|Year : 2017 | Volume
| Issue : 4 | Page : 1-6
Effects of exercise training on systolic and diastolic function of mice with diabetic cardiomyopathy
Guo Lu1, Xu Zhang2, Zhongguang Sun1, Xiaowei Shi1, Tingliang Liu2, Xin Xu1
1 Department of School of Exercise Science, Shanghai University of Sport, Shanghai 200438, China
2 Department of Cardiology, Shanghai Children's Medical Center, Shanghai Jiao Tong University School of Medicine, Shanghai 200127, China
|Date of Web Publication||12-Mar-2018|
Dr. Tingliang Liu
Department of Cardiology, Shanghai Children's Medical Center, Shanghai Jiao Tong University School of Medicine, No. 1678 Dongfang Road, Shanghai 200127
School of Exercise Science, Shanghai University of Sport, No. 399 Changhai Road, Shanghai 200438
Source of Support: None, Conflict of Interest: None
Objective: This study aims to evaluate the effects of exercise training on heart function of mice with diabetic cardiomyopathy.
Materials and Methods: Twenty-four healthy C57 mice were randomly divided into three groups high-fat exercise group (n = 8), high-fat control group (n = 8), and low-fat control group (n = 8). High-fat groups were fed with a high-fat diet for 16 weeks, and the high-fat exercise group was subjected to aerobic treadmill exercise and resistance exercise for 8 weeks. After 24 weeks, the cardiac structure and function of the three groups were detected, and the indexes of the mouse heart were analyzed and compared. Results: The high-fat control group maintained hyperglycemia. The results of echocardiography showed that left ventricular eject fraction in the high-fat exercise group and the low-fat control group was significantly higher than that of the high-fat control group (68.99% ± 2.04% vs. 60.41% ± 2.31%, 66.16% ± 2.12% vs. 60.41% ± 2.31%, P < 0.01). In the diastolic function of the heart, blood flow peak velocities of the early peak at the mitral valve in the high-fat exercise group and the low-fat control group were significantly higher than that in the high-fat control group (709.73 ± 45.48 mm/s vs. 441.51 ± 44.83 mm/s, 632.92 ± 27.22 mm/s vs. 441.51 ± 44.83 mm/s, P < 0.01), the peak velocities of the atrial peak at the mitral valve were significantly lower than that of the high-fat control group (443.77 ± 18.09 mm/s vs. 523.67 ± 57.87 mm/s, 460.36 ± 18.24 mm/s vs. 523.67 ± 57.87 mm/s, P < 0.05), and the ratio of E/A was significantly higher than that of the high-fat control group (1.63 ± 0.06 vs. 0.85 ± 0.045, 1.38 ± 0.072 vs. 0.85 ± 0.045, P < 0.01). Myocardial performance index decreased (0.86 ± 0.095 vs. 0.97 ± 0.091, 0.88 ± 0.073 vs. 0.97 ± 0.091, P > 0.05), but there was no significant difference. Conclusion: The above data indicated that 8 weeks of exercise training can improve the heart function of mice with diabetic cardiomyopathy, especially diastolic heart function. Left ventricular systolic function had some trend to improve, but there is no statistical difference. Exercise intervention may promote the rehabilitation of diabetic cardiomyopathy.
Keywords: Cardiac function, diabetic cardiomyopathy, echocardiography, exercise
|How to cite this article:|
Lu G, Zhang X, Sun Z, Shi X, Liu T, Xu X. Effects of exercise training on systolic and diastolic function of mice with diabetic cardiomyopathy. Cardiol Plus 2017;2:1-6
|How to cite this URL:|
Lu G, Zhang X, Sun Z, Shi X, Liu T, Xu X. Effects of exercise training on systolic and diastolic function of mice with diabetic cardiomyopathy. Cardiol Plus [serial online] 2017 [cited 2020 Jul 10];2:1-6. Available from: http://www.cardiologyplus.org/text.asp?2017/2/4/1/227167
Guo Lu and Xu Zhang. These authors have contributed equally to this work.
| Introduction|| |
Diabetes cardiomyopathy is a complication of diabetes mellitus and is the leading cause of heart failure or death in diabetic patients. The pathogenesis of diabetic cardiomyopathy is multifactorial. Hyperglycemia, hyperinsulinemia, and dyslipidemia may trigger an altered cardiac structure caused by cell signaling. The clinical manifestations are cardiac diastolic and/or systolic dysfunction, left ventricular remodeling, which ultimately leads to heart failure, arrhythmia, and cardiogenic shock, and even sudden death in patients with severe illness.
