Metabolic Studies

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Extended List of Studies (by year)

2015-2019

Mitochondrial complex activity in permeabilised cells of chronic fatigue syndrome patients using two cell types. [PDF]
Tomas C, Brown AE, Newton JL, Elson JL. Peer J. 2019
The results showing no difference in mitochondrial activity in permeabilised PBMCs were unexpected given that mitochondrial function in PBMCs has previously been shown to be significantly lower in CFS (Tomas et al., 2017). However, the lack of difference in complex activity in CFS PBMCs is in agreement with results reported by other groups who showed normal mitochondrial respiratory chain complex activity (Lawson et al., 2016; Vermeulen et al., 2010), and postulated that changes in mitochondrial ATP synthesis should be attributed to other causes such as the transport capacity of oxygen (Vermeulen et al., 2010). Given the results here, the future of bioenergetic studies in CFS should concentrate on mechanisms upstream of the mitochondrial respiratory chain.

Pharmacological activation of AMPK and glucose uptake in cultured human skeletal muscle cells from patients with ME/CFS. [Full Text] [PDF]
Brown AE, Dibnah B, Fisher E, Newton JL, Walker M. Biosci Rep. 2018

Prospective Biomarkers from Plasma Metabolomics of Myalgic Encephalomyelitis/Chronic Fatigue Syndrome Implicate Redox Imbalance in Disease Symptomatology. [PDF]
Germain, A. et al., MDPI Metabolites. 2018
In this report, we elaborate on 14 metabolites that we found to be different in abundance between our patient and healthy cohorts of females, and link this finding to a larger picture of metabolic pathway dysfunction. The highlighted pathways steer our understanding of the disease towards an effect on redox reactions, which has been a focal point in various studies. We demonstrate that we can cross-validate our own studies with data from other investigators’ published reports. Our intent is to inspire deeper investigation into metabolomics in ME/CFS, with the goal of developing diagnostic tests.

[HIGHLIGHT] Myalgic Encephalomyelitis/Chronic Fatigue Syndrome-Metabolic Disease or Disturbed Homeostasis due to Focal Inflammation in the Hypothalamus?
Hatziagelaki E, Adamaki M, Tsilioni I, Dimitriadis G, Theoharides TC. J Pharmacol Exp Ther. 2018.
The ME/CFS phenotype has been associated with abnormalities in energy metabolism, which are apparently due to mitochondrial dysfunction in the absence of mitochondrial diseases, resulting in reduced oxidative metabolism. Such mitochondria may be further contributing to the ME/CFS symptomatology by extracellular secretion of mitochondrial DNA, which could act as an innate pathogen and create an autoinflammatory state in the hypothalamus. We propose that stimulation of hypothalamic mast cells by environmental, neuroimmune, pathogenic and stress triggers activates microglia, leading to focal inflammation in the brain and disturbed homeostasis. This process could be targeted for the development of novel effective treatments.

KPAX002 as a treatment for Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS): a prospective, randomized trial. [PDF]
Montoya, JLG, Anderson JN, Adolphs DL, Bateman L, Klimas NG, Levine SM, Garvert DW, Kaiser JD. Int J Clin Exp Med. 2018
Mitochondrial dysfunction and a hypometabolic state are present in patients with Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS). KPAX002 consists of low-dose methylphenidate hydrochloride to treat a hypometabolic state combined with key micronutrients intended to broadly support mitochondrial function.

Insights into myalgic encephalomyelitis/chronic fatigue syndrome phenotypes through comprehensive metabolomics. [PDF]
Nagy-Szakal D, Barupal DK, Lee B, Che X, Williams BL, Kahn EJR, Ukaigwe JE, Bateman L, Klimas NG,  Komaroff AL, Levine S, Montoya JG, Peterson DL, Levin B, Hornig M, Fiehn O, Lipkin WI. Sci Rep. 2018

Higher Prevalence of "Low T3 Syndrome" in Patients With Chronic Fatigue Syndrome: A Case-Control Study.
[Full Text] [PDF]
Ruiz-Núñez B, Tarasse R, Vogelaar EF, Janneke Dijck-Brouwer DA, Muskiet FAJ. Front Endocrinol (Lausanne). 2018

