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Exercise-Induced Changes in Glucose Metabolism Promote Physiological Cardiac Growth
BACKGROUND: Exercise promotes metabolic remodeling in the heart, which is associated with physiological cardiac growth; however, it is not known whether or how physical activity–induced changes in cardiac metabolism cause myocardial remodeling. In this study, we tested whether exercise-mediated chan...
Autores principales: | , , , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Lippincott Williams & Wilkins
2017
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5704654/ https://www.ncbi.nlm.nih.gov/pubmed/28860122 http://dx.doi.org/10.1161/CIRCULATIONAHA.117.028274 |
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author | Gibb, Andrew A. Epstein, Paul N. Uchida, Shizuka Zheng, Yuting McNally, Lindsey A. Obal, Detlef Katragadda, Kartik Trainor, Patrick Conklin, Daniel J. Brittian, Kenneth R. Tseng, Michael T. Wang, Jianxun Jones, Steven P. Bhatnagar, Aruni Hill, Bradford G. |
author_facet | Gibb, Andrew A. Epstein, Paul N. Uchida, Shizuka Zheng, Yuting McNally, Lindsey A. Obal, Detlef Katragadda, Kartik Trainor, Patrick Conklin, Daniel J. Brittian, Kenneth R. Tseng, Michael T. Wang, Jianxun Jones, Steven P. Bhatnagar, Aruni Hill, Bradford G. |
author_sort | Gibb, Andrew A. |
collection | PubMed |
description | BACKGROUND: Exercise promotes metabolic remodeling in the heart, which is associated with physiological cardiac growth; however, it is not known whether or how physical activity–induced changes in cardiac metabolism cause myocardial remodeling. In this study, we tested whether exercise-mediated changes in cardiomyocyte glucose metabolism are important for physiological cardiac growth. METHODS: We used radiometric, immunologic, metabolomic, and biochemical assays to measure changes in myocardial glucose metabolism in mice subjected to acute and chronic treadmill exercise. To assess the relevance of changes in glycolytic activity, we determined how cardiac-specific expression of mutant forms of 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase affect cardiac structure, function, metabolism, and gene programs relevant to cardiac remodeling. Metabolomic and transcriptomic screenings were used to identify metabolic pathways and gene sets regulated by glycolytic activity in the heart. RESULTS: Exercise acutely decreased glucose utilization via glycolysis by modulating circulating substrates and reducing phosphofructokinase activity; however, in the recovered state following exercise adaptation, there was an increase in myocardial phosphofructokinase activity and glycolysis. In mice, cardiac-specific expression of a kinase-deficient 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase transgene (Glyco(Lo) mice) lowered glycolytic rate and regulated the expression of genes known to promote cardiac growth. Hearts of Glyco(Lo) mice had larger myocytes, enhanced cardiac function, and higher capillary-to-myocyte ratios. Expression of phosphatase-deficient 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase in the heart (Glyco(Hi) mice) increased glucose utilization and promoted a more pathological form of hypertrophy devoid of transcriptional activation of the physiological cardiac growth program. Modulation of phosphofructokinase activity was sufficient to regulate the glucose–fatty acid cycle in the heart; however, metabolic inflexibility caused by invariantly low or high phosphofructokinase activity caused modest mitochondrial damage. Transcriptomic analyses showed that glycolysis regulates the expression of key genes involved in cardiac metabolism and remodeling. CONCLUSIONS: Exercise-induced decreases in glycolytic activity stimulate physiological cardiac remodeling, and metabolic flexibility is important for maintaining mitochondrial health in the heart. |
format | Online Article Text |
id | pubmed-5704654 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2017 |
publisher | Lippincott Williams & Wilkins |
record_format | MEDLINE/PubMed |
