title: Myocardial energy shortage and unmet anaplerotic needs in the fasted long-chain acyl-CoA dehydrogenase knockout mouse.
abstract: OBJECTIVE
  The aim of this animal study is to assess fasting-induced changes in myocardial substrate metabolism and energy status as a consequence of mitochondrial long-chain fatty acid β-oxidation deficiency, using magnetic resonance spectroscopy (MRS).
  
  
  RESULTS
  Carbon-13 ((13)C) MRS of hyperpolarized [1-(13)C]pyruvate was used to assess in vivo pyruvate dehydrogenase (PDH) activity in fed and fasted wild-type (WT) mice and long-chain acyl-CoA 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 the (13)C label into the myocardial malate and aspartate pools in fasted LCAD KO mice demonstrates enhanced activity of anaplerotic pathways in fasted LCAD KO hearts. These findings were corroborated by ex 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 ((31)P) MRS, was lower in fasted LCAD KO mice than in fasted WT mice.
  
  
  CONCLUSIONS
  This study revealed that the heart of fasted LCAD KO mice has an elevated reliance on glucose oxidation, in combination with an unmet demand for myocardial anaplerosis. Due to a 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.
authors.affiliation: Biomedical NMR, Department of Biomedical Engineering, Eindhoven University of Technology, Eindhoven, The Netherlands.
authors.forename: Adrianus J
authors.initials: AJ
authors.lastname: Bakermans
authors.forename: Michael S
authors.initials: MS
authors.lastname: Dodd
authors.forename: Klaas
authors.initials: K
authors.lastname: Nicolay
authors.forename: Jeanine J
authors.initials: JJ
authors.lastname: Prompers
authors.forename: Damian J
authors.initials: DJ
authors.lastname: Tyler
authors.forename: Sander M
authors.initials: SM
authors.lastname: Houten
mesh_terms: D044942:Acyl-CoA Dehydrogenase, Long-Chain / Q000172:deficiency* / Q000235:genetics; D000818:Animals; D001224:Aspartic Acid / Q000378:metabolism; D002952:Citric Acid Cycle; D004195:Disease Models, Animal; D004734:Energy Metabolism; D005215:Fasting / Q000378:metabolism*; D005947:Glucose / Q000378:metabolism; D008052:Lipid Metabolism, Inborn Errors / Q000201:enzymology* / Q000235:genetics; D009682:Magnetic Resonance Spectroscopy; D008293:Malates / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008929:Mitochondria, Heart / Q000378:metabolism*; D009206:Myocardium / Q000378:metabolism*; D011768:Pyruvate Dehydrogenase Complex / Q000378:metabolism
chemical_list: D008293:Malates; D011768:Pyruvate Dehydrogenase Complex; D001224:Aspartic Acid; C030298:malic acid; D044942:Acyl-CoA Dehydrogenase, Long-Chain; D005947:Glucose
keywords: Carbon-13 magnetic resonance spectroscopy; Inborn errors of metabolism; MRI; Mouse model; Phosphorous-31 magnetic resonance spectroscopy