{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,24]],"date-time":"2026-09-24T19:06:55Z","timestamp":1790276815932,"version":"4.1.0"},"reference-count":49,"publisher":"Wiley","issue":"4","license":[{"start":{"date-parts":[[2020,2,5]],"date-time":"2020-02-05T00:00:00Z","timestamp":1580860800000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0\/"}],"funder":[{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","award":["072011"],"award-info":[{"award-number":["072011"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100013428","name":"Stichting Spieren voor Spieren","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100013428","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["J of Inher Metab Disea"],"published-print":{"date-parts":[[2020,7]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>\n                    A maladaptive shift from fat to carbohydrate (CHO) oxidation during exercise is thought to underlie myopathy and exercise\u2010induced 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\u2010Chain acyl\u2010CoA Dehydrogenase (VLCAD). Five patients (range 17\u201045 y; 4 M\/1F) patients were included in an investigator\u2010initiated, randomised, blinded, placebo\u2010controlled, 2\u2010way cross\u2010over study. Patients drank either a KE\u2009+\u2009CHO mix or an isocaloric CHO equivalent and performed 35\u2009minutes upright cycling followed by 10 minutes supine cycling inside a Magnetic Resonance scanner at individual maximal FAO work rate (\n                    <jats:italic>fatmax<\/jats:italic>\n                    ; approximately 40% VO\n                    <jats:sub>2<\/jats:sub>\n                    max). The protocol was repeated after a 1\u2010week interval with the alternate drink. Primary outcome measures were quadriceps phosphocreatine (PCr), Pi and pH dynamics during exercise and recovery assayed by in vivo\n                    <jats:sup>31<\/jats:sup>\n                    P\u2010MR 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\u2010specific plasma acylcarnitine levels, quadriceps glycolytic intermediate levels and in vivo Pi\/PCr ratio were all lower in KE\u2009+\u2009CHO than CHO. These results provide a rational basis for future clinical trials of synthetic ketone ester supplementation therapy in patients with FAO disorders.\n                  <\/jats:p>\n                  <jats:p>\n                    Trial registration:\n                    <jats:ext-link xmlns:xlink=\"http:\/\/www.w3.org\/1999\/xlink\" xlink:href=\"http:\/\/clinicaltrials.gov\">ClinicalTrials.gov<\/jats:ext-link>\n                    . Protocol ID: NCT03531554; METC2014.492; ABR51222.042.14.\n                  <\/jats:p>","DOI":"10.1002\/jimd.12217","type":"journal-article","created":{"date-parts":[[2020,1,19]],"date-time":"2020-01-19T01:54:46Z","timestamp":1579398886000},"page":"787-799","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":39,"title":["Nutritional ketosis improves exercise metabolism in patients with very long\u2010chain acyl\u2010CoA dehydrogenase deficiency"],"prefix":"10.1002","volume":"43","author":[{"given":"Jeannette C.","family":"Bleeker","sequence":"first","affiliation":[{"name":"Department of Metabolic Diseases, Wilhelmina Children's Hospital University Medical Center Utrecht  Utrecht The Netherlands"},{"name":"Department of Metabolic Diseases, Emma Children's Hospital, Amsterdam UMC University of Amsterdam  Amsterdam The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7618-6767","authenticated-orcid":false,"given":"Gepke","family":"Visser","sequence":"additional","affiliation":[{"name":"Department of Metabolic Diseases, Wilhelmina Children's Hospital University Medical Center Utrecht  Utrecht The Netherlands"},{"name":"Department of Metabolic Diseases, Emma Children's Hospital, Amsterdam UMC University of Amsterdam  Amsterdam The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kieran","family":"Clarke","sequence":"additional","affiliation":[{"name":"Department of Physiology, Anatomy and Genetics University of Oxford  Oxford UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sacha","family":"Ferdinandusse","sequence":"additional","affiliation":[{"name":"Laboratory Genetic Metabolic Diseases, Amsterdam Gastroenterology and Metabolism, Amsterdam UMC University of Amsterdam  Amsterdam The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ferdinand H.","family":"de Haan","sequence":"additional","affiliation":[{"name":"ACHIEVE, Center for Applied Research, Faculty of Health University of Applied Sciences Amsterdam  Amsterdam The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Riekelt H.","family":"Houtkooper","sequence":"additional","affiliation":[{"name":"Laboratory Genetic Metabolic Diseases, Amsterdam Gastroenterology and Metabolism, Amsterdam UMC University of Amsterdam  Amsterdam The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lodewijk","family":"IJlst","sequence":"additional","affiliation":[{"name":"Laboratory Genetic Metabolic Diseases, Amsterdam Gastroenterology and Metabolism, Amsterdam UMC University of Amsterdam  Amsterdam The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Irene L.","family":"Kok","sequence":"additional","affiliation":[{"name":"Department of Metabolic Diseases, Wilhelmina Children's Hospital University Medical Center Utrecht  Utrecht The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mirjam","family":"Langeveld","sequence":"additional","affiliation":[{"name":"Department of Endocrinology and Metabolism, Amsterdam UMC University of Amsterdam  Amsterdam The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"W. Ludo","family":"van der Pol","sequence":"additional","affiliation":[{"name":"Department of Neurology and Neurosurgery, Rudolf Magnus Institute of Neuroscience, Spieren voor Spieren Kindercentrum University Medical Center Utrecht  Utrecht The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Monique G. M.","family":"de Sain\u2010van der Velden","sequence":"additional","affiliation":[{"name":"Department of Metabolic Diseases, Wilhelmina Children's Hospital University Medical Center Utrecht  Utrecht The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anita","family":"Sibeijn\u2010Kuiper","sequence":"additional","affiliation":[{"name":"Neuroimaging Center, Department of Biomedical Sciences of Cells and Systems University Medical Center Groningen  Groningen The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tim","family":"Takken","sequence":"additional","affiliation":[{"name":"Center for Child Development &amp; Exercise, Department of Medical Physiology University Medical Center Utrecht  Utrecht The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ronald J. A.","family":"Wanders","sequence":"additional","affiliation":[{"name":"Department of Metabolic Diseases, Emma Children's Hospital, Amsterdam UMC University of Amsterdam  Amsterdam The Netherlands"},{"name":"Laboratory Genetic Metabolic Diseases, Amsterdam Gastroenterology and Metabolism, Amsterdam UMC University of Amsterdam  Amsterdam The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michel","family":"van Weeghel","sequence":"additional","affiliation":[{"name":"Laboratory Genetic Metabolic Diseases, Amsterdam Gastroenterology and Metabolism, Amsterdam UMC University of Amsterdam  Amsterdam The Netherlands"},{"name":"Laboratory Genetic Metabolic Diseases, Amsterdam UMC University of Amsterdam, Amsterdam Cardiovascular Sciences  Amsterdam The Netherlands"},{"name":"Core Facility Metabolomics, Amsterdam UMC University of Amsterdam  Amsterdam The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Frits A.","family":"Wijburg","sequence":"additional","affiliation":[{"name":"Department of Metabolic Diseases, Emma Children's Hospital, Amsterdam UMC University of Amsterdam  Amsterdam The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Luc H.","family":"van der Woude","sequence":"additional","affiliation":[{"name":"Human Movement Sciences University Medical Center Groningen  Groningen The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rob C. 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