Physical Exercise and Its Protective Effects on Diabetic Cardiomyopathy: What Is the Evidence?

As one of the most serious complications of diabetes, diabetic cardiomyopathy (DCM) imposes a huge burden on individuals and society, and represents a major public health problem. It has long been recognized that physical exercise has important health benefits for patients with type 2 diabetes, and regular physical exercise can delay or prevent the complications of diabetes. Current studies show that physical exercise has been regarded as an importantly non-pharmacological treatment for diabetes and DCM, with high efficacy and low adverse events. It can inhibit the pathological processes of myocardial apoptosis, myocardial fibrosis, and myocardial microvascular diseases through improving myocardial metabolism, enhancing the regulation of Ca2+, and protecting the function of mitochondria. Eventually, it can alleviate the occurrence and development of diabetic complications. Describing the mechanisms of physical exercise on DCM may provide a new theory for alleviating, or even reversing the development of DCM, and prevent it from developing to heart failure.


INTRODUCTION
The prevalence of type 2 diabetes mellitus (T2DM) continues to increase dramatically, and is now considered as an epidemic worldwide. It is estimated that the number of people with diabetes will exhibit a 45% increase in three decades (1). Uncontrolled diabetes can lead to a number of long-term health complications, including heart diseases, nerve damage, vision problems, and amputation. Among the various complications of diabetes, cardiovascular disease (CVD) represents the major cause of mortality and morbidity in diabetic patients, accounting for nearly 70% of related heart failure cases (2). Diabetic patients, when compared with nondisease subjects, are two to four times more likely to experience CVD events, due to micro-and macrovascular atherosclerosis, which is often exacerbated by the presence of concomitant CVD risk factors, including hypertension, dyslipidemia, and activation of neuro-hormonal and inflammatory mechanisms (3,4).

THE PATHOGENESIS OF DCM
Diabetic cardiomyopathy (DCM), a distinct condition that develops in diabetic patients, is defined by the presence of myocardial dysfunction in the absence of coronary atherosclerosis, overt clinical coronary artery disease (CAD), and valvular heart disease (5,6). It is characterized by cardiac structure and function disorders, including myocardial fibrosis, dysfunctional remodeling, and associated metabolic deregulation and left ventricular dysfunction (7)(8)(9). DCM is associated with diastolic dysfunction, with depressed myocardial contractility and relaxation, and eventually by clinical heart failure (10). Left ventricular diastolic dysfunction with increased wall stiffness is common in subjects with well-controlled T2DM who are free of clinically detectable heart diseases (11). The pathogenesis of DCM is a multifactorial process that includes altered myocardial metabolism (impaired energy metabolism, calcium regulation, and mitochondrial function) (12,13), increased oxidative stress (14), altered myocardial structure with fibrosis (15), higher induction of apoptosis (16), and microvascular disease (9).

CURRENT STRATEGIES FOR DCM INTERVENTION
Despite prominent advances in the prevention and treatment of diabetes, diabetic complications, especially for DCM still remain rigorous in patients with T2DM (17, 18). Nowadays, treatments for DCM include glucose and lipid control, hypertension treatment, and CAD intervention. Currently, pharmacological treatment is accepted as the common strategy for CVD in diabetic patients, such as β-blockers, Ca 2+ antagonist, β-blockers, renin-angiotensin-aldosterone system inhibitors (9). In recent years, it demonstrated that metformin and sodium-dependent glucose transporters 2 (SGLT2) inhibitors are also benefit for DCM (19). A systematic review of observational studies showed that metformin reduced all-cause mortality in patients with diabetes with congestive heart failure (20). Pan et al. found that empagliflozin ameliorated DCM in diabetic ALDH2 * 2 mutant