Epigenetic modifications and glucocorticoid sensitivity in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS). [PDF]
de Vega WC, et al. BMC Med Genomics. 2017

[HIGHLIGHT] Metabolic profiling of a myalgic encephalomyelitis/chronic fatigue syndrome discovery cohort reveals disturbances in fatty acid and lipid metabolism. [Full Text] [PDF]
Germain A, Ruppert D, Levine SM, Hanson MR. Mol Biosyst. 2017
In this pilot study, we compare plasma metabolic signatures in a discovery cohort, 17 patients and 15 matched controls, and explore potential metabolic perturbations as the aftermath of the complex interactions between genes, transcripts and proteins. This approach to examine the complex array of symptoms and underlying foundation of ME/CFS revealed 74 differentially accumulating metabolites, out of 361 (P < 0.05), and 35 significantly altered after statistical correction (Q < 0.15). The latter list includes several essential energy-related compounds which could theoretically be linked to the general lack of energy observed in ME/CFS patients.

Pathway analysis points to a few pathways with high impact and therefore potential disturbances in patients, mainly taurine metabolism and glycerophospholipid metabolism, combined with primary bile acid metabolism, as well as glyoxylate and dicarboxylate metabolism and a few other pathways, all involved broadly in fatty acid metabolism. Purines, including ADP and ATP, pyrimidines and several amino acid metabolic pathways were found to be significantly disturbed. Finally, glucose and oxaloacetate were two main metabolites affected that have a major effect on sugar and energy levels. Our work provides a prospective path for diagnosis and understanding of the underlying mechanisms of ME/CFS.

Cellular bioenergetics is impaired in patients with chronic fatigue syndrome. [PDF]
Tomas C, Brown A, Strassheim V, Elson J, Newton J, Manning P. PLoS ONE. 2017

Mitochondrial DNA variants correlate with symptoms in myalgic encephalomyelitis/ chronic fatigue syndrome.
[PDF]
Billing-Ross P, Germain A, Ye K, Keinan A, Gu Z, Hanson MR. Journal of Translational Medicine. 2016

[HIGHLIGHT] Metabolic profiling indicates impaired pyruvate dehydrogenase function in myalgic encephalopathy/chronic fatigue syndrome. [PDF]
Fluge Ø, Mella O, Bruland O, Risa K, Dyrstad SE, Alme K, Rekeland IG, Sapkota D, Røsland GV, Fosså A, Ktoridou-Valen I, Lunde S, Sørland K, Lien K, Herder I, Thürmer H, Gotaas ME, Baranowska KA, Bohnen LM, Schäfer C, McCann A, Sommerfelt K, Helgeland L, Ueland PM, Dahl O, Tronstad KJ. JCI Insight. 2016
We hypothesized that changes in serum amino acids may disclose specific defects in energy metabolism in ME/CFS. Analysis 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).

Association of mitochondrial DNA variants with myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) symptoms. [PDF]
Hanson MR, et al. J Transl Med. 2016

[HIGHLIGHT] Metabolic features of chronic fatigue syndrome. [Full Text] [PDF]
Naviaux, R.K. et al., PNAS. 2016
Patients with CFS showed abnormalities in 20 metabolic pathways. Eighty percent of the diagnostic metabolites were decreased, consistent with a hypometabolic syndrome. Pathway abnormalities included sphingolipid, phospholipid, purine, cholesterol, microbiome, pyrroline-5-carboxylate, riboflavin, branch chain amino acid, peroxisomal, and mitochondrial metabolism. Our data show that despite the heterogeneity of factors leading to CFS, the cellular metabolic response in patients was homogeneous, statistically robust, and chemically similar to the evolutionarily conserved persistence response to environmental stress known as dauer.

Metabolomics showed that chronic fatigue syndrome is a highly concerted hypometabolic response to environmental stress that traces to mitochondria and was similar to the classically studied developmental state of dauer.  The finding of an objective chemical signature helps to remove diagnostic uncertainty, will help clinicians monitor individualized responses to treatment, and will facilitate multicenter clinical trials.

