein expression (Palee et al., 2019) and Ca2+ uptake activities. In addition, obese-insulin resistant rats indicated disturbance in cardiac [Ca2+]i regulation as indicated by a decrease in [Ca2+]i transient amplitude, [Ca2+]i transient decay rate and an increase in [Ca2+]i diastolic level (Apaijai et al., 2014).

Lifestyle modifications used in diabetic management include calorie restriction (CR) and exercise (Ex) (Feinman et al., 2015). Clinical studies have also shown that the combination of CR and Ex attenuated metabolic disturbance and reduced CVDs incidence in Type 2 diabetes mellitus (T2DM) patient (Foster-Schubert et al., 2012; Wycherley et al., 2008). However, the cellular mechanisms responsible for these improvements are unclear (Oh et al., 2018; Weiss et al., 2016). Our previous study reported that the combination of CR and Ex exerts greater efficacy on cardioprotection than either as a monotherapy in obese-insulin resistant rats through the improvement of cardiac calcium regulation (Palee et al., 2019). In this study, we tested the hypothesis that the combination of CR and Ex attenuates cardiac dysfunction through the improvement of cardiac mitochondrial function and their dynamics and [Ca2+]i transient homeostasis in estrogen-deprived obese prediabetic rats.

Section snippets

Ethical approval

This study was approved by the Institutional Animal Care and Use Committee of the Faculty of Medicine, Chiang Mai University (approval no. 5/2559 on May 5, 2016).

Animal preparation

Fifty-six female Wistar rats weighing 200–220 g were obtained from the National Animal Center (Salaya campus, Mahidol University, Bangkok, Thailand) and the rats were housed in a 25 °C temperature-controlled room with a 12-hour dark/light cycle throughout the experimental protocol.

Experimental protocol

The rats in the study were randomly divided into two

The combination of calorie restriction and exercise attenuated metabolic disturbance in ovariectomized prediabetic rats

Following 13 weeks consuming a HFD, all HFD-fed rats developed insulin resistance as determined by a significant increase in body weight and HOMA index compared to NDV rats (Table 1). The fasting blood glucose level was not significantly different between the HFD rats and ND rats, indicating the prediabetic condition in these HFD rats. However, following six weeks of estrogen deprivation, there was a marked increase in the severity of insulin resistance in HFOV rats, compared to HFSV rats, as

Discussion

This study demonstrate that estrogen deprivation causes an aggravation in metabolic disturbance, oxidative stress, cardiac autonomic imbalance, LV dysfunction, mitochondrial dysfunction, and increased mitochondrial fission in prediabetic rats. However, the severity of these cardiometabolic adverse effects was decreased after the interventions with calorie restriction, exercise and the combined therapy as well as estrogen therapy. A summary of these findings is shown in Table 3.

In this study,

Funding

This work was supported by the Thailand Research Fund grants RSA6180056 (SP), RSA6180071 (WP), and RTA6080003 (SCC); the NSTDA Research Chair grant from the National Science and Technology Development Agency Thailand (NC), and the Chiang Mai University Center of Excellence Award (NC).

CRediT authorship contribution statement

Siripong Palee:Methodology, Investigation, Formal analysis, Writing - original draft, Funding acquisition.Thidarat Jaiwongkam:Methodology, Investigation, Formal analysis.Sasiwan Kerdphoo:Methodology, Investigation, Formal analysis.Wasana Pratchayasakul:Methodology, Investigation, Formal analysis, Funding acquisition.Siriporn C. Chattipakorn:Conceptualization, Methodology, Investigation, Writing - review & editing, Funding acquisition.Nipon Chattipakorn:Conceptualization, Methodology,

Declaration of competing interest

The authors declare that they have no conflict of interest.

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