CLINICAL STUDIES ABOUT EXERCISE AND DIABETES-RELATED CARDIOVASCULAR DISEASES
Physical activity plays an essential role in the maintenance of human health. Chronic diseases, such as metabolic syndrome and diabetes, are a tremendous burden to our society. Regular physical activity is a primary recommendation for the prevention and treatment of these diseases (36). Physical exercise has a wide array of beneficial effects, including improving glucose and insulin metabolism, and reducing the risks of CVDs in diabetic patients (37). The intensive weight loss intervention was effective in increasing physical activity and improving cardiorespiratory fitness in overweight and obese individuals with T2DM (31). Physical activity was associated with reduced risks of CVD, cardiovascular death, and total mortality in patients with T2DM (32,38). In addition, the benefits of exercise may depend on the intensity of exercise. It showed that a moderate to high level of physical fitness was independently associated with several cardiovascular risk markers, which may contribute to decreasing the burden of morbidity and mortality in patients with T2DM (33). Hu et al. also showed that a moderate or high level of physical activity was associated with a reduced risk of total and cardiovascular mortality among patients with T2DM, which was regardless of the levels of body mass index, blood pressure, total cholesterol, and smoking (34). Furthermore, the duration of exercise is also an important factor for its benefits of CVD. Karjalainen et al. found that there was an inverse association between leisure-time physical activity and short-term CVD outcome. However, controlled, home-based exercise training had minor effects on the risk profile of CVD in CAD patients with T2DM. These findings highlight the significance of lifelong physical activity instead of a short-term exercise program in the prevention of future unfavorable outcomes in patients with CAD (35

Physical Exercise Increases Energy Metabolism
Disorders of myocardial glucose and lipid metabolism lead to changes in pathways related with myocardial energy metabolism. Abnormalities that produce cardiac structure and function are called "metabolic remodeling of the heart, " which ultimately leads to the development of cardiomyopathy. Glucose transporter-4 (GLUT-4) is an intracellular protein that can be translocated to cell membrane induced by insulin, and then it can participate in glucose uptake and utilization. The expression of GLUT-4 was decreased and abnormally distributed in diabetic state, resulting in a significant decrease in glucose transport and impaired myocardium energy utilization (58). Studies indicate that moderate exercise can upregulate GLUT-4 expression, and also can increase glucose transport and activate pyruvate dehydrogenase complexes, even in the absence of insulin (59). It suggests that exercise can compensate for impaired energy metabolism in insulin-deficient state, which may be related to the increase of insulin-sensitive adenosine monophosphate activated protein kinase (AMPK) expression, thereby protecting pancreatic β cells. Exercise may also enhance insulin-mediated glucose transport by increasing the expression of protein kinase C-δ (60, 61). Exercise can also increase insulin and its downstream protein expressions in the myocardium of diet-induced obesity rats, as well as forkhead box protein o1 (Foxo1) and other key regulators of pancreatic β cells, and also activate insulin signaling pathway (40). Thus, exercise can protect pancreatic β cells, promote insulin secretion, activate insulin signaling pathway, increase GLUT4 expression, improve intracellular energy metabolism, and ultimately protect cardiomyocytes.

Physical Exercise Enhances Calcium Regulation
Calcium is a crucial mediator of cell signaling in skeletal muscles for cellular functions and specific functions, including contraction, fiber-type differentiation, and energy production. Intracellular Ca 2+ dyshomeostasis is one of the main markers of DCM, which can affect myocardial contractile function, directly leading to the occurrence and development of DCM. It is even worse in altered sarcoplasmic reticulum Ca 2+ uptake rate accompanied by decreased function of sarcoplasmic reticulum Ca2+-ATPase (SERCA2a) (62). In T2DM patients, the Na + -Ca 2+ exchange of cardiomyocytes is inhibited, while the sarcoplasmic reticulum Ca 2+ pump is normal, and Ca 2+ is gradually concentrated in the sarcoplasmic reticulum. Thus, the amplitude and attenuation rate of Ca 2+ concentration in the myocardium is decreased. Conversely, exercise can improve the expression and activity of SERCA2a, which can regulate Ca 2+ release and recapture in the myocardium. Exercise can increase Ca 2+ -calmodulin-dependent protein kinase phosphorylation, reduce Ca 2+ efflux, facilitate Ca 2+ regulation, and ultimately improves myocardial contraction and diastolic function (41). Stølen et al. found that high intensity intermittent exercise improved myocardial contractility by restoring L-type Ca 2+ channels, increasing the density of T-transverse tubules, and increasing the synchrony of Ca 2+ release and excitatory contraction coupling (42).

