Nutritional ketosis improves exercise metabolism in patients with very long-chain acyl-CoA dehydrogenase deficiency

Jeannette C Bleeker, Gepke Visser, Kieran Clarke, Sacha Ferdinandusse, Ferdinand H de Haan, Riekelt H Houtkooper, Lodewijk IJlst, Irene L Kok, Mirjam Langeveld, W Ludo van der Pol, Monique G M de Sain-van der Velden, Anita Sibeijn-Kuiper, Tim Takken, Ronald J A Wanders, Michel van Weeghel, Frits A Wijburg, Luc H van der Woude, Rob C I Wüst, Pete J Cox, Jeroen A L Jeneson

    Research output: Contribution to JournalArticleAcademicpeer-review


    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 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% VO2 max). 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 31 P-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: Protocol ID: NCT03531554; METC2014.492; ABR51222.042.14.

    Original languageEnglish
    Pages (from-to)787-799
    JournalJournal of Inherited Metabolic Disease
    Issue number4
    Publication statusE-pub ahead of print - 18 Jan 2020

    Bibliographical note

    © 2020 The Authors. Journal of Inherited Metabolic Disease published by John Wiley & Sons Ltd on behalf of SSIEM.


    Dive into the research topics of 'Nutritional ketosis improves exercise metabolism in patients with very long-chain acyl-CoA dehydrogenase deficiency'. Together they form a unique fingerprint.

    Cite this