Exercise enhances cardiac function by improving mitochondrial dysfunction and maintaining energy homoeostasis in the development of diabetic cardiomyopathy

AbstractDiabetic cardiomyopathy (DCM) lacks diagnostic biomarkers. Circulating long non-coding RNAs (lncRNAs) can serve as valuable diagnostic biomarkers in cardiovascular disease. To seek potential lncRNAs as a diagnostic biomarker for DCM, we investigated the genome-wide expression profiling of circulating lncRNAs and mRNAs in type 2 diabetic db/db mice with and without DCM and performed bioinformatic analyses of the deregulated lncRNA-mRNA co-expression network. Db/db mice had obesity and hyperglycemia with normal cardiac function at 6 weeks of age (diabetes without DCM) but with an impaired cardiac function at 20 weeks of age (DCM) on an isolated Langendorff apparatus. Compared with the age-matched controls, 152 circulating lncRNAs, 127 mRNAs and 3355 lncRNAs, 2580 mRNAs were deregulated in db/db mice without and with DCM, respectively. The lncRNA-mRNA co-expression network analysis showed that five deregulated lncRNAs, XLOC015617, AK035192, Gm10435, TCR-α chain, and MouselincRNA0135, have the maximum connections with differentially expressed mRNAs. Bioinformatic analysis revealed that these five lncRNAs were highly associated with the development and motion of myofilaments, regulation of inflammatory and immune responses, and apoptosis. This finding was validated by the ultrastructural examination of myocardial samples from the db/db mice with DCM using electron microscopy and changes in the expression of myocardial tumor necrosis factor-α and phosphorylated p38 mitogen-activated protein kinase in db/db mice with DCM. These results indicate that XLOC015617, AK035192, Gm10435, TCR-α chain, and MouselincRNA0135 are crucial circulating lncRNAs in the pathogenesis of DCM. These five circulating lncRNAs may have high potential as a diagnostic biomarker for DCM.

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Salidroside protects cardiac function in mice with diabetic cardiomyopathy via activation of mitochondrial biogenesis and SIRT3

Phytotherapy Research ◽

10.1002/ptr.7175 ◽

2021 ◽

Author(s):

Ye Li ◽

Xin Wei ◽

Shu‐Li Liu ◽

Ying Zhao ◽

Si Jin ◽

...

Keyword(s):

Cardiac Function ◽

Diabetic Cardiomyopathy ◽

Mitochondrial Biogenesis

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Abstract P233: Diabetic Cardiomyopathy is Reversed by Increased Mitochondrial Bioenergetics Due to PGC-1α Activation by EET Treatment of Obese Mice

Hypertension ◽

10.1161/hyp.68.suppl_1.p233 ◽

2016 ◽

Vol 68 (suppl_1) ◽

Author(s):

Jian Cao ◽

John A McClung ◽

Shailendra P Singh ◽

Lars Bellner ◽

Maayan Waldman ◽

...

Keyword(s):

