Metabolic profiling indicates impaired pyruvate dehydrogenase function in myalgic encephalopathy/chronic fatigue syndrome
Øystein Fluge, Olav Mella, Ove Bruland, Kristin Risa, Sissel E. Dyrstad, Kine Alme, Ingrid G. Rekeland, Dipak Sapkota, Gro V. Røsland, Alexander Fosså, Irini Ktoridou-Valen, Sigrid Lunde, Kari Sørland, Katarina Lien, Ingrid Herder, Hanne Thürmer, Merete E. Gotaas, Katarzyna A. Baranowska, Louis M.L.J. Bohnen, Christoph Schäfer, Adrian McCann, Kristian Sommerfelt, Lars Helgeland, Per M. Ueland, Olav Dahl, Karl J. Tronstad
Øystein Fluge, Olav Mella, Ove Bruland, Kristin Risa, Sissel E. Dyrstad, Kine Alme, Ingrid G. Rekeland, Dipak Sapkota, Gro V. Røsland, Alexander Fosså, Irini Ktoridou-Valen, Sigrid Lunde, Kari Sørland, Katarina Lien, Ingrid Herder, Hanne Thürmer, Merete E. Gotaas, Katarzyna A. Baranowska, Louis M.L.J. Bohnen, Christoph Schäfer, Adrian McCann, Kristian Sommerfelt, Lars Helgeland, Per M. Ueland, Olav Dahl, Karl J. Tronstad
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Research Article Metabolism

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

Øystein Fluge, Olav Mella, Ove Bruland, Kristin Risa, Sissel E. Dyrstad, Kine Alme, Ingrid G. Rekeland, Dipak Sapkota, Gro V. Røsland, Alexander Fosså, Irini Ktoridou-Valen, Sigrid Lunde, Kari Sørland, Katarina Lien, Ingrid Herder, Hanne Thürmer, Merete E. Gotaas, Katarzyna A. Baranowska, Louis M.L.J. Bohnen, Christoph Schäfer, Adrian McCann, Kristian Sommerfelt, Lars Helgeland, Per M. Ueland, Olav Dahl, Karl J. Tronstad

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Figure 5

Effects of ME/CFS patient and healthy control serum on muscle cell metabolism.

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Effects of ME/CFS patient and healthy control serum on muscle cell metab...
Rates of oxygen consumption and lactate production were measured simultaneously in cultures of human muscle cells (HSMM) after exposure (6 days) to serum from healthy individuals (n = 12) or ME/CFS patients (n = 12). Glucose (GLC), oligomycin (OLIGO), carbonyl cyanide 3-chlorophenylhydrazone (CCCP), and rotenone/antimycin A (ROT/AMA) were administered sequentially during the analysis to assess specific properties of cellular energy metabolism. The consequent energetic states of the cells were classified as follows: I Resting (AAs), II Resting (AAs+GLC), III Anaerobic strain, and IV Aerobic strain, as described in the Methods. (A) Recordings of oxygen consumption rate are shown for muscle cells preexposed to healthy control (black) and ME/CFS patient (red) serum. The substance additions and the resultant energetic conditions of the cells are indicated (conditions I–IV). (B) Statistical analysis of the data in A. (C) Recordings of the lactate production rate from the same experiment as A and B. (D) Statistical analysis of the data in C. (E) Specific descriptors of mitochondrial respiration were calculated as indicated, based on the data in A. (F) Specific descriptors of inducible lactate production were calculated as indicated, based on the data in C. The analysis was performed with 5 replicate wells for each serum sample and is representative of 3 separate experiments. Statistical comparisons between healthy controls and ME/CFS samples were performed by Mann-Whitney U test for independent samples.