Physical Exercise Improves Mitochondrial Function
Mitochondrion is the center of energy metabolism, and recent evidence suggests that mitochondrial dysfunction may play a critical role in the pathogenesis of DCM. The imbalance of energy supply and demand directly leads to the decline of myocardial function and induction of DCM (63). The ultrastructure of mitochondria in DCM shows reduced density, mitochondrial swelling, and destruction of the intima and adventitia, and an increase in mitochondrial matrix, while exercise attenuates diabetes-induced ultrastructural changes in rat cardiac tissue (43). Moderate exercise intervention has a protective effect on mitochondrial function. Exercise can regulate the key regulator of mitochondrial metabolism, peroxisome proliferator-activated receptor gamma co-stimulatory factor-1α (PGC-1α), and activate its downstream transcription factors. Thus, it can enhance mitochondrial DNA replication and transcription, and increase mitochondria biosynthesis (44). Furthermore, the mechanisms by which exercise improves mitochondrial function may be related to the regulation of Ca 2+ in mitochondria. Ca 2+ is a key metabolic enzyme activator in mitochondria, and mitochondrial Ca 2+ circulatory balance can be easily affected by intracellular Ca 2+ homeostasis (41,42). Resistance exercise improves cardiac function and mitochondrial efficiency in hearts, of diabetic rat, which were accompanied by higher expressions of mitochondrial biogenesis proteins such as PGC-1α and mitochondrial transcription factor A (TFAM) (45). In addition, studies have shown that high intensity exercise can increase myocardial mitochondrial contents, but no change in moderate intensity exercise (46,47). However, Veeranki et al. showed that moderate intensity exercise prevented DCM associated contractile dysfunction through restoration of mitochondrial function and connexin 43 levels in db/db mice (30). These indicate that myocardial mitochondrial biosynthesis may be associated with exercise intensity, and exercise intensity should be further investigated about its effects on DCM.

Physical Exercise Relieves Oxidative Stress Damage
Oxidative stress is considered to be a key link in the development of DCM. Under physiological conditions, there is a balance system of oxygen free radicals and free radicals in the body. Oxygen atoms play an important role in the redox signaling pathway. Moderate oxidation can increase protein activity, but excessive reactive oxygen species can cause pathological changes through interaction with lipids, proteins, and DNA (64). Hyperglycemia can directly promote the production of oxygen free radicals, induce oxidative stress, and promote cardiomyocyte apoptosis. The mechanisms by which exercise ameliorates oxidative stress is complex, including: (1) reducing the production of reactive oxygen species. Exercise can ameliorate the damage caused by excessive oxidative stress in the diabetic myocardium and pancreas, thereby improving glucose metabolism and reducing damage caused by reactive oxygen species (48). Long-term exercise can also directly reduce the level of reactive oxygen species in the body by reducing the activity of nicotinamide adenine dinucleotide phosphate (NADPH) oxidase in diabetic rats (49). (2) Enhancing the ability of anti-oxidative stress. Exercise can increase the expression of nitric oxide synthase and nitric oxide, and ultimately enhance the antioxidant function in endothelial cells (49). Nuclear factor E2-related factor 2 (Nrf2) can regulate the expressions of antioxidants mediated by antioxidant response elements. It is an important transcription factor for intracellular defense of reactive oxygen species (50,65). Studies have shown that acute exercise can promote the function of Nrf2, activate downstream antioxidant response elements, and ultimately enhance the activity of anti-oxidative stress. In addition, knocking out the Nrf2 gene can increase the sensitivity of cardiomyocytes to oxidative stress, leading to increased oxidative damage in cells (50). Kanter et al. showed that low intensity exercise decreased the elevated tissue malondialdehyde (MDA) levels and increased the reduced activities of the enzymatic antioxidants superoxide dismutase (SOD), glutathione peroxidase (GSH-Px), and catalase (CAT) in cardiac tissue (51). It indicates that exercise improves the biological mechanisms of DCM by affecting the levels of plasminogen activator inhibitor 1 (PAI-1) and endothelial nitric oxide synthase (eNOS), and it is dependent on the intensity of exercise (52).

