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

J Inherit Metab Dis. 2020 Jul;43(4):787-799. doi: 10.1002/jimd.12217. Epub 2020 Feb 5.

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 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: ClinicalTrials.gov. Protocol ID: NCT03531554; METC2014.492; ABR51222.042.14.

Keywords: VLCADD; fatty acid oxidation; in vivo 31P MRS; ketone ester; mitochondrial energy transduction; muscle; nutritional ketosis; very long-chain acyl-CoA dehydrogenase.

Publication types

  • Multicenter Study
  • Randomized Controlled Trial
  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adolescent
  • Adult
  • Beverages*
  • Blood Glucose / analysis
  • Carnitine / analogs & derivatives
  • Carnitine / blood
  • Congenital Bone Marrow Failure Syndromes / diet therapy*
  • Congenital Bone Marrow Failure Syndromes / metabolism
  • Cross-Over Studies
  • Diet, Ketogenic
  • Endurance Training*
  • Esters / administration & dosage
  • Exercise Test
  • Female
  • Humans
  • Ketones / administration & dosage
  • Ketosis / chemically induced*
  • Lipid Metabolism, Inborn Errors / diet therapy*
  • Lipid Metabolism, Inborn Errors / metabolism
  • Magnetic Resonance Spectroscopy
  • Male
  • Middle Aged
  • Mitochondrial Diseases / diet therapy*
  • Mitochondrial Diseases / metabolism
  • Muscle, Skeletal / metabolism
  • Muscle, Skeletal / pathology
  • Muscular Diseases / diet therapy*
  • Muscular Diseases / metabolism
  • Netherlands
  • Pulmonary Gas Exchange
  • Young Adult

Substances

  • Blood Glucose
  • Esters
  • Ketones
  • acylcarnitine
  • Carnitine

Supplementary concepts

  • VLCAD deficiency

Associated data

  • ClinicalTrials.gov/NCT03531554