Exercise plays an important role in the prevention of various chronic diseases including cardiovascular disease. Regular exercise is beneficial for both Type 1 and Type 2 diabetes patients. While it possesses great health benefits for cardiovascular fitness, muscle strength, and insulin sensitivity in Type 1 diabetes patients, regular exercise may prevent the development of Type 2 diabetes. Studies have reported that diabetes is associated with chronic low systemic inflammation. Animal studies have shown that exercise intervention has a positive effect on the prevention of diabetes. Exercise has anti-inflammatory effects, where regular exercise can prevent atherosclerosis and insulin resistance, thereby preventing diabetes. Exercise can also improve blood glucose control in type 2 diabetes, reduce cardiovascular risk factors, contribute to weight loss, and improve overall health.
Although diabetes cardiomyopathy is widely recognized, effective treatments have yet to be discovered. Altered myocardial energy metabolic substrates, which are new therapies for the treatment and/or prevention of diabetic cardiomyopathy, may improve the development of diabetic heart dysfunction by activating pyruvate dehydrogenase to restore diastolic dysfunction and blood glucose level. We demonstrated that treatment of type 2 diabetic rats with Zn reduced plasma glucose levels and prevented diabetic cardiomyopathy.
Studies have found that elevated high-density lipoprotein levels can increase the risk of diabetic cardiomyopathy in patients with type 1 diabetes mellitus. As a result, the study proves that exercise training is effective in the treatment and prevention of obesity. In addition to the beneficial effects of changes in diabetes-/obesity-related systems, obesity may also amend many of the metabolic disturbances characterizing the diabetic myocardium.
In this study, exercise intervention was performed with aerobic treadmill exercise and resistance exercise, based on the model of diabetic cardiomyopathy. The study observed the effects of exercise intervention on cardiac systolic and diastolic function in diabetic cardiomyopathy in mice and provided experimental basis for further study.
| Materials and Methods|| |
Experimental animals and grouping
Twenty-four healthy C57BL6 mice were purchased from the Animal Experimental Center of the Second Military Medical University and were housed in the specific-pathogen-free-level barrier of the animal laboratory of the Shanghai University of Sport. High-fat exercise group (F + Ex group, n = 8) and low-fat control group (L + Ctr group, n = 8), high-fat control group (F + Ctr group, n = 8), and high-fat exercise group and high-fat control group were fed a high fat and high sugar diet (60% kcal fat, 20% kcal protein, 20% kcal carbohydrate, based on OpenSource Diets No. D12492) from the first 8 weeks and maintained for 16 weeks to establish diabetic cardiomyopathy mice. The diagnosis of diabetic cardiomyopathy was determined by glucose tolerance test and cardiac ultrasonography. The low-fat control group was fed with a normal diet. All mice were free to eat and drink. The incubation temperature was maintained at 21°C–24°C and the relative humidity was 40%–60%. All operations strictly abide by the Shanghai Institute of Physical Education Ethics Committee requirements.
According to Sigal and Kenny and other clinical research on the treatment of type 2 diabetes, aerobic and antiresistance exercise were used for exercise intervention. The high-fat exercise group was exercised at intervals of one day of aerobic exercise and 1 day of resistance exercise, 6 days a week, for a total of 8 weeks.
Before the start of the experiment, 3–5 days of exercise preconditioning, exercise intensity gradually increased, where the speed does not exceed 20 m/min. Time of exercise gradually increased from 30 to 60 m/min. Antiresistance sports ladder gradient gradually increased from 30° to 90°, from the beginning of the two groups, each group twice, gradually increased to four groups, each group four times. Aerobic exercise consisted of treadmill movement, time 60 ± 5 min, speed and deceleration process, the slope is 0.5 min before the start of the movement, the speed gradually increased to 15 m/min, after the end of the movement, the speed from high to low, slow down until the speed is 0. Resistance movement: Ladder movement, each four groups, each group four times, the slope of 90°, the speed is not limited. Each training from 6 to 7 pm. Sound, light, electricity, and other stimulus means are not used to stress mice.
Glucose tolerance test
The mice were subjected to a glucose tolerance test after 16 weeks of diet intervention. The mice were fasted for 12 h before administering glucose tolerance test. After intraperitoneal injection of glucose (2 g/kg body weight), blood samples were taken from the tail of the mice for 0, 30, 60, 90, and 120 min timepoints for glucose tolerance test. Tolerance assessment was based on the area under the glucose tolerance curve (area under the curve [AUC]).
