Journal of IiMER Dr Øystein Fluge Chief Physician, Department of Oncology, Haukeland University Hospital, University of Bergen, Norway Dr Øystein Fluge received medical degree in 1988 at the University of Bergen, and is a specialist in oncology since 2004. He has worked as a Research Fellow with support from the Norwegian Cancer Society and is now chief physician at the Cancer Department, Haukeland University Hospital. Doctoral work emanates from the Surgical Institute and Department of Molecular Biology, University of Bergen. Abstract: Metabolic profiling indicates impaired pyruvate dehydrogenase function in ME/CFS patients Øystein Fluge, Department of Oncology, Haukeland University Hospital, Bergen, Norway. Metabolic dysfunction has emerged as a plausible contributing factor to ME/CFS. Previous studies have shown reduced levels of selected amino acids in serum or urine from ME/CFS patients. 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 tricarboxylic acid (TCA) cycle. The levels of amino acids that may convert to acetyl-CoA independent of pyruvate dehydrogenase (PDH), and also of anaplerotic amino acids that may replenish TCA cycle intermediates thus increasing the cycle capacity, were particularly reduced mainly in female ME/CFS patients. Amino acids that may convert to pyruvate, and are dependent on PDH for oxidation in the TCA cycle, were not reduced in ME/CFS patients. Serum 3methylhistidine, 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 (PDKs) 1, 2 and 4, sirtuin 4, and of peroxisome proliferator-activated receptor δ, in peripheral blood mononuclear cells from both genders. Myoblasts grown in presence of serum from patients with severe ME/CFS showed metabolic adaptations, including increased mitochondrial respiration and excessive lactate secretion. The pattern of amino acid changes could not be explained by symptom severity, disease duration, age, body mass index, or physical activity level among patients. These data support a metabolic “obstruction” in the central energy pathway in ME/CFS, a functional impairment possibly at the PDH level with difficulties in metabolizing glucose to energy in the TCA cycle, and with compensatory use of alternative substrates for acetyl-CoA such as ketogenic amino acids and fatty acids. Presently, we are investigating lipid alterations and B-vitamins in the same serum samples. We hypothesize that the inhibition of energy metabolism is caused by an aberrant immune response, in a subgroup of ME/CFS patients with a central role for B-cells and possibly antibodies. These findings are in agreement with the clinical disease presentation of ME/CFS, with inadequate ATP www.investinme.org Page 76 of 82
77 Publizr Home