title: Altered Energetics of Exercise Explain Risk of Rhabdomyolysis in Very Long-Chain Acyl-CoA Dehydrogenase Deficiency.
abstract: Rhabdomyolysis is common in very long-chain acyl-CoA dehydrogenase deficiency (VLCADD) and other metabolic myopathies, but its pathogenic basis is poorly understood. Here, we show that prolonged bicycling exercise against a standardized moderate workload in VLCADD patients is associated with threefold bigger changes in phosphocreatine (PCr) and inorganic phosphate (Pi) concentrations in quadriceps muscle and twofold lower changes in plasma acetyl-carnitine levels than in healthy subjects. This result is consistent with the hypothesis that muscle ATP homeostasis during exercise is compromised in VLCADD. However, the measured rates of PCr and Pi recovery post-exercise showed that the mitochondrial capacity for ATP synthesis in VLCADD muscle was normal. Mathematical modeling of oxidative ATP metabolism in muscle composed of three different fiber types indicated that the observed altered energy balance during submaximal exercise in VLCADD patients may be explained by a slow-to-fast shift in quadriceps fiber-type composition corresponding to 30% of the slow-twitch fiber-type pool in healthy quadriceps muscle. This study demonstrates for the first time that quadriceps energy balance during exercise in VLCADD patients is altered but not because of failing mitochondrial function. Our findings provide new clues to understanding the risk of rhabdomyolysis following exercise in human VLCADD.
authors.affiliation: Department of Metabolic Diseases, Wilhelmina Children's Hospital, University Medical Center Utrecht, Utrecht, the Netherlands.|Laboratory of Genetic Metabolic Diseases, Departments of Clinical Chemistry and Pediatrics, Emma Children's Hospital, Academic Medical Center, University of Amsterdam, Amsterdam, the Netherlands.
authors.forename: E F
authors.initials: EF
authors.lastname: Diekman
authors.affiliation: Department of Metabolic Diseases, Wilhelmina Children's Hospital, University Medical Center Utrecht, Utrecht, the Netherlands.|Laboratory of Genetic Metabolic Diseases, Departments of Clinical Chemistry and Pediatrics, Emma Children's Hospital, Academic Medical Center, University of Amsterdam, Amsterdam, the Netherlands.
authors.forename: G
authors.initials: G
authors.lastname: Visser
authors.affiliation: Computational Biology Group, Department of Biomedical Technology, Eindhoven University of Technology, Eindhoven, the Netherlands.|Systems Bioinformatics, Department of Life and Earth Sciences, Vrije Universiteit, Amsterdam, the Netherlands.
authors.forename: J P J
authors.initials: JP
authors.lastname: Schmitz
authors.affiliation: Department of Radiology, University Medical Center Utrecht, Utrecht, the Netherlands.
authors.forename: R A J
authors.initials: RA
authors.lastname: Nievelstein
authors.affiliation: Department of Metabolic Diseases, Wilhelmina Children's Hospital, University Medical Center Utrecht, Utrecht, the Netherlands.
authors.forename: M
authors.initials: M
authors.lastname: de Sain-van der Velden
authors.affiliation: Child Development & Exercise Center, Wilhelmina Children's Hospital, University Medical Center Utrecht, Utrecht, the Netherlands.
authors.forename: M
authors.initials: M
authors.lastname: Wardrop
authors.affiliation: Rudolf Magnus Institute of Neuroscience, Spieren voor Spieren Children's Center, Department of Neurology and Neurosurgery, University Medical Center Utrecht, Utrecht, the Netherlands.
authors.forename: W L
authors.initials: WL
authors.lastname: Van der Pol
authors.affiliation: Laboratory of Genetic Metabolic Diseases, Departments of Clinical Chemistry and Pediatrics, Emma Children's Hospital, Academic Medical Center, University of Amsterdam, Amsterdam, the Netherlands.
authors.forename: S M
authors.initials: SM
authors.lastname: Houten
authors.affiliation: Systems Bioinformatics, Department of Life and Earth Sciences, Vrije Universiteit, Amsterdam, the Netherlands.
authors.forename: N A W
authors.initials: NA
authors.lastname: van Riel
authors.affiliation: Child Development & Exercise Center, Wilhelmina Children's Hospital, University Medical Center Utrecht, Utrecht, the Netherlands.
authors.forename: T
authors.initials: T
authors.lastname: Takken
authors.affiliation: Child Development & Exercise Center, Wilhelmina Children's Hospital, University Medical Center Utrecht, Utrecht, the Netherlands.|Laboratory of Liver, Digestive and Metabolic Diseases, Department of Pediatrics, University Medical Center Groningen, Groningen, the Netherlands.
authors.forename: J A L
authors.initials: JA
authors.lastname: Jeneson
mesh_terms: D000108:Acetylcarnitine / Q000097:blood; D044942:Acyl-CoA Dehydrogenase, Long-Chain / Q000172:deficiency* / Q000378:metabolism; D000255:Adenosine Triphosphate / Q000096:biosynthesis*; D000293:Adolescent; D000328:Adult; D016022:Case-Control Studies; D000080984:Congenital Bone Marrow Failure Syndromes; D015444:Exercise; D005260:Female; D006801:Humans; D008052:Lipid Metabolism, Inborn Errors / Q000150:complications / Q000378:metabolism* / Q000473:pathology / Q000503:physiopathology; D008297:Male; D008928:Mitochondria / Q000378:metabolism; D028361:Mitochondrial Diseases / Q000150:complications / Q000378:metabolism* / Q000473:pathology / Q000503:physiopathology; D015233:Models, Statistical; D018656:Muscle Fibers, Fast-Twitch / Q000378:metabolism / Q000473:pathology; D018657:Muscle Fibers, Slow-Twitch / Q000378:metabolism / Q000473:pathology; D009135:Muscular Diseases / Q000150:complications / Q000378:metabolism* / Q000473:pathology / Q000503:physiopathology; D010085:Oxidative Phosphorylation; D010710:Phosphates / Q000378:metabolism; D010725:Phosphocreatine / Q000378:metabolism; D012206:Rhabdomyolysis / Q000150:complications / Q000378:metabolism* / Q000473:pathology / Q000503:physiopathology
chemical_list: D010710:Phosphates; D010725:Phosphocreatine; D000108:Acetylcarnitine; D000255:Adenosine Triphosphate; D044942:Acyl-CoA Dehydrogenase, Long-Chain