Impaired in vivo mitochondrial Krebs cycle activity after myocardial infarction assessed using hyperpolarized magnetic resonance spectroscopy.
BACKGROUND: Myocardial infarction (MI) is one of the leading causes of heart failure. An increasing body of evidence links alterations in cardiac metabolism and mitochondrial function with the progression of heart disease. The aim of this work was to, therefore, follow the in vivo mitochondrial meta...
| Príomhchruthaitheoirí: | , , , , , , , , , |
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| Formáid: | Journal article |
| Teanga: | English |
| Foilsithe / Cruthaithe: |
2014
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| _version_ | 1826303905502330880 |
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| author | Dodd, M Atherton, H Carr, C Stuckey, D West, J Griffin, J Radda, G Clarke, K Heather, L Tyler, D |
| author_facet | Dodd, M Atherton, H Carr, C Stuckey, D West, J Griffin, J Radda, G Clarke, K Heather, L Tyler, D |
| author_sort | Dodd, M |
| collection | OXFORD |
| description | BACKGROUND: Myocardial infarction (MI) is one of the leading causes of heart failure. An increasing body of evidence links alterations in cardiac metabolism and mitochondrial function with the progression of heart disease. The aim of this work was to, therefore, follow the in vivo mitochondrial metabolic alterations caused by MI, thereby allowing a greater understanding of the interplay between metabolic and functional abnormalities. METHODS AND RESULTS: Using hyperpolarized carbon-13 ((13)C)-magnetic resonance spectroscopy, in vivo alterations in mitochondrial metabolism were assessed for 22 weeks after surgically induced MI with reperfusion in female Wister rats. One week after MI, there were no detectable alterations in in vivo cardiac mitochondrial metabolism over the range of ejection fractions observed (from 28% to 84%). At 6 weeks after MI, in vivo mitochondrial Krebs cycle activity was impaired, with decreased (13)C-label flux into citrate, glutamate, and acetylcarnitine, which correlated with the degree of cardiac dysfunction. These changes were independent of alterations in pyruvate dehydrogenase flux. By 22 weeks, alterations were also seen in pyruvate dehydrogenase flux, which decreased at lower ejection fractions. These results were confirmed using in vitro analysis of enzyme activities and metabolomic profiles of key intermediates. CONCLUSIONS: The in vivo decrease in Krebs cycle activity in the 6-week post-MI heart may represent an early maladaptive phase in the metabolic alterations after MI in which reductions in Krebs cycle activity precede a reduction in pyruvate dehydrogenase flux. Changes in mitochondrial metabolism in heart disease are progressive and proportional to the degree of cardiac impairment. |
| first_indexed | 2024-03-07T06:09:48Z |
| format | Journal article |
| id | oxford-uuid:ef15c732-57ad-430f-be7f-983bd6da75cc |
| institution | University of Oxford |
| language | English |
| last_indexed | 2024-03-07T06:09:48Z |
| publishDate | 2014 |
| record_format | dspace |
| spelling | oxford-uuid:ef15c732-57ad-430f-be7f-983bd6da75cc2022-03-27T11:37:45ZImpaired in vivo mitochondrial Krebs cycle activity after myocardial infarction assessed using hyperpolarized magnetic resonance spectroscopy.Journal articlehttp://purl.org/coar/resource_type/c_dcae04bcuuid:ef15c732-57ad-430f-be7f-983bd6da75ccEnglishSymplectic Elements at Oxford2014Dodd, MAtherton, HCarr, CStuckey, DWest, JGriffin, JRadda, GClarke, KHeather, LTyler, DBACKGROUND: Myocardial infarction (MI) is one of the leading causes of heart failure. An increasing body of evidence links alterations in cardiac metabolism and mitochondrial function with the progression of heart disease. The aim of this work was to, therefore, follow the in vivo mitochondrial metabolic alterations caused by MI, thereby allowing a greater understanding of the interplay between metabolic and functional abnormalities. METHODS AND RESULTS: Using hyperpolarized carbon-13 ((13)C)-magnetic resonance spectroscopy, in vivo alterations in mitochondrial metabolism were assessed for 22 weeks after surgically induced MI with reperfusion in female Wister rats. One week after MI, there were no detectable alterations in in vivo cardiac mitochondrial metabolism over the range of ejection fractions observed (from 28% to 84%). At 6 weeks after MI, in vivo mitochondrial Krebs cycle activity was impaired, with decreased (13)C-label flux into citrate, glutamate, and acetylcarnitine, which correlated with the degree of cardiac dysfunction. These changes were independent of alterations in pyruvate dehydrogenase flux. By 22 weeks, alterations were also seen in pyruvate dehydrogenase flux, which decreased at lower ejection fractions. These results were confirmed using in vitro analysis of enzyme activities and metabolomic profiles of key intermediates. CONCLUSIONS: The in vivo decrease in Krebs cycle activity in the 6-week post-MI heart may represent an early maladaptive phase in the metabolic alterations after MI in which reductions in Krebs cycle activity precede a reduction in pyruvate dehydrogenase flux. Changes in mitochondrial metabolism in heart disease are progressive and proportional to the degree of cardiac impairment. |
| spellingShingle | Dodd, M Atherton, H Carr, C Stuckey, D West, J Griffin, J Radda, G Clarke, K Heather, L Tyler, D Impaired in vivo mitochondrial Krebs cycle activity after myocardial infarction assessed using hyperpolarized magnetic resonance spectroscopy. |
| title | Impaired in vivo mitochondrial Krebs cycle activity after myocardial infarction assessed using hyperpolarized magnetic resonance spectroscopy. |
| title_full | Impaired in vivo mitochondrial Krebs cycle activity after myocardial infarction assessed using hyperpolarized magnetic resonance spectroscopy. |
| title_fullStr | Impaired in vivo mitochondrial Krebs cycle activity after myocardial infarction assessed using hyperpolarized magnetic resonance spectroscopy. |
| title_full_unstemmed | Impaired in vivo mitochondrial Krebs cycle activity after myocardial infarction assessed using hyperpolarized magnetic resonance spectroscopy. |
| title_short | Impaired in vivo mitochondrial Krebs cycle activity after myocardial infarction assessed using hyperpolarized magnetic resonance spectroscopy. |
| title_sort | impaired in vivo mitochondrial krebs cycle activity after myocardial infarction assessed using hyperpolarized magnetic resonance spectroscopy |
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