We measured the cardiac structure and function of mice by Visual Sonics Vevo1100 imaging system. Measurements include left ventricular end-diastolic dimension (LVEDD), left ventricular end-systolic dimension (LVESD), ejection fraction, stroke volume (SV), mitral valvular diastolic E peak blood flow velocity (E), A peak velocity and ratio (E/A), and myocardial comprehensive index (MPI).
All data were expressed as mean ± standard deviation. Statistical data were analyzed by the Statistical Package for Social Sciences, version 23.0 software (SPSS, Chicago, IL, USA). Single factor analysis of variance was used to compare the data. P < 0.05 for a significant difference, P < 0.01 was very significant difference.
| Results|| |
The results of echocardiography in mice at 24 weeks are listed in [Table 1].
After 30 min of glucose injection, all mice had elevated blood glucose levels. The mice reached their maximum at 30 min and began to drop after 30 min. The blood glucose of the F + Ctr mice was higher than the other two groups and showed significant difference at 0, 60, 90, and 120 min timepoints. Compared with low-fat group and high-fat group, the area under 0, 60, 90, and 120 min timepoints and intraperitoneal glucose tolerance test blood glucose curve (AUC) were significantly different (P< 0.01) [Figure 1].
|Figure 1: (a) Mice were injected with glucose, 0, 30, 60, 90, and 120 min of blood glucose. (b) The area under the glucose tolerance curve.###P < 0.01 (L + Ctr vs. F + Ctr); **P < 0.01 (F + Ctr vs. F + Ex)|
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The results of echocardiography showed that the diastolic function of the heart, blood flow peak velocities of the early peak at the mitral valve in the high-fat exercise group, and the low-fat control group were significantly higher than that in the high-fat control group (709.73 ± 45.48 mm/s vs. 441.51 ± 44.83 mm/s, 632.92 ± 27.22 mm/s vs. 441.51 ± 44.83 mm/s, P < 0.01). The peak velocities of the atrial peak at the mitral valve were significantly lower than the high-fat control group (443.77 ± 18.09 mm/s vs. 523.67 ± 57.87 mm/s, 460.36 ± 18.24 mm/s vs. 523.67 ± 57.87 mm/s, P < 0.05), and the ratio of E/A was significantly higher than that of the high-fat control group (1.63 ± 0.06 vs. 0.85 ± 0.045, 1.38 ± 0.072 vs. 0.85 ± 0.045, P < 0.01) [Figure 2].
|Figure 2: Mitral valvular diastolic E peak blood flow velocity (E), A peak velocity and ratio (E/A) in three groups. (a) A peak, (b) E peak, (c) E/A ratio.#P < 0.05,##P < 0.01(L + Ctr vs. F + Ctr). *P < 0.05, **P < 0.01 (F + Ctr vs. F + Ex)|
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The left ventricular eject fraction (LVEF) in the high-fat exercise group and the low-fat control group was significantly higher than that of the high-fat control group (68.99% ± 2.04% vs. 60.41 ± 2.31%, 66.16% ± 2.12% vs. 60.41 ± 2.31%, P < 0.01). There was no significant difference in LVEDD, LVESD, and SV between the high-fat exercise group and the low-fat control group, when compared with the high-fat control group [Figure 3].
|Figure 3: Left ventricular end-diastolic dimension, left ventricular end-systolic dimension, ejection fraction, and stroke volume in three groups. (a) Ejection fraction, (b) cardiac output, (c) left ventricular end-diastolic dimension, and (d) left ventricular end-systolic dimension in all groups after 24 weeks.#P < 0.05,##P < 0.01 (L + Ctr vs. F + Ctr); *P < 0.05, **P < 0.01 (F + Ctr vs. F + Ex)|
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Myocardial performance index (MPI) decreased (0.86 ± 0.095 vs. 0.97 ± 0.091, 0.88 ± 0.073 vs. 0.97 ± 0.091, P > 0.05), but there was no significant difference [Figure 4].
|Figure 4: Myocardial performance index in three groups (F + Ex vs. F + Ctr: 0.86 ± 0.095 vs. 0.97 ± 0.091, P > 0.05); (L + Ctr vs. F + Ctr: 0.88 ± 0.073 vs. 0.97 ± 0.091, P > 0.05)|
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| Discussion|| |
The study found that high-fat and high-sugar diet-induced diabetic cardiomyopathy in mice decreased left ventricular function, especially in the diastolic function. Diastolic function can significantly improve by means of 8 weeks of aerobic and resistive exercise intervention.
