Impaired anaplerosis after exercise in murine very long-chain acylCoA dehydrogenase deficiency (VLCAD-/-) is improved with Triheptanoin chow.

Garen Gaston, MS1, Jon A. Gangoiti, MS2, Bruce A. Barshop, MD, PhD2, Shelley Winn, PhD1, Cary O. Harding, MD1, Melanie B. Gillingham1

1Department of Molecular & Medical Genetics at Oregon Health & Science University, Portland, Oregon, USA,

2 D epartment of Pediatrics, Genetics Division, University of California San Diego, La Jolla, California, USA.

Odd-chain fatty acid supplementation has been suggested as a  way  to  increase  citric  acid  cycle intermediate (CACi) pools and energy metabolism in subjects with  long-chain  FAO  disorders  but the evidence for CACi depletion in these disorders has not been  conclusively  demonstrated. We  exercised murine VLCAD-/- at 60% VO2 max to exhaustion on a treadmill and exercised wild  type  (WT)  animals similarly and measured CACi in cardiac tissue by stable-isotope dilution targeted metabolomics after homogenization and extraction with ice-cold methanol.  (AB  Sciex  API  4000 tandem  mass  spectrometer). WT mice increased cardiac malate and citrate concentrations with exercise but VLCAD-/- animals did not suggest impaired anaplerosis with high-energy demands of exercise. WT and VLCAD-/- animals chow were then fed MCT or  Triheptanoin at 30% of total energy for 4 weeks. Animals were exercised at 60% VO2  max  for 60 minutes on a treadmill and CACi was measured in cardiac tissue as described above. There was no difference in citrate concentrations but malate concentration in cardiac tissue was higher in both WT and VLCAD-/- animals fed Triheptanoin compared to animals fed MCT. These observations suggest that a Triheptanoin diet likely induces an anaplerotic effect. Funded by Ultragenyx Inc.

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