Aubert, Gregory ORCID: 0000-0002-5539-0224, Martin, Ola J., Horton, Julie L., Lai, Ling, Vega, Rick B., Leone, Teresa C., Koves, Timothy, Gardell, Stephen J., Krueger, Marcus, Hoppel, Charles L., Lewandowski, E. Douglas, Crawford, Peter A., Muoio, Deborah M. and Kelly, Daniel P. (2016). The Failing Heart Relies on Ketone Bodies as a Fuel. Circulation, 133 (8). S. 698 - 706. PHILADELPHIA: LIPPINCOTT WILLIAMS & WILKINS. ISSN 1524-4539

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Abstract

Background Significant evidence indicates that the failing heart is energy starved. During the development of heart failure, the capacity of the heart to utilize fatty acids, the chief fuel, is diminished. Identification of alternate pathways for myocardial fuel oxidation could unveil novel strategies to treat heart failure. Methods and Results Quantitative mitochondrial proteomics was used to identify energy metabolic derangements that occur during the development of cardiac hypertrophy and heart failure in well-defined mouse models. As expected, the amounts of proteins involved in fatty acid utilization were downregulated in myocardial samples from the failing heart. Conversely, expression of -hydroxybutyrate dehydrogenase 1, a key enzyme in the ketone oxidation pathway, was increased in the heart failure samples. Studies of relative oxidation in an isolated heart preparation using ex vivo nuclear magnetic resonance combined with targeted quantitative myocardial metabolomic profiling using mass spectrometry revealed that the hypertrophied and failing heart shifts to oxidizing ketone bodies as a fuel source in the context of reduced capacity to oxidize fatty acids. Distinct myocardial metabolomic signatures of ketone oxidation were identified. Conclusions These results indicate that the hypertrophied and failing heart shifts to ketone bodies as a significant fuel source for oxidative ATP production. Specific metabolite biosignatures of in vivo cardiac ketone utilization were identified. Future studies aimed at determining whether this fuel shift is adaptive or maladaptive could unveil new therapeutic strategies for heart failure.

Item Type: Journal Article
Creators:
CreatorsEmailORCIDORCID Put Code
Aubert, GregoryUNSPECIFIEDorcid.org/0000-0002-5539-0224UNSPECIFIED
Martin, Ola J.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Horton, Julie L.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Lai, LingUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Vega, Rick B.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Leone, Teresa C.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Koves, TimothyUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Gardell, Stephen J.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Krueger, MarcusUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Hoppel, Charles L.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Lewandowski, E. DouglasUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Crawford, Peter A.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Muoio, Deborah M.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Kelly, Daniel P.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
URN: urn:nbn:de:hbz:38-284293
DOI: 10.1161/CIRCULATIONAHA.115.017355
Journal or Publication Title: Circulation
Volume: 133
Number: 8
Page Range: S. 698 - 706
Date: 2016
Publisher: LIPPINCOTT WILLIAMS & WILKINS
Place of Publication: PHILADELPHIA
ISSN: 1524-4539
Language: English
Faculty: Unspecified
Divisions: Unspecified
Subjects: no entry
Uncontrolled Keywords:
KeywordsLanguage
FATTY-ACID OXIDATION; MYOCARDIAL SUBSTRATE METABOLISM; PRESSURE-OVERLOAD; CARDIAC-HYPERTROPHY; DILATED CARDIOMYOPATHY; PALMITATE OXIDATION; ENERGY-METABOLISM; FAILURE SEVERITY; SKELETAL-MUSCLE; GENE-EXPRESSIONMultiple languages
Cardiac & Cardiovascular Systems; Peripheral Vascular DiseaseMultiple languages
Refereed: Yes
URI: http://kups.ub.uni-koeln.de/id/eprint/28429

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