Exercise in Diabetic Cardiomyopathy: Its Protective Effects and Molecular Mechanism

Figure 1. Exercise-mediated amelioration of diabetic cardiomyopathy (DCM). (A) Human studies have demonstrated that multiple types of exercise, including aerobic exercise and resistance exercise, can improve the cardiac function of patients with DCM and ameliorate the clinical symptoms of DCM through pathways such as reducing left ventricular diastolic dysfunction (LVDD), improving glycemic control, increasing global insulin sensitivity, and reducing chronic cardiac inflammation. (B) In animal studies, exercise has been proven to improve DCM through multiple pathways. For example, it can enhance cardiomyocyte contractility by strengthening Ca2+ homeostasis, increase glucose oxidation rates and utilization, reduce extracellular matrix deposition, and suppress cardiac inflammation to alleviate DCM-induced myocardial damage. Additionally, excessive oxidative stress in DCM heart is inhibited after exercise. Exercise improves mitochondrial function and then alleviates cardiac remodeling in DCM by increasing mitochondrial density and biogenesis, while reducing mitochondrial fission. Moreover, exercise enhances the expression of cardioprotective genes, which is beneficial for the prevention and…

Figure 2. The protective role of fibroblast growth factor 21 (FGF21) and irisin in the exercise-mediated alleviation of DCM. (A) FGF21 is involved in the exercise-mediated improvement of DCM. Exercise upregulates the level of circulating FGF21 and enhances the sensitivity of its receptor KLB (β-klotho) on cardiomyocytes. After their combination, the AMPK signaling is activated to promote FOXO3 phosphorylation. FOXO3 directly transactivates the expression of SIRT3. The increased SIRT3 leads to the inhibition of the hyperacetylation of mitochondrial enzymes’ long-chain acyl-CoA dehydrogenase (LCDA), superoxide dismutase 2 (SOD2), and succinate dehydrogenase complex flavoprotein subunit A complex II subunits (SDHA) to enhance their activity. As a result, the production of ATP is enhanced, and the generation of ROS is reduced, which contributes to the improvement of cardiac mitochondrial function. On the other hand, in the heart with myocardial infarction (MI), exercise promotes cardiomyocytes to secrete FGF21. FGF21 binds to its receptor FGFR1 and then activates the phosphorylation of the PI3K-Akt pathway, which inhibits the expression of lysocardiolipin acyltransferase 1 (ALCAT1) to suppress…

Figure 3. The role and mechanism of exercise-induced growth differentiation factor 15 (GDF15) and apelin in DCM. (A) In mice with global GDF15 knockout, the expressions of myocardial glucose transporters (GLUT1, GLUT2) are downregulated, which results in myocardial insulin resistance (IR) and reduced myocardial glucose tolerance, thereby inducing the DCM-related deterioration of cardiac function. Aerobic exercise raises the level of circulating GDF15. GDF15 reduces myocardial fat mass, promotes fat oxidation, and enhances insulin sensitivity in a certain way. This result indicates that exercise can induce an increase in the circulating level of GDF15 in elderly obese adults. However, whether exercise can increase the serum level of GDF15 in diabetic patients remains to be further investigated. (B) Exercise can increase the level of apelin to alleviate DCM. Apelin binds to the receptor APJ on cardiac endothelial cells, potentially activating the SIRT3 signal, which promotes the expression of vascular endothelial growth factor (VEGF) and its receptor VEGFR2. Apelin may also enhance the expression of Angiopoietin-1 (Ang-1) and its receptor Tyrosine kinase receptor with immunoglobulin-like and…