spelling | pubmed-57046542017-12-11 Exercise-Induced Changes in Glucose Metabolism Promote Physiological Cardiac Growth Gibb, Andrew A. Epstein, Paul N. Uchida, Shizuka Zheng, Yuting McNally, Lindsey A. Obal, Detlef Katragadda, Kartik Trainor, Patrick Conklin, Daniel J. Brittian, Kenneth R. Tseng, Michael T. Wang, Jianxun Jones, Steven P. Bhatnagar, Aruni Hill, Bradford G. Circulation Original Research Articles BACKGROUND: Exercise promotes metabolic remodeling in the heart, which is associated with physiological cardiac growth; however, it is not known whether or how physical activity–induced changes in cardiac metabolism cause myocardial remodeling. In this study, we tested whether exercise-mediated changes in cardiomyocyte glucose metabolism are important for physiological cardiac growth. METHODS: We used radiometric, immunologic, metabolomic, and biochemical assays to measure changes in myocardial glucose metabolism in mice subjected to acute and chronic treadmill exercise. To assess the relevance of changes in glycolytic activity, we determined how cardiac-specific expression of mutant forms of 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase affect cardiac structure, function, metabolism, and gene programs relevant to cardiac remodeling. Metabolomic and transcriptomic screenings were used to identify metabolic pathways and gene sets regulated by glycolytic activity in the heart. RESULTS: Exercise acutely decreased glucose utilization via glycolysis by modulating circulating substrates and reducing phosphofructokinase activity; however, in the recovered state following exercise adaptation, there was an increase in myocardial phosphofructokinase activity and glycolysis. In mice, cardiac-specific expression of a kinase-deficient 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase transgene (Glyco(Lo) mice) lowered glycolytic rate and regulated the expression of genes known to promote cardiac growth. Hearts of Glyco(Lo) mice had larger myocytes, enhanced cardiac function, and higher capillary-to-myocyte ratios. Expression of phosphatase-deficient 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase in the heart (Glyco(Hi) mice) increased glucose utilization and promoted a more pathological form of hypertrophy devoid of transcriptional activation of the physiological cardiac growth program. Modulation of phosphofructokinase activity was sufficient to regulate the glucose–fatty acid cycle in the heart; however, metabolic inflexibility caused by invariantly low or high phosphofructokinase activity caused modest mitochondrial damage. Transcriptomic analyses showed that glycolysis regulates the expression of key genes involved in cardiac metabolism and remodeling. CONCLUSIONS: Exercise-induced decreases in glycolytic activity stimulate physiological cardiac remodeling, and metabolic flexibility is important for maintaining mitochondrial health in the heart. Lippincott Williams & Wilkins 2017-11-28 2017-11-20 /pmc/articles/PMC5704654/ /pubmed/28860122 http://dx.doi.org/10.1161/CIRCULATIONAHA.117.028274 Text en © 2017 The Authors. Circulation is published on behalf of the American Heart Association, Inc., by Wolters Kluwer Health, Inc. This is an open access article under the terms of the Creative Commons Attribution Non-Commercial-NoDerivs (https://creativecommons.org/licenses/by-nc-nd/4.0/) License, which permits use, distribution, and reproduction in any medium, provided that the original work is properly cited, the use is noncommercial, and no modifications or adaptations are made. |
spellingShingle | Original Research Articles Gibb, Andrew A. Epstein, Paul N. Uchida, Shizuka Zheng, Yuting McNally, Lindsey A. Obal, Detlef Katragadda, Kartik Trainor, Patrick Conklin, Daniel J. Brittian, Kenneth R. Tseng, Michael T. Wang, Jianxun Jones, Steven P. Bhatnagar, Aruni Hill, Bradford G. Exercise-Induced Changes in Glucose Metabolism Promote Physiological Cardiac Growth |
title | Exercise-Induced Changes in Glucose Metabolism Promote Physiological Cardiac Growth |
title_full | Exercise-Induced Changes in Glucose Metabolism Promote Physiological Cardiac Growth |
title_fullStr | Exercise-Induced Changes in Glucose Metabolism Promote Physiological Cardiac Growth |
title_full_unstemmed | Exercise-Induced Changes in Glucose Metabolism Promote Physiological Cardiac Growth |
title_short | Exercise-Induced Changes in Glucose Metabolism Promote Physiological Cardiac Growth |
title_sort | exercise-induced changes in glucose metabolism promote physiological cardiac growth |
topic | Original Research Articles |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5704654/ https://www.ncbi.nlm.nih.gov/pubmed/28860122 http://dx.doi.org/10.1161/CIRCULATIONAHA.117.028274 |
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