Myocardial energy shortage and unmet anaplerotic needs in the fasted long-chain acyl-Co A dehydrogenase knockout mouse

Adrianus J. Bakermans, Michael S. Dodd, Klaas Nicolay, Jeanine J. Prompers, Damian J. Tyler, Sander M. Houten

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25 Citations (Scopus)

Abstract

Aims: The aim of this animal study istoassess fasting-induced changes in myocardial substrate metabolism and energy statusas a consequence of mitochondrial long-chain fatty acid β-oxidation deficiency, using magnetic resonance spectroscopy (MRS). Methods and results: Carbon-13 (13C) MRS of hyperpolarized [1-13C]pyruvate was used to assess in vivo pyruvate dehydrogenase (PDH) activity in fed and fasted wild-type (WT) mice and long-chain acyl-Co A dehydrogenase knockout (LCAD KO) mice. PDH activity decreased after fasting in both genotypes, but was 2.7-fold higher in fasted LCAD KO mice compared with fasted WT mice. Incorporation of the13C label into themyocardial malate and as partate poolsinfasted LCADKOmice demonstrates enhanced activity of anaplerotic pathways in fasted LCAD KO hearts. These findings were corroborated byex vivo assays revealing partially depleted pools of citric acid cycle intermediates in fasted LCAD KO myocardium, suggesting an increased, but unmet need for anaplerosis. The in vivo myocardial energy status, assessed using phosphorous-31 (31P) MRS, was lower in fasted LCAD KO mice than in fasted WT mice. Conclusion: This study revealed that the heart of fasted LCAD KO mice has an elevated reliance on glucose oxidation, in combination withanunmet demand for myocardial anaplerosis. Due toa lack of substrate availability, the sustained myocardial glucose uptake and PDH activity in LCAD KO mice are ineffective to maintain metabolic homeostasis during fasting, which is reflected by an impaired myocardial energy status in fasted LCAD KO mice.

Original languageEnglish
Pages (from-to)441-449
Number of pages9
JournalCardiovascular Research
Volume100
Issue number3
DOIs
Publication statusPublished - 1 Dec 2013
Externally publishedYes

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Keywords

  • Carbon-13 magnetic resonance spectroscopy
  • Inborn errors of metabolism
  • Mouse model
  • MRI
  • Phosphorous-31 magnetic resonance spectroscopy

ASJC Scopus subject areas

  • Cardiology and Cardiovascular Medicine
  • Physiology (medical)
  • Physiology

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