title: Metabolic profiling indicates impaired pyruvate dehydrogenase function in myalgic encephalopathy/chronic fatigue syndrome.
abstract: Myalgic encephalopathy/chronic fatigue syndrome (ME/CFS) is a debilitating disease of unknown etiology, with hallmark symptoms including postexertional malaise and poor recovery. Metabolic dysfunction is a plausible contributing factor. We hypothesized that changes in serum amino acids may disclose specific defects in energy metabolism in ME/CFS. Analysis in 200 ME/CFS patients and 102 healthy individuals showed a specific reduction of amino acids that fuel oxidative metabolism via the TCA cycle, mainly in female ME/CFS patients. Serum 3-methylhistidine, a marker of endogenous protein catabolism, was significantly increased in male patients. The amino acid pattern suggested functional impairment of pyruvate dehydrogenase (PDH), supported by increased mRNA expression of the inhibitory PDH kinases 1, 2, and 4; sirtuin 4; and PPARδ in peripheral blood mononuclear cells from both sexes. Myoblasts grown in presence of serum from patients with severe ME/CFS showed metabolic adaptations, including increased mitochondrial respiration and excessive lactate secretion. The amino acid changes could not be explained by symptom severity, disease duration, age, BMI, or physical activity level among patients. These findings are in agreement with the clinical disease presentation of ME/CFS, with inadequate ATP generation by oxidative phosphorylation and excessive lactate generation upon exertion.
authors.affiliation: Department of Oncology and Medical Physics, Haukeland University Hospital, Bergen, Norway.
authors.forename: Øystein
authors.initials: Ø
authors.lastname: Fluge
authors.affiliation: Department of Oncology and Medical Physics, Haukeland University Hospital, Bergen, Norway.|Department of Clinical Science, University of Bergen, Bergen, Norway.
authors.forename: Olav
authors.initials: O
authors.lastname: Mella
authors.affiliation: Department of Oncology and Medical Physics, Haukeland University Hospital, Bergen, Norway.|Department of Medical Genetics and Molecular Medicine, Haukeland University Hospital, Bergen, Norway.
authors.forename: Ove
authors.initials: O
authors.lastname: Bruland
authors.affiliation: Department of Oncology and Medical Physics, Haukeland University Hospital, Bergen, Norway.
authors.forename: Kristin
authors.initials: K
authors.lastname: Risa
authors.affiliation: Department of Biomedicine, University of Bergen, Bergen, Norway.
authors.forename: Sissel E
authors.initials: SE
authors.lastname: Dyrstad
authors.affiliation: Department of Oncology and Medical Physics, Haukeland University Hospital, Bergen, Norway.
authors.forename: Kine
authors.initials: K
authors.lastname: Alme
authors.affiliation: Department of Oncology and Medical Physics, Haukeland University Hospital, Bergen, Norway.
authors.forename: Ingrid G
authors.initials: IG
authors.lastname: Rekeland
authors.affiliation: Department of Oncology and Medical Physics, Haukeland University Hospital, Bergen, Norway.
authors.forename: Dipak
authors.initials: D
authors.lastname: Sapkota
authors.affiliation: Department of Biomedicine, University of Bergen, Bergen, Norway.
authors.forename: Gro V
authors.initials: GV
authors.lastname: Røsland
authors.affiliation: Department of Oncology, Norwegian Radium Hospital, Oslo University Hospital, Oslo, Norway.
authors.forename: Alexander
authors.initials: A
authors.lastname: Fosså
authors.affiliation: Department of Oncology and Medical Physics, Haukeland University Hospital, Bergen, Norway.
authors.forename: Irini
authors.initials: I
authors.lastname: Ktoridou-Valen
authors.affiliation: Department of Oncology and Medical Physics, Haukeland University Hospital, Bergen, Norway.
authors.forename: Sigrid
authors.initials: S
authors.lastname: Lunde
authors.affiliation: Department of Oncology and Medical Physics, Haukeland University Hospital, Bergen, Norway.
authors.forename: Kari
authors.initials: K
authors.lastname: Sørland
authors.affiliation: CFS/ME Center, Division of Medicine, Oslo University Hospital, Oslo, Norway.
authors.forename: Katarina
authors.initials: K
authors.lastname: Lien
authors.affiliation: CFS/ME Center, Division of Medicine, Oslo University Hospital, Oslo, Norway.
authors.forename: Ingrid
authors.initials: I
authors.lastname: Herder
authors.affiliation: Telemark Hospital, Department of Medicine, Notodden, Norway.
authors.forename: Hanne
authors.initials: H
authors.lastname: Thürmer
authors.affiliation: Department of Pain and Complex Disorders, St. Olav's Hospital, Trondheim, Norway.
authors.forename: Merete E
authors.initials: ME
authors.lastname: Gotaas
authors.affiliation: Department of Pain and Complex Disorders, St. Olav's Hospital, Trondheim, Norway.
authors.forename: Katarzyna A
authors.initials: KA
authors.lastname: Baranowska
authors.affiliation: Division of Rehabilitation Services, University Hospital of Northern Norway, Tromsø, Norway.
authors.forename: Louis Mlj
authors.initials: LM
authors.lastname: Bohnen
authors.affiliation: Division of Rehabilitation Services, University Hospital of Northern Norway, Tromsø, Norway.
authors.forename: Christoph
authors.initials: C
authors.lastname: Schäfer
authors.affiliation: Bevital AS, Bergen, Norway.
authors.forename: Adrian
authors.initials: A
authors.lastname: McCann
authors.affiliation: Department of Pediatrics and.
authors.forename: Kristian
authors.initials: K
authors.lastname: Sommerfelt
authors.affiliation: Department of Pathology, Haukeland University Hospital, Bergen, Norway.
authors.forename: Lars
authors.initials: L
authors.lastname: Helgeland
authors.affiliation: Department of Clinical Science, University of Bergen, Bergen, Norway.|Bevital AS, Bergen, Norway.
authors.forename: Per M
authors.initials: PM
authors.lastname: Ueland
authors.affiliation: Department of Oncology and Medical Physics, Haukeland University Hospital, Bergen, Norway.|Department of Clinical Science, University of Bergen, Bergen, Norway.
authors.forename: Olav
authors.initials: O
authors.lastname: Dahl
authors.affiliation: Department of Biomedicine, University of Bergen, Bergen, Norway.
authors.forename: Karl J
authors.initials: KJ
authors.lastname: Tronstad