Maintaining Myocardial Glucose Utilization in Diabetic Cardiomyopathy Accelerates Mitochondrial Dysfunction
| Autor: | Manoja K. Brahma, Chase A. Andrizzi, Renata O. Pereira, E. Dale Abel, Wayne E. Bradley, Oleh Khalimonchuk, John C. Schell, Ariel Contreras-Ferrat, Curtis D. Olsen, Adam R. Wende, Chae-Myeong Ha, Li Wang, Sheldon E. Litwin, Hansjörg Schwertz, Louis J. Dell'Italia, Joseph Tuinei, Wolfgang H. Dillmann, Mark E Pepin |
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| Rok vydání: | 2020 |
| Předmět: |
0301 basic medicine
medicine.medical_specialty Diabetic Cardiomyopathies Endocrinology Diabetes and Metabolism Glucose uptake 030209 endocrinology & metabolism Oxidative phosphorylation Mitochondrion Mice 03 medical and health sciences 0302 clinical medicine Commentaries Diabetes mellitus Diabetic cardiomyopathy Internal medicine Diabetes Mellitus Internal Medicine medicine Animals biology business.industry Myocardium Fatty Acids Glucose transporter medicine.disease Streptozotocin Mitochondria Glucose 030104 developmental biology Endocrinology biology.protein business GLUT4 medicine.drug |
| Zdroj: | Diabetes |
| ISSN: | 1939-327X 0012-1797 |
| DOI: | 10.2337/db19-1057 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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