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Maintaining Myocardial Glucose Utilization in Diabetic Cardiomyopathy Accelerates Mitochondrial Dysfunction.

ABSTRACT: Cardiac glucose uptake and oxidation are reduced in diabetes despite hyperglycemia. Mitochondrial dysfunction contributes to heart failure in diabetes. It is unclear whether these changes are adaptive or maladaptive. To directly evaluate the relationship between glucose delivery and mitochondrial dysfunction in diabetic cardiomyopathy, we generated transgenic mice with inducible cardiomyocyte-specific expression of the GLUT4. We examined mice rendered hyperglycemic following low-dose streptozotocin prior to increasing cardiomyocyte glucose uptake by transgene induction. Enhanced myocardial glucose in nondiabetic mice decreased mitochondrial ATP generation and was associated with echocardiographic evidence of diastolic dysfunction. Increasing myocardial glucose delivery after short-term diabetes onset exacerbated mitochondrial oxidative dysfunction. Transcriptomic analysis revealed that the largest changes, driven by glucose and diabetes, were in genes involved in mitochondrial function. This glucose-dependent transcriptional repression was in part mediated by O-GlcNAcylation of the transcription factor Sp1. Increased glucose uptake induced direct O-GlcNAcylation of many electron transport chain subunits and other mitochondrial proteins. These findings identify mitochondria as a major target of glucotoxicity. They also suggest that reduced glucose utilization in diabetic cardiomyopathy might defend against glucotoxicity and caution that restoring glucose delivery to the heart in the context of diabetes could accelerate mitochondrial dysfunction by disrupting protective metabolic adaptations.

SUBMITTER: Wende AR

PROVIDER: S-EPMC7506832 | biostudies-literature | 2020 Oct

REPOSITORIES: biostudies-literature

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Maintaining Myocardial Glucose Utilization in Diabetic Cardiomyopathy Accelerates Mitochondrial Dysfunction.

Wende Adam R AR Schell John C JC Ha Chae-Myeong CM Pepin Mark E ME Khalimonchuk Oleh O Schwertz Hansjörg H Pereira Renata O RO Brahma Manoja K MK Tuinei Joseph J Contreras-Ferrat Ariel A Wang Li L Andrizzi Chase A CA Olsen Curtis D CD Bradley Wayne E WE Dell'Italia Louis J LJ Dillmann Wolfgang H WH Litwin Sheldon E SE Abel E Dale ED

Diabetes 20200504 10

Cardiac glucose uptake and oxidation are reduced in diabetes despite hyperglycemia. Mitochondrial dysfunction contributes to heart failure in diabetes. It is unclear whether these changes are adaptive or maladaptive. To directly evaluate the relationship between glucose delivery and mitochondrial dysfunction in diabetic cardiomyopathy, we generated transgenic mice with inducible cardiomyocyte-specific expression of the GLUT4. We examined mice rendered hyperglycemic following low-dose streptozoto ...[more]

PMID: 32366681

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Project description:ObjectiveIncreasing evidence highlights the critical role of Piezo1 in cardiovascular diseases, with its expression upregulated in diabetic heart. However, the involvement of Piezo1 in the pathogenesis of diabetic cardiomyopathy (DCM) remains unclear. This study aims to elucidate the regulatory role of Piezo1 in mitochondrial dynamics within the context of DCM and to investigate the underlying mechanisms.MethodsWe constructed cardiac-specific knockout of Piezo1 (Piezo1∆Myh6) mice. Type 1 diabetes was induced using streptozotocin (STZ) injection while type 2 diabetes was established through a high-fat diet combined with STZ. Echocardiography assessed left ventricular function, histological evaluations used HE and Masson staining to examine cardiac pathology in Piezo1fl/fl controls, Piezo1∆Myh6 controls, Piezo1fl/fl diabetic and Piezo1∆Myh6 diabetic mice. Mitochondrial function including oxygen species level, mitochondrial morphology, and respiration rate were also assessed.ResultsOur findings revealed that Piezo1 expression was upregulated in the myocardium of diabetic mice and in high-glucose-treated cells. Cardiac-specific knockout of Piezo1 improved cardiac dysfunction and ameliorated cardiac fibrosis in diabetic mice. Moreover, Piezo1 deficiency also attenuated mitochondrial impairment. Piezo1fl/fl diabetic mice exhibited increased calpain activity and excessive mitochondrial fission mediated by Drp1 and obvious reduced fusion; however, Piezo1 deficiency restored calpain levels and mitochondrial dysfunction. These observations were also corroborated in H9C2 cells and neonatal mouse cardiomyocytes. Cardiac-specific knockout of Piezo1 increased phosphorylation of Drp1 and ERK1/2 in vivo and in vitro. Piezo1 knockout or treatment with inhibitor improved mitochondrial function.ConclusionsThis study provides the first evidence that Piezo1 is elevated in DCM through the modulation of mitochondrial dynamics, which is reversed by Piezo1 deficiency. Thus, Piezo1 inhibition may provide a promising therapeutic strategy for the treatment of DCM.

