TY - JOUR
T1 - Nutritional ketosis improves exercise metabolism in patients with very long-chain acyl-CoA dehydrogenase deficiency
AU - Bleeker, Jeannette C.
AU - Visser, Gepke
AU - Clarke, Kieran
AU - Ferdinandusse, Sacha
AU - de Haan, Ferdinand H.
AU - Houtkooper, Riekelt H.
AU - IJlst, Lodewijk
AU - Kok, Irene L.
AU - Langeveld, Mirjam
AU - van der Pol, W. Ludo
AU - de Sain-van der Velden, Monique G.M.
AU - Sibeijn-Kuiper, Anita
AU - Takken, Tim
AU - Wanders, Ronald J.A.
AU - van Weeghel, Michel
AU - Wijburg, Frits A.
AU - van der Woude, Luc H.
AU - Wüst, Rob C.I.
AU - Cox, Pete J.
AU - Jeneson, Jeroen A.L.
N1 - 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
PY - 2020/7
Y1 - 2020/7
N2 - 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% 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.
AB - 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% 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.
KW - fatty acid oxidation
KW - in vivo P MRS
KW - ketone ester
KW - mitochondrial energy transduction
KW - muscle
KW - nutritional ketosis
KW - very long-chain acyl-CoA dehydrogenase
KW - VLCADD
UR - http://www.scopus.com/inward/record.url?scp=85079004627&partnerID=8YFLogxK
U2 - 10.1002/jimd.12217
DO - 10.1002/jimd.12217
M3 - Article
C2 - 31955429
AN - SCOPUS:85079004627
SN - 0141-8955
VL - 43
SP - 787
EP - 799
JO - Journal of Inherited Metabolic Disease
JF - Journal of Inherited Metabolic Disease
IS - 4
ER -