Heart Failure ◽

Insulin Resistance ◽

Oxidative Phosphorylation ◽

Mitochondrial Dysfunction ◽

Diabetic Cardiomyopathy ◽

Cardiac Fibrosis ◽

Systolic Function ◽

Control Group ◽

Protein Markers ◽

Obesity And Diabetes

Introduction: Obesity and diabetes are associated with progressive cardiac fibrosis that, sequentially, results in diastolic dysfunction, reduced contractility, and ultimately heart failure. Contributing factors include hyperglycemia, insulin resistance, mitochondrial dysfunction, and a reduction in AMPK signaling. PGC-1α activates mitochondrial biogenesis and oxidative phosphorylation and is decreased in patients with diabetes mellitus (DM). We hypothesize that an epoxyeicosatrienoic acids (EETs) agonist (EET-A) will increase PGC-1α levels in a db mouse model of DM attenuate cardiomyopathy, and prevent heart failure. Methods: Db mice (4-wks), were allowed to acclimatize for 16-wks and were then divided into 3 treatment groups for an additional 16 wks: A) control, B) EET-A 1.5mg/100g BW 2 weeks and C) EET-A-Ln-PGC-1α shRNA. Ln-PGC-1α shRNA suppressed PGC-1α protein in heart tissue by 40-50%. Oxygen consumption (VO 2 ), and blood glucose was determined. Heart tissues were harvested to measure PGC-1α, HO-1, pAMPK, PGC-1α, echocardiographic fractional shortening, mitochondrial oxidative phosphorylation (OXPHOS) and mitofusion protein markers. Results: All mice developed heart failure by the end of 16 weeks and were characterized by a decrease in myocardial contractility, an increase in insulin resistance and blood pressure, decreased VO 2 , the appearance of mitochondria dysfunction and a decrease in AMPK and downstream PGC-1α signaling. Mice treated with EET-A demonstrated an increase in PGC-1α levels, improved mitochondrial function and oxidative phosphorylation (p<0.01 vs control), increased NO bioavailability (p<0.05 vs control), and normalization of glucose metabolism, insulin levels, VO 2 and LV systolic function (p<0.05 vs control). All of these findings were suppressed by PGC-1α inhibition which was accompanied by the onset of even more severe LV dysfunction than in the control group. Conclusion: Increased EET levels result in activation of PGC-1α-HO-1 which reverses diabetes induced insulin resistance, mitochondrial dysfunction, and cardiomyopathy. EET may have potential as a powerful agent for therapeutic application in the treatment of diabetic cardiomyopathy.

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GESTATIONAL DIABETES PROGRAMS MITOCHONDRIAL DYSFUNCTION AND IMPAIRS CARDIAC FUNCTION IN THE OFFSPRING

Canadian Journal of Cardiology ◽

10.1016/j.cjca.2016.07.108 ◽

2016 ◽

Vol 32 (10) ◽

pp. S82-S83

Author(s):

S.M. Kereliuk ◽

K.G. Cheung ◽

B. Xiang ◽

L.K. Cole ◽

T.J. Pereira ◽

...

Keyword(s):

Gestational Diabetes ◽

Cardiac Function ◽

Mitochondrial Dysfunction

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5213Manipulation of cardiac O-GlcNAc modification alters cardiac function and remodelling in the setting of diabetic cardiomyopathy

European Heart Journal ◽

10.1093/eurheartj/ehy566.5213 ◽

2018 ◽

Vol 39 (suppl_1) ◽

Author(s):

D Prakoso ◽

H Kiriazis ◽

M Tate ◽

H Qian ◽

M Deo ◽

...

Keyword(s):

Cardiac Function ◽

Diabetic Cardiomyopathy

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Rutin alleviates diabetic cardiomyopathy and improves cardiac function in diabetic ApoEknockout mice

European Journal of Pharmacology ◽

10.1016/j.ejphar.2017.08.023 ◽

2017 ◽

Vol 814 ◽

pp. 151-160 ◽

Cited By ~ 8

Author(s):

Ruo Huang ◽

Zhendong Shi ◽

Li Chen ◽

Yanqun Zhang ◽

Jing Li ◽

...

Keyword(s):

Cardiac Function ◽

Diabetic Cardiomyopathy

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The Effect of Gypenosides on Cardiac Function and Expression of Cytoskeletal Genes of Myocardium in Diabetic Cardiomyopathy Rats

The American Journal of Chinese Medicine ◽

10.1142/s0192415x09007491 ◽

2009 ◽

Vol 37 (06) ◽

pp. 1059-1068 ◽

Cited By ~ 4

Author(s):

Min Ge ◽

Shanfeng Ma ◽

Liang Tao ◽

Sudong Guan

Keyword(s):

