Daily exercise prevents diastolic dysfunction and oxidative stress in a female mouse model of western diet induced obesity by maintaining cardiac heme oxygenase-1 levels

Abstract

Objective: Obesity is a global epidemic with profound cardiovascular disease (CVD) complications. Obese women are particularly vulnerable to CVD, suffering higher rates of CVD compared to non-obese females. Diastolic dysfunction is the earliest manifestation of CVD in obese women but remains poorly understood with no evidence-based therapies. We have shown early diastolic dysfunction in obesity is associated with oxidative stress and myocardial fibrosis. Recent evidence suggests exercise may increase levels of the antioxidant heme oxygenase-1 (HO-1). Accordingly, we hypothesized that diastolic dysfunction in female mice consuming a western diet (WD) could be prevented by daily volitional exercise with reductions in oxidative stress, myocardial fibrosis and maintenance of myocardial HO-1 levels.

Materials/methods: Four-week-old female C57BL/6J mice were fed a high-fat/high-fructose WD for 16weeks (N=8) alongside control diet fed mice (N=8). A separate cohort of WD fed females was allowed a running wheel for the entire study (N=7). Cardiac function was assessed at 20weeks by high-resolution cardiac magnetic resonance imaging (MRI). Functional assessment was followed by immunohistochemistry, transmission electron microscopy (TEM) and Western blotting to identify pathologic mechanisms and assess HO-1 protein levels.

Results: There was no significant body weight decrease in exercising mice, normalized body weight 14.3g/mm, compared to sedentary mice, normalized body weight 13.6g/mm (p=0.38). Total body fat was also unchanged in exercising, fat mass of 6.6g, compared to sedentary mice, fat mass 7.4g (p=0.55). Exercise prevented diastolic dysfunction with a significant reduction in left ventricular relaxation time to 23.8ms for exercising group compared to 33.0ms in sedentary group (p<0.01). Exercise markedly reduced oxidative stress and myocardial fibrosis with improved mitochondrial architecture. HO-1 protein levels were increased in the hearts of exercising mice compared to sedentary WD fed females.

Conclusions: This study provides seminal evidence that exercise can prevent diastolic dysfunction in WD-induced obesity in females even without changes in body weight. Furthermore, the reduction in myocardial oxidative stress and fibrosis and improved HO-1 levels in exercising mice suggests a novel mechanism for the antioxidant effect of exercise.

Keywords: Diastolic dysfunction; Exercise; Heme oxygenase; Obesity; Oxidative stress.