PMID- 31955429
OWN - NLM
STAT- MEDLINE
DCOM- 20210823
LR  - 20210823
IS  - 1573-2665 (Electronic)
IS  - 0141-8955 (Print)
IS  - 0141-8955 (Linking)
VI  - 43
IP  - 4
DP  - 2020 Jul
TI  - Nutritional ketosis improves exercise metabolism in patients with very long-chain 
      acyl-CoA dehydrogenase deficiency.
PG  - 787-799
LID - 10.1002/jimd.12217 [doi]
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% VO(2) 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: 
      ClinicalTrials.gov. Protocol ID: NCT03531554; METC2014.492; ABR51222.042.14.
CI  - (c) 2020 The Authors. Journal of Inherited Metabolic Disease published by John 
      Wiley & Sons Ltd on behalf of SSIEM.
FAU - Bleeker, Jeannette C
AU  - Bleeker JC
AD  - Department of Metabolic Diseases, Wilhelmina Children's Hospital, University 
      Medical Center Utrecht, Utrecht, The Netherlands.
AD  - Department of Metabolic Diseases, Emma Children's Hospital, Amsterdam UMC, 
      University of Amsterdam, Amsterdam, The Netherlands.
FAU - Visser, Gepke
AU  - Visser G
AUID- ORCID: 0000-0002-7618-6767
AD  - Department of Metabolic Diseases, Wilhelmina Children's Hospital, University 
      Medical Center Utrecht, Utrecht, The Netherlands.
AD  - Department of Metabolic Diseases, Emma Children's Hospital, Amsterdam UMC, 
      University of Amsterdam, Amsterdam, The Netherlands.
FAU - Clarke, Kieran
AU  - Clarke K
AD  - Department of Physiology, Anatomy and Genetics, University of Oxford, Oxford, UK.
FAU - Ferdinandusse, Sacha
AU  - Ferdinandusse S
AD  - Laboratory Genetic Metabolic Diseases, Amsterdam Gastroenterology and Metabolism, 
      Amsterdam UMC, University of Amsterdam, Amsterdam, The Netherlands.
FAU - de Haan, Ferdinand H
AU  - de Haan FH
AD  - ACHIEVE, Center for Applied Research, Faculty of Health, University of Applied 
      Sciences Amsterdam, Amsterdam, The Netherlands.
FAU - Houtkooper, Riekelt H
AU  - Houtkooper RH
AD  - Laboratory Genetic Metabolic Diseases, Amsterdam Gastroenterology and Metabolism, 
      Amsterdam UMC, University of Amsterdam, Amsterdam, The Netherlands.
FAU - IJlst, Lodewijk
AU  - IJlst L
AD  - Laboratory Genetic Metabolic Diseases, Amsterdam Gastroenterology and Metabolism, 
      Amsterdam UMC, University of Amsterdam, Amsterdam, The Netherlands.
FAU - Kok, Irene L
AU  - Kok IL
AD  - Department of Metabolic Diseases, Wilhelmina Children's Hospital, University 
      Medical Center Utrecht, Utrecht, The Netherlands.
FAU - Langeveld, Mirjam
AU  - Langeveld M
AD  - Department of Endocrinology and Metabolism, Amsterdam UMC, University of 
      Amsterdam, Amsterdam, The Netherlands.
FAU - van der Pol, W Ludo
AU  - van der Pol WL
AD  - Department of Neurology and Neurosurgery, Rudolf Magnus Institute of 
      Neuroscience, Spieren voor Spieren Kindercentrum, University Medical Center 
      Utrecht, Utrecht, The Netherlands.
FAU - de Sain-van der Velden, Monique G M
AU  - de Sain-van der Velden MGM
AD  - Department of Metabolic Diseases, Wilhelmina Children's Hospital, University 
      Medical Center Utrecht, Utrecht, The Netherlands.
FAU - Sibeijn-Kuiper, Anita
AU  - Sibeijn-Kuiper A
AD  - Neuroimaging Center, Department of Biomedical Sciences of Cells and Systems, 
      University Medical Center Groningen, Groningen, The Netherlands.
FAU - Takken, Tim
AU  - Takken T
AD  - Center for Child Development & Exercise, Department of Medical Physiology, 
      University Medical Center Utrecht, Utrecht, The Netherlands.
FAU - Wanders, Ronald J A
AU  - Wanders RJA
AD  - Department of Metabolic Diseases, Emma Children's Hospital, Amsterdam UMC, 
      University of Amsterdam, Amsterdam, The Netherlands.
AD  - Laboratory Genetic Metabolic Diseases, Amsterdam Gastroenterology and Metabolism, 
      Amsterdam UMC, University of Amsterdam, Amsterdam, The Netherlands.
FAU - van Weeghel, Michel
AU  - van Weeghel M
AD  - Laboratory Genetic Metabolic Diseases, Amsterdam Gastroenterology and Metabolism, 
      Amsterdam UMC, University of Amsterdam, Amsterdam, The Netherlands.
AD  - Laboratory Genetic Metabolic Diseases, Amsterdam UMC, University of Amsterdam, 
      Amsterdam Cardiovascular Sciences, Amsterdam, The Netherlands.