Physical Exercise Improves Myocardial Fibrosis
Myocardial fibrosis is the most prominent histopathological change in DCM, characterized by myocardial cell collagen deposition, interstitial fibrosis, and perivascular fibrosis, and ultimately induce the reconstruction of cardiac structure and function (53). Numerous studies indicated that moderate exercise can decrease blood glucose, reduce myocardial fibrosis, promote myocardial reverse remodeling in diabetic rats, and improve cardiac function (30, 53). The mechanisms may be that exercise reduces pressure overload by improving blood pressure, thereby alleviating myocardial fibrosis (53). Exercise can increase the content of matrix metalloproteinase-2 (Mmp-2) in obese rats, increase the degradation of collagen and inhibit the formation of myocardial fibrosis (47). The interaction of collagen with glucose can further cause chemical modification of glycated collagen to form advanced glycation end products (AGEs) that promote arterial and cardiac cirrhosis, as well as endothelial dysfunction (66). Other mechanism by which exercise improves myocardial fibrosis may be related to improving energy metabolism, decreasing blood glucose, and myocardial glycogen deposition (54). Novoa et al. showed that high intensity chronic exercise had a positive impact on cardiac remodeling, evidenced as reduction in myocyte hypertrophy, reduced collagen deposition, and amelioration of myocardial fibrosis (55).

Physical Exercise Inhibits Cardiomyocyte Apoptosis
Diabetes-induced cardiomyocyte apoptosis is a typical feature of DCM. Hyperglycemia can directly promote cytochrome C release to the cytoplasm by activating cytochrome C in mitochondria, triggering cascade activation of caspase-3, leading to endogenous apoptosis of cardiomyocytes. This change plays an important role in the development of diabetic cardiac hypertrophy, myocardial remodeling, and heart failure. C-Jun N-terminal kinase is a member of the mitogen-activated protein kinase (MAPK) family, which can activate caspase-8 and the apoptotic protein Bax, and release cytochromes to promote apoptosis (67     (BCL-2) in diabetic rats, with improved left ventricular ejection fraction (LVEF%) and fractional shortening (FS%) (57). A recent study suggested that exercise appeared to ameliorate DCM by inhibiting endoplasmic reticulum stress-induced apoptosis in diabetic rats, which was in an intensity-dependent manner (52).

Physical Exercise Improves Microvascular Disorders
Microvascular disease is also one of the pathological changes of DCM. Under the influence of hyperglycemia, the function and structure of microvessels will undergo pathological changes, which are characterized by vascular endothelial defects, endothelial cell dysfunction, and aggravated inflammatory response of partial vascular endothelium. It can affect the transport of substances, such as glucose and insulin into other tissues of the body, which can lead to abnormal tissue function. The mechanisms underlying the protective effects of exercise on microvessels mainly include two aspects: (1) exercise can protect vascular endothelial cells, increase the expression of nitric oxide, enhance the diastolic function of microvessels, and increase blood perfusion (66). (2) Exercise can enhance microvascular response to insulin and improve insulin signaling. Increased insulin can activate both insulin receptor substrate-1/phosphatidylinositol-3-kinase/protein kinase B (IRS-1/PI3K/AKT) and MAPK pathways, leading to equilibrium between the vasopressor substance nitric oxide and endothelin-1, ensuring normal vasomotor function (68). The pre-clinical experiments and the potential mechanisms about physical exercise and DCM is shown in Table 2 and Figure 1.

CONCLUSIONS
In summary, as a fundamental component of the human condition, physical exercise plays a critical role in human health. Exercise training is considered as a cornerstone in the management of T2DM, possessing a potency to decrease the risks of CVD in patients with diabetes. Exercise can protect the myocardium by improving myocardial cell metabolism, alleviating oxidative stress damage, improving myocardial fibrosis, inhibiting apoptosis, and ameliorating microvascular disorders, and ultimately it is proposed to have the potential impacts to protect against DCM. Exercise is an importantly nonpharmacological strategy in reducing the risk factors of diabetes and its complications. It can be considered as a promising agent for alternative therapies for the prevention and treatment of diabetes and its cardiovascular complications. However, more clinical trials and pre-clinical studies are required to promote the translation of molecular findings to therapeutics of physical exercise.

AUTHOR CONTRIBUTIONS
JZ and JC collected data, synthesized data, and wrote the manuscript. SZ, LZ, and XHG reviewed and edited the manuscript. JQZ and XHX contributed to the design of this review. Conflict of Interest Statement: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

FUNDING
Copyright © 2018 Zheng, Cheng, Zheng, Zhang, Guo, Zhang and Xiao. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.