Nutritional ketosis improves exercise metabolism in patients with very long-chain acyl-CoA dehydrogenase deficiency
Bleeker, Jeannette C.; Visser, Gepke; Clarke, Kieran; Ferdinandusse, Sacha; de Haan, Ferdinand H.; Houtkooper, Riekelt H.; IJlst, Lodewijk; Kok, Irene L.; Langeveld, Mirjam; van der Pol, W. Ludo; de Sain-van der Velden, Monique G.M.; Sibeijn-Kuiper, Anita; Takken, Tim; Wanders, Ronald J.A.; van Weeghel, Michel; Wijburg, Frits A.; van der Woude, Luc H.; Wüst, Rob C.I.; Cox, Pete J.; Jeneson, Jeroen A.L.
(2020) Journal of Inherited Metabolic Disease, volume 43, issue 4, pp. 787 - 799
(Article)
Abstract
A maladaptive shift from fat to carbohydrate (CHO) oxidation during exercise is thought to underlie myopathy and exercise-induced rhabdomyolysis in patients with fatty acid oxidation (FAO) disorders. We hypothesised that ingestion of a ketone ester (KE) drink prior to exercise could serve as an alternative oxidative substrate supply to boost
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muscular ATP homeostasis. To establish a rational basis for therapeutic use of KE supplementation in FAO, we tested this hypothesis in patients deficient in Very Long-Chain acyl-CoA Dehydrogenase (VLCAD). Five patients (range 17-45 y; 4 M/1F) patients were included in an investigator-initiated, randomised, blinded, placebo-controlled, 2-way cross-over study. Patients drank either a KE + CHO mix or an isocaloric CHO equivalent and performed 35 minutes upright cycling followed by 10 minutes supine cycling inside a Magnetic Resonance scanner at individual maximal FAO work rate (fatmax; approximately 40% VO2max). The protocol was repeated after a 1-week interval with the alternate drink. Primary outcome measures were quadriceps phosphocreatine (PCr), Pi and pH dynamics during exercise and recovery assayed by in vivo 31P-MR spectroscopy. Secondary outcomes included plasma and muscle metabolites and respiratory gas exchange recordings. Ingestion of KE rapidly induced mild ketosis and increased muscle BHB content. During exercise at FATMAX, VLCADD-specific plasma acylcarnitine levels, quadriceps glycolytic intermediate levels and in vivo Pi/PCr ratio were all lower in KE + CHO than CHO. These results provide a rational basis for future clinical trials of synthetic ketone ester supplementation therapy in patients with FAO disorders. Trial registration: ClinicalTrials.gov. Protocol ID: NCT03531554; METC2014.492; ABR51222.042.14.
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Keywords: fatty acid oxidation, in vivo P MRS, ketone ester, mitochondrial energy transduction, muscle, nutritional ketosis, very long-chain acyl-CoA dehydrogenase, VLCADD, Genetics, Genetics(clinical)
ISSN: 0141-8955
Publisher: Springer Netherlands
Note: Funding Information: Funding: This study was supported by ESN, the Dutch Society for Inborn Errors of Metabolism (to J.C.B.), and donation by Stichting Spieren voor Spieren (to W.L.v.d.P.) and in part by a subcontract to NIH grant HL‐072011 (to J.A.L.J.). Publisher Copyright: © 2020 The Authors. Journal of Inherited Metabolic Disease published by John Wiley & Sons Ltd on behalf of SSIEM
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