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Maintaining Myocardial Glucose Utilization in Diabetic Cardiomyopathy Accelerates Mitochondrial Dysfunction

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 dy...

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Autores principales: Wende, Adam R., Schell, John C., Ha, Chae-Myeong, Pepin, Mark E., Khalimonchuk, Oleh, Schwertz, Hansjörg, Pereira, Renata O., Brahma, Manoja K., Tuinei, Joseph, Contreras-Ferrat, Ariel, Wang, Li, Andrizzi, Chase A., Olsen, Curtis D., Bradley, Wayne E., Dell’Italia, Louis J., Dillmann, Wolfgang H., Litwin, Sheldon E., Abel, E. Dale
Formato: Online Artículo Texto
Lenguaje:English
Publicado: American Diabetes Association 2020
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7506832/
https://www.ncbi.nlm.nih.gov/pubmed/32366681
http://dx.doi.org/10.2337/db19-1057
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author Wende, Adam R.
Schell, John C.
Ha, Chae-Myeong
Pepin, Mark E.
Khalimonchuk, Oleh
Schwertz, Hansjörg
Pereira, Renata O.
Brahma, Manoja K.
Tuinei, Joseph
Contreras-Ferrat, Ariel
Wang, Li
Andrizzi, Chase A.
Olsen, Curtis D.
Bradley, Wayne E.
Dell’Italia, Louis J.
Dillmann, Wolfgang H.
Litwin, Sheldon E.
Abel, E. Dale
author_facet Wende, Adam R.
Schell, John C.
Ha, Chae-Myeong
Pepin, Mark E.
Khalimonchuk, Oleh
Schwertz, Hansjörg
Pereira, Renata O.
Brahma, Manoja K.
Tuinei, Joseph
Contreras-Ferrat, Ariel
Wang, Li
Andrizzi, Chase A.
Olsen, Curtis D.
Bradley, Wayne E.
Dell’Italia, Louis J.
Dillmann, Wolfgang H.
Litwin, Sheldon E.
Abel, E. Dale
author_sort Wende, Adam R.
collection PubMed
description 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.
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spelling pubmed-75068322021-10-01 Maintaining Myocardial Glucose Utilization in Diabetic Cardiomyopathy Accelerates Mitochondrial Dysfunction Wende, Adam R. Schell, John C. Ha, Chae-Myeong Pepin, Mark E. Khalimonchuk, Oleh Schwertz, Hansjörg Pereira, Renata O. Brahma, Manoja K. Tuinei, Joseph Contreras-Ferrat, Ariel Wang, Li Andrizzi, Chase A. Olsen, Curtis D. Bradley, Wayne E. Dell’Italia, Louis J. Dillmann, Wolfgang H. Litwin, Sheldon E. Abel, E. Dale Diabetes Metabolism 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. American Diabetes Association 2020-10 2020-05-04 /pmc/articles/PMC7506832/ /pubmed/32366681 http://dx.doi.org/10.2337/db19-1057 Text en © 2020 by the American Diabetes Association https://www.diabetesjournals.org/content/licenseReaders may use this article as long as the work is properly cited, the use is educational and not for profit, and the work is not altered. More information is available at https://www.diabetesjournals.org/content/license.
spellingShingle Metabolism
Wende, Adam R.
Schell, John C.
Ha, Chae-Myeong
Pepin, Mark E.
Khalimonchuk, Oleh
Schwertz, Hansjörg
Pereira, Renata O.
Brahma, Manoja K.
Tuinei, Joseph
Contreras-Ferrat, Ariel
Wang, Li
Andrizzi, Chase A.
Olsen, Curtis D.
Bradley, Wayne E.
Dell’Italia, Louis J.
Dillmann, Wolfgang H.
Litwin, Sheldon E.
Abel, E. Dale
Maintaining Myocardial Glucose Utilization in Diabetic Cardiomyopathy Accelerates Mitochondrial Dysfunction
title Maintaining Myocardial Glucose Utilization in Diabetic Cardiomyopathy Accelerates Mitochondrial Dysfunction
title_full Maintaining Myocardial Glucose Utilization in Diabetic Cardiomyopathy Accelerates Mitochondrial Dysfunction
title_fullStr Maintaining Myocardial Glucose Utilization in Diabetic Cardiomyopathy Accelerates Mitochondrial Dysfunction
title_full_unstemmed Maintaining Myocardial Glucose Utilization in Diabetic Cardiomyopathy Accelerates Mitochondrial Dysfunction
title_short Maintaining Myocardial Glucose Utilization in Diabetic Cardiomyopathy Accelerates Mitochondrial Dysfunction
title_sort maintaining myocardial glucose utilization in diabetic cardiomyopathy accelerates mitochondrial dysfunction
topic Metabolism
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7506832/
https://www.ncbi.nlm.nih.gov/pubmed/32366681
http://dx.doi.org/10.2337/db19-1057
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