AD  - Core Facility Metabolomics, Amsterdam UMC, University of Amsterdam, Amsterdam, 
      The Netherlands.
FAU - Wijburg, Frits A
AU  - Wijburg FA
AD  - Department of Metabolic Diseases, Emma Children's Hospital, Amsterdam UMC, 
      University of Amsterdam, Amsterdam, The Netherlands.
FAU - van der Woude, Luc H
AU  - van der Woude LH
AD  - Human Movement Sciences, University Medical Center Groningen, Groningen, The 
      Netherlands.
FAU - Wust, Rob C I
AU  - Wust RCI
AD  - Laboratory Genetic Metabolic Diseases, Amsterdam Gastroenterology and Metabolism, 
      Amsterdam UMC, University of Amsterdam, Amsterdam, The Netherlands.
FAU - Cox, Pete J
AU  - Cox PJ
AD  - Department of Physiology, Anatomy and Genetics, University of Oxford, Oxford, UK.
FAU - Jeneson, Jeroen A L
AU  - Jeneson JAL
AD  - Neuroimaging Center, Department of Biomedical Sciences of Cells and Systems, 
      University Medical Center Groningen, Groningen, The Netherlands.
AD  - Center for Child Development & Exercise, Department of Medical Physiology, 
      University Medical Center Utrecht, Utrecht, The Netherlands.
AD  - Department of Radiology, Amsterdam UMC, University of Amsterdam, Amsterdam, The 
      Netherlands.
LA  - eng
SI  - ClinicalTrials.gov/NCT03531554
PT  - Journal Article
PT  - Multicenter Study
PT  - Randomized Controlled Trial
PT  - Research Support, N.I.H., Extramural
PT  - Research Support, Non-U.S. Gov't
DEP - 20200205
PL  - United States
TA  - J Inherit Metab Dis
JT  - Journal of inherited metabolic disease
JID - 7910918
RN  - 0 (Blood Glucose)
RN  - 0 (Esters)
RN  - 0 (Ketones)
RN  - 0 (acylcarnitine)
RN  - S7UI8SM58A (Carnitine)
RN  - VLCAD deficiency
SB  - IM
MH  - Adolescent
MH  - Adult
MH  - *Beverages
MH  - Blood Glucose/analysis
MH  - Carnitine/analogs & derivatives/blood
MH  - Congenital Bone Marrow Failure Syndromes/*diet therapy/metabolism
MH  - Cross-Over Studies
MH  - Diet, Ketogenic
MH  - *Endurance Training
MH  - Esters/administration & dosage
MH  - Exercise Test
MH  - Female
MH  - Humans
MH  - Ketones/administration & dosage
MH  - Ketosis/*chemically induced
MH  - Lipid Metabolism, Inborn Errors/*diet therapy/metabolism
MH  - Magnetic Resonance Spectroscopy
MH  - Male
MH  - Middle Aged
MH  - Mitochondrial Diseases/*diet therapy/metabolism
MH  - Muscle, Skeletal/metabolism/pathology
MH  - Muscular Diseases/*diet therapy/metabolism
MH  - Netherlands
MH  - Pulmonary Gas Exchange
MH  - Young Adult
PMC - PMC7384182
OTO - NOTNLM
OT  - VLCADD
OT  - fatty acid oxidation
OT  - in vivo 31P MRS
OT  - ketone ester
OT  - mitochondrial energy transduction
OT  - muscle
OT  - nutritional ketosis
OT  - very long-chain acyl-CoA dehydrogenase
COIS- The intellectual property and patents covering the uses of ketone bodies and 
      esters are owned by BTG Ltd, The University of Oxford, the NIH, and TDeltaS Ltd. 
      Should royalties ever accrue from these patents, K.C. and P.J.C. as named 
      inventors may receive a share of royalties as determined by the terms of the 
      respective institutions. K.C. is director of TDeltaS Ltd, a University of Oxford 
      company with the aim of developing and commercialising products based on the 
      ketone ester. P.J.C. is a former employee of TdeltaS. J.C.B., G.V., S.F., 
      F.H.d.H., R.H.H., L.I., I.L.K., M.L., W.L.v.d.P., M.G.M.d.S.-v.d.V., A.S.-K., 
      T.T., R.J.A.W., M.v.W., F.A.W., L.H.v.d.W., R.C.I.W., and J.A.L.J. declare that 
      they have no conflict of interest.
EDAT- 2020/01/20 06:00
MHDA- 2021/08/24 06:00
PMCR- 2020/07/27
CRDT- 2020/01/20 06:00
PHST- 2019/11/05 00:00 [received]
PHST- 2019/12/23 00:00 [revised]
PHST- 2020/01/14 00:00 [accepted]
PHST- 2020/01/20 06:00 [pubmed]
PHST- 2021/08/24 06:00 [medline]
PHST- 2020/01/20 06:00 [entrez]
PHST- 2020/07/27 00:00 [pmc-release]
AID - JIMD12217 [pii]
AID - 10.1002/jimd.12217 [doi]
PST - ppublish
SO  - J Inherit Metab Dis. 2020 Jul;43(4):787-799. doi: 10.1002/jimd.12217. Epub 2020 
      Feb 5.