Cardiac Function ◽

Diabetic Cardiomyopathy ◽

Diastolic Pressure ◽

Pure Water ◽

Systolic Pressure ◽

Left Ventricular ◽

Control Group ◽

Sprague Dawley ◽

Gene Expressions ◽

Ventricular Systolic Pressure

The relationship between changes of cardiac function and the gene expressions of two major myocardial skeleton proteins, titin and nebulin, and the effect of gypenosides on these gene expressions in diabetic cardiomyopathy rat were explored in the present study. Forty Sprague-Dawley rats were randomly divided into three groups: control group, diabetic cardiomyopathy group and gypenosides-treated diabetic cardiomyopathy group. The diabetic cardiomyopathy was induced in rats by injecting streptozotocin (STZ, 55 mg/kg) intraperitoneally. Seven weeks after the rats suffered from diabetes, the rats were treated with gypenosides 100 mg/kg per day orally for six weeks in gypenosides-treated group. In the meanwhile, the pure water was given to diabetic cardiomyopathy and the control groups. Subsequently, the cardiac functions, including left ventricular systolic pressure (LVSP), left ventricular end diastolic pressure (LVEDP), ± dP/dtmax and t–dP/dmaxt, as well as the mRNA content and proteins of titin and nebulin in myocardium were determined. The results indicated that (1) the diabetic cardiomyopathy rats had decreased LVSP and ± dP/dtmax, increased LVEDP, and prolonged t–dP/dtmax than normal rats; (2) LVSP and ± dP/dtmax in diabetic cardiomyopathy rats treated with gypenosides were significantly higher and LVEDP and t–dP/dtmax were significantly lower than those without giving gypenosides; (3) the mRNA contents and proteins of titin and nebulin in diabetic cardiomyopathy rats were remarkably lower than those in the control rats and gypenosides had no effect on mRNA and protein expression levels of titin and nebulin in diabetic cardiomyopathy rats. We conclude that (1) the cardiac function as well as the mRNA expressions of titin and nebulin decreased in diabetic cardiomyopathy rats; (2) gypenosides secure cardiac muscles and their function from diabetic impairment and these beneficial effects of gypenosides are not by changing the expressions of titin and nebulin.

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Abstract 2769: Impaired Skeletal Muscle Oxygen Utilization Contributes to Exercise Intolerance in Barth Syndrome

Circulation ◽

10.1161/circ.116.suppl_16.ii_615 ◽

2007 ◽

Vol 116 (suppl_16) ◽

Author(s):

Carolyn T Spencer ◽

Randall M Bryant ◽

Barry Byrne ◽

Elisabeth Heal ◽

Renee Margossian ◽

...

Keyword(s):

Skeletal Muscle ◽

Cardiac Function ◽

Mitochondrial Dysfunction ◽

Near Infrared ◽

Vastus Lateralis ◽

Barth Syndrome ◽

Exercise Intolerance ◽

Peak Exercise ◽

Indirect Measure ◽

Muscle Oxygen

Objective s: Barth Syndrome (BTHS) is an X-linked mutation in the TAZ gene characterized by cardiolipin deficiency, mitochondrial dysfunction and cardio-skeletal myopathy. We hypothe- sized that abnormal skeletal muscle oxygen (O 2 ) utilization contributes to exercise intolerance in BTHS. Methods : Boys with BTHS (n=13) and healthy male controls (n=7) performed a graded exercise test on a cycle ergometer with continuous metabolic and EKG monitoring. Near infrared spectroscopy (NIRS), an indirect measure of tissue O 2 saturation and index of skeletal muscle O 2 utilization, was applied to the vastus lateralis during exercise. Cardiac function in BTHS was assessed by echocardiography and serum BNP to examine the relationship between resting cardiac function and exercise capacity in BTHS. Results : Age (16±5 vs 13±3 years; p=0.22), BMI (17±3 vs. 20±5; p=0.14) and BSA (1.0±0.5 vs 1.2±0.6 m 2 ; p=0.3) were not different between BTHS and controls. BTHS had lower peak VO 2 (19±6 vs. 52±6 ml/kg/min, p < 0.001), lower % of predicted peak VO 2 (40±10% vs. 115±12%, p=0.0004), lower peak work rate (58±18 vs. 205±69 watts, p=0.0004), and lower peak O 2 pulse (4.6±1.6 vs. 14±6 ml O 2 /kg/beat, p< 0.00001) than controls. Peak HR in BTHS was lower but remained within normal peak predicted rate (172±14 vs. 197±11 bpm, p=0.001). Vastus lateralis tissue O 2 saturation at peak exercise decreased from baseline in controls as expected (-18±16%, p<0.001) but paradoxically increased from baseline in BTHS (+17±14%, p<0.03, p=0.0005 BTHS vs. controls) indicating impaired muscle O 2 utilization. Absolute (r= - 0.70, p<0.0001) and percent (r= - 0.70, p<0.001) change in NIRS from baseline was negatively associated with peak VO 2 . There was no correlation between peak VO 2 and resting EF (55±7%; r=0.12), SF (30±4%; r= -.26), myocardial performance index (0.4±0.1; r= -.3) or serum BNP (232±381; r=0.1). Conclusion : O 2 consumption during exercise in BTHS is severely reduced and caused, at least in part, by impaired skeletal muscle O 2 utilization. Resting cardiac function is not related to O 2 consumption in BTHS but cardiac dysfunction during exercise in BTHS is not excluded without further studies. Mitochondrial dysfunction likely mediates skeletal muscle O 2 utilization deficits during exercise in BTHS.