Project description:Diabetic cardiomyopathy (DCM) is one of the most essential cardiovascular complications in diabetic patients associated with glucose and lipid metabolism disorder, fibrosis, oxidative stress, and inflammation in cardiomyocytes. Despite increasing research on the molecular pathogenesis of DCM, it is still unclear whether metabolic pathways and alterations are probably involved in the development of DCM. This study aims to characterize the metabolites of DCM and to identify the relationship between metabolites and their biological processes or biological states through untargeted metabolic profiling. UPLC-MS/MS was applied to profile plasma metabolites from 78 patients with diabetes (39 diabetes with DCM and 39 diabetes without DCM as controls). A total of 2,806 biochemical were detected. Compared to those of DM patients, 78 differential metabolites in the positive-ion mode were identified in DCM patients, including 33 up-regulated and 45 down-regulated metabolites; however, there were only six differential metabolites identified in the negative mode including four up-regulated and two down-regulated metabolites. Alterations of several serum metabolites, including lipids and lipid-like molecules, organic acids and derivatives, organic oxygen compounds, benzenoids, phenylpropanoids and polyketides, and organoheterocyclic compounds, were associated with the development of DCM. KEGG enrichment analysis showed that there were three signaling pathways (metabolic pathways, porphyrin, chlorophyll metabolism, and lysine degradation) that were changed in both negative- and positive-ion modes. Our results demonstrated that differential metabolites and lipids have specific effects on DCM. These results expanded our understanding of the metabolic characteristics of DCM and may provide a clue in the future investigation of reducing the incidence of DCM. Furthermore, the metabolites identified here may provide clues for clinical management and the development of effective drugs.

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Project description:AimTo uncover sex-related microvascular abnormalities that underlie the early presentation of reduced perfusion in leg skeletal muscle in a type II rat model of diabetic cardiomyopathy.Methods and resultsDiabetes was induced using a non-obese, diet-based, low-dose streptozotocin model in adult female (18 diabetic, 9 control) and male rats (29 diabetic, 11 control). Time-course monitoring over 12 months following diabetes induction was performed using echocardiography, treadmill exercise, photoacoustic imaging, flow-mediated dilation (FMD), histopathology, and immunohistochemistry. Diabetic rats maintained normal weights. Hypertension appeared late in both diabetic males (7 months) and females (10 months), while only diabetic males had elevated cholesterol (7 months). On echocardiography, all diabetic animals maintained normal ejection fraction and exhibited diastolic dysfunction, mild systolic dysfunction, and a slightly enlarged left ventricle. Exercise tolerance declined progressively and early in males (4 months), later in females (8 months); FMD showed lower baseline femoral arterial flow but unchanged reactivity in both sexes (5 months); and photoacoustic imaging showed lower tissue oxygen saturation in the legs of diabetic males (4 months) and diabetic females (10 months). Myocardial perfusion was normal in both sexes. Histopathology at the final timepoint of Month 10 (males) and Month 12 (females) revealed that myocardial microvasculature was normal in both vessel density and structure, thus explaining normal perfusion on imaging. However, leg muscle microvasculature exhibited perivascular smooth muscle thickening around small arterioles in diabetic females and around large arterioles in diabetic males, explaining the depressed readings on photoacoustic and FMD. Histology also confirmed the absence of commonly reported HFpEF markers, including microvessel rarefaction, myocardial fibrosis, and left ventricular hypertrophy.ConclusionExercise intolerance manifesting early in the progression of diabetic cardiomyopathy can be attributed to decreased perfusion to the leg skeletal muscle due to perivascular smooth muscle thickening around small arterioles in females and large arterioles in males. This microvascular abnormality was absent in the myocardium, where perfusion levels remained normal throughout the study. We conclude that although skeletal muscle microvascular dysfunction of the vasculature presents at different levels depending on sex, it consistently presents early in both sexes prior to overt cardiac changes such as rarefaction, fibrosis, or hypertrophy.

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Maintaining Myocardial Glucose Utilization in Diabetic Cardiomyopathy Accelerates Mitochondrial Dysfunction.

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Maintaining Myocardial Glucose Utilization in Diabetic Cardiomyopathy Accelerates Mitochondrial Dysfunction.

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