Previous animal studies used intraperitoneal injection of streptozotocin to develop a diabetic cardiomyopathy model. Long-term high-fat diet may induce the formation of early diabetic cardiomyopathy. The 16-week high-fat diet could induce insulin resistance and increase the supply of exogenous fat, making the weight of the mice in the high-fat control group significantly higher than the low-fat control group. Similarly, the blood glucose of the high-fat control group maintained a stable high level of state. Fasting blood glucose was significantly higher in the low-fat control group. Echocardiographic results showed that the E peak and E/A ratio in the high-fat control group were significantly lower than in the low-fat control group. A peak was significantly higher than in the low control group, and E, E/A, and A are the indicators of left ventricular diastolic function, suggesting that high-fat quiet mice had left ventricular diastolic dysfunction.
The study of diabetic cardiomyopathy prevention and treatment often involves drug therapy, gene therapy, and exercise as forms of intervention. Although much progress has been made in drug therapy as a form of treatment,, a specific and effective drug for diabetic cardiomyopathy has not been found. In addition, the cost of drug therapy is expensive and often has side effects as a result.,
While gene therapy is under development and takes time to apply in a clinical setting, exercise intervention is considered a relatively cost-effective treatment and presents significant benefits. The benefits of exercise as treatment of type 2 diabetes have been recognized which includes the improvement of cardiac function. 2007 Neil Smart has demonstrated that exercise can improve diastolic function. In this study selected participants have completed three aerobic exercises a week which intensity at 60% -70% in 16 weeks. Participants have completed three aerobic exercises a week at 60%–70% intensity. After 8 weeks, the participants also did strength training. Results showed that the diastolic function of participants improved.
Mice in the high-fat exercise group had higher E peak and E/A ratio than those in high-fat control group. In respect to the systolic function of the heart, the LVEF in the high-fat exercise group was significantly higher than in the high-fat control group. However, there was no significant difference in LVEDD, LVESD, and SV between the high-fat exercise group and the low-fat control group compared with the high-fat control group.
A large number of reports confirm that exercise may improve insulin sensitivity and reduce intracellular fatty acid content. Exercise can also improve damaged myocardial function, which plays an important role in the treatment of diabetic cardiomyopathy.,
However, there are very few clinical studies which show on the impact of exercise on diabetes cardiomyopathy. In 2004, Korte et al. prepared a 20-week porcine model of diabetic dyslipidemia. Some of the pigs were subjected to 14 weeks of exercise training. The results of echocardiography showed that the left ventricular shortening fraction in the exercise group was significantly higher than in the control group. They believed that exercise may improve the heart function of diabetic cardiomyopathy. Wang et al. utilized a long-term exercise intervention in mice and found that exercise has a beneficial effect on the treatment of diabetic cardiomyopathy by reducing myocardial cell apoptosis and fibrosis, improving mitochondrial biogenesis.
At present, the effect of different exercise intensity on the cardiac function of diabetic cardiomyopathy is not clear. Previous studies have used moderately intensive exercise to prevent dystrophic dysfunction in diabetic cardiomyopathy by restoring the mitochondrial function of mice in db/db (leptin receptor gene deficiency-induced obese spontaneous type 2 diabetic mice).
Hafstad et al. utilized differing intensities of exercise interventions on diet-induced obese C57 mice to confirm whether high-intensity intermittent training is superior to moderate-intensity training in counteracting obesity-induced impairment of left ventricular performance and function. They found that both exercise programs could improve cardiac function and structural remodeling caused by obesity. It was also found that low-intensity swimming training can reduce the pathological changes of cardiomyocyte systolic dysfunction in diabetic rats. Diabetic cardiomyopathy is closely related to cardiac remodeling, myocardial dysfunction, and low inflammation in type 2 diabetes mellitus.
At present, exercise intensity and time in patients with diabetic cardiomyopathy still present controversy. In the future, this study will also investigate the effects of different exercise time on diabetes mellitus, which will provide the theoretical basis for patients with clinical diabetic cardiomyopathy to select the best exercise regimen.
| Conclusion|| |
The above data indicates that 8 weeks of exercise intervention can improve diastolic heart function of mice with diabetic cardiomyopathy. In addition, improvement in left ventricular systolic function was found, but there is no statistical difference. Overall, the study suggests that exercise intervention has beneficial therapeutic effects on diabetic cardiomyopathy.
Financial support and sponsorship
This work was financially supported by the grant from Science and Technology Development Fund of Science and technology committee of Shanghai Pudong (Grant No.: PKJ2011-Y38).
Conflicts of interest
There are no conflicts of interest.
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[Figure 1], [Figure 2], [Figure 3], [Figure 4]