Figure 4. Exercise-induced adiponection (APN) and alpha-ketoglutarate (α-KG) signaling in DCM. (A) Exercise can elevate the serum level of APN, which may be beneficial for relieving DCM. In cardiomyocytes, APN may bind to its receptor adipoR1 and adipoR2 under exercise stimulation and then activates the AMPK signal to upregulate the expression of PGC-1α, which contributes to the improvement of mitochondrial function, thus reducing cardiac energy metabolism disorder induced by DCM. In cardiac endothelial cells, exercise may promote the binding of APN to adipoR1 and adipoR2, thereby activating the AMPK-Akt signal, which leads to the phosphorylation of FOXO1 (the downstream target of Akt) to inhibit the activity of FOXO1, thus promoting the production of eNOS to reduce the oxidative stress of cardiac blood vessels; this mechanism remains to be further verified. (B) α-KG has been proven to alleviate DCM as an exercise-induced metabolite. Mechanistically, α-KG promotes the binding of TET1 to the promoters of TGFBR2 and TGFBR3 genes, respectively, reducing the enrichment degrees of methylation and hydroxymethylation in the intron region of the profibrotic genes TGFBR2 and TGFBR3, thus…

Figure 5. The involvement of immune-related factors in the amelioration of DCM by exercise. (A) Exercise may increase the proportion and polarization of M2 macrophages to reduce inflammation in diabetic hearts, thereby alleviating inflammation-induced fibrosis in DCM. (B) Exercise is involved in the amelioration of DCM via regulatory T cells (Tregs). Exercise improves the body’s glucose metabolism to reduce the glycosylation modification of Tregs, which enhances the immune function of Tregs and may alleviate cardiac inflammation in DCM. (C) Natural killer cells (NK cells) and their cytotoxic activity are involved in the exercise-mediated improvement of DCM. Exercise upregulates serum NK cells and may alleviate DCM in some way. In addition, exercise can enhance the cytotoxic activity of NK cells, thereby improving their immune function, which contributes to mitigating DCM. The red question mark indicate that the mechanism is not yet clear. The figure was created with BioRender.com, accessed on 30 January 2025.

Figure 6. Cardioprotective effect of exercise-regulated microRNAs (miRNAs) and long non-coding RNAs (lncRNAs) on DCM. (A) MiRNAs play a significant role in exercise-mediated alleviation in DCM. Exercise inhibited the level of miR-206 in cardiomyocytes to increase the expression of heat shock protein 60 (HSP60), which reduces myocardial apoptosis. Exercise elevates the level of miR-486-5p to inhibit the expression of mammalian sterile 20-like kinase 1 (Mst1), which suppresses cardiac apoptosis. After exercise, the expression of miR-1 in cardiac tissues decreases, subsequently increasing the expression of insulin-like growth factor 1 (IGF) and its receptor IGF-1R, which helps alleviate cardiac apoptosis. Additionally, exercise facilitates the entry of more exosomes carrying miR-29b and miR-455 into the cardiac vascular wall. Subsequently, these exosomes enter the heart tissues and release miR-29b and miR-455 to inhibit the expression of matrix metalloprotease 9 (MMP9), thereby inhibiting cardiac fibrosis. Additionally, exercise combined with sodium butyrate treatment is able to suppress the expression of miR-34a in cardiomyocytes. Subsequently, this upregulates the expression of SIRT1 in…

Figure 7. The role of other exercise-related effectors and processes in improving DCM. The level of PGC-1α in heart tissues is upregulated by exercise, which in turn promotes the expression of its downstream transcription factors NRD1, TFAM, and TFB2M, leading to an increase in the expression of genes related to mitochondrial biosynthesis in DCM. Exercise inhibits the expression of P2X7R in diabetic hearts and then suppresses the level of lncRNA MIAT to upregulate the expression of miR-50, which alleviates cardiac fibrosis in DCM. Exercise may alleviate DCM by upregulating the expression of SIRT1. In heart tissues with MI in T2DM, exercise can activate the phosphorylation signal of AMPK and then upregulate the expression of SIRT1 to promote the production of PGC-1α, thereby reducing inflammation. Moreover, exercise may reduce the cardiac expression of O-GlcNAc transferase (OGT), which weakens the O-GlcNAcylation of PI3k and Akt to promote their phosphorylation and then increases their activity, thus suppressing cardiac dysfunction in DCM. Additionally, after exercise, the number of Veillonella increased, decomposing lactate into propionate in the intestine. Propionate induces the secretion…