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Kir6.1 improves cardiac dysfunction in diabetic cardiomyopathy via the AKT-Foxo1 signaling pathway

10.21203/rs.3.rs-33214/v1 ◽

2020 ◽

Author(s):

Jinxin Wang ◽

Jing Bai ◽

Peng Duan ◽

Hao Wang ◽

Yang Li ◽

...

Keyword(s):

Cardiac Function ◽

Signaling Pathway ◽

Diabetic Cardiomyopathy ◽

Cardiac Dysfunction ◽

Diabetic Patients ◽

Protein Levels ◽

Inwardly Rectifying Potassium Channel ◽

Transmission Electron ◽

Hematoxylin And Eosin ◽

And Function

Abstract Background: Diabetic cardiomyopathy (DCM) severely impairs the health of diabetic patients. Previous studies have shown that the expression of inwardly rectifying potassium channel 6.1 (Kir6.1) in heart mitochondria is significantly reduced in type 1 diabetes. However, whether its expression and function are changed and what role it plays in type 2 DCM have not been reported. This study investigated the role and mechanism of Kir6.1 in DCM.Methods: The cardiac function in mice was analyzed by echocardiography, ELISA, hematoxylin and eosin staining, TUNEL and transmission electron microscopy. The mitochondrial function in cardiomyocytes was measured by the oxygen consumption rate and the mitochondrial membrane potential (ΔΨm). Kir6.1 expression at the mRNA and protein levels was analyzed by quantitative real-time PCR and western blotting (WB), respectively. The protein expression of t-AKT, p-AKT, t-Foxo1, and p-Foxo1 was analyzed by WB.Results: We found that the cardiac function and the Kir6.1 expression in DCM mice were decreased. Kir6.1 overexpression improved cardiac dysfunction and upregulated the phosphorylation of AKT and Foxo1 in the DCM mouse model. Furthermore, Kir6.1 overexpression also improved cardiomyocyte dysfunction and upregulated the phosphorylation of AKT and Foxo1 in cardiomyocytes with insulin resistance. In contrast, cardiac-specific Kir6.1 knockout aggravated the cardiac dysfunction and downregulated the phosphorylation of AKT and Foxo1 in DCM mice. Furthermore, Foxo1 activation downregulated the expression of Kir6.1 and decreased the ΔΨm in cardiomyocytes. In contrast, Foxo1 inactivation upregulated the expression of Kir6.1 and increased the ΔΨm in cardiomyocytes. Chromatin immunoprecipitation assay demonstrated that the Kir6.1 promoter region contains a functional Foxo1-binding site .Conclusions: Kir6.1 improves cardiac dysfunction in DCM, probably through the AKT-Foxo1 signaling pathway. Moreover, the crosstalk between Kir6.1 and the AKT-Foxo1 signaling pathway may provide new strategies for reversing the defective signaling in DCM.

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