Naviaux’s metabolism paper is about as big as you think.
Seltzer, JB. #ME Action - A platform for myalgic encephalomyelitis. 2016

Evidence for sensitized fatigue pathways in patients with chronic fatigue syndrome. [Full Text] [PDF]
Staud R, Mokthech M, Price DD, Robinson ME. Pain. 2015

[HIGHLIGHT] Metabolic profiling reveals anomalous energy metabolism and oxidative stress pathways in chronic fatigue syndrome patients. [PDF]
Armstrong, CW, McGregor NR, Lewis DP, Butt HL, Gooley PR. Metabolomics. 2015
Energy metabolism and oxidative stress have been recent focal points of ME/CFS research and in this study we were able to elucidate metabolic pathways that were indicative of their dysfunction. Blood and urine samples were collected from 34 females with ME/CFS (34.9 ± 1.8 SE years old) and 25 non-ME/CFS female participants (33.0 ± 1.6 SE years old). All samples underwent metabolic profiling via 1D 1H Nuclear magnetic resonance spectroscopy and quantitated metabolites were assessed for significance. Blood glucose was elevated while blood lactate, urine pyruvate, and urine alanine were reduced indicating an inhibition of glycolysis that may potentially reduce the provision of adequate acetyl-CoA for the citric acid cycle.

We propose that amino acids are being increasingly used to provide an adequate carbohydrate source for the citric acid cycle. We suggest that this is via glutamate forming 2-oxoglutarate through an enzyme that deaminates it and subsequently elevates blood aspartate. Dysfunctional energy metabolism appears to have impacted creatinine and its elevation in urine suggests that it may be used as an alternative for anaerobic ATP production within muscle. A decrease in blood hypoxanthine and an increase in urine allantoin further suggest the elevation of reactive oxygen species in ME/CFS patients. These findings bring new information to the research of energy metabolism, chronic immune activation and oxidative stress issues within ME/CFS.

2010-2014

Metabolism in chronic fatigue syndrome.
Armstrong CW, McGregor NR, Butt HL, Gooley PR. Adv Clin Chem. 2014
Studies on metabolism and CFS suggest irregularities in energy metabolism, amino acid metabolism, nucleotide metabolism, nitrogen metabolism, hormone metabolism, and oxidative stress metabolism. The overwhelming body of evidence suggests an oxidative environment with the minimal utilization of mitochondria for efficient energy production. This is coupled with a reduced excretion of amino acids and nitrogen in general.

[HIGHLIGHT] Mitochondrial dysfunctions in myalgic encephalomyelitis/chronic fatigue syndrome explained by activated immuno-inflammatory, oxidative and nitrosative stress pathways.
Morris, G. et al. Metabolic Brain Disorders. 2014.

Immuno-inflammatory and O&NS pathways may play a role in the mitochondrial dysfunctions and consequently the bioenergetic abnormalities seen in patients with ME/CFS....mitochondrial dysfunctions, e.g. lowered ATP production, may play a role in the onset of symptoms and may explain in part the central metabolic abnormalities observed, e.g. glucose hypometabolism and cerebral hypoperfusion.

[HIGHLIGHT] Metabolic Feature of the Cell Danger Response. [PDF]
Naviaux, R. Mitochondria in Health and Disease. 2014
The cell danger response (CDR) is the evolutionarily conserved metabolic response that protects cells and hosts from harm. It is triggered by encounters with chemical, physical, or biological threats that exceed the cellular capacity for homeostasis. The resulting metabolic mismatch between available resources and functional capacity produces a cascade of changes in cellular electron flow, oxygen consumption, redox, membrane fluidity, lipid dynamics, bioenergetics, carbon and sulfur resource allocation, protein folding and aggregation, vitamin availability, metal homeostasis, indole, pterin, 1-carbon and polyamine metabolism, and polymer formation. The first wave of danger signals consists of the release of metabolic intermediates like ATP and ADP, Krebs cycle intermediates, oxygen, and reactive oxygen species (ROS), and is sustained by purinergic signaling.

After the danger has been eliminated or neutralized, a choreographed sequence of anti-inflammatory and regenerative pathways is activated to reverse the CDR and to heal. When the CDR persists abnormally, whole body metabolism and the gut microbiome are disturbed, the collective performance of multiple organ systems is impaired, behavior is changed, and chronic disease results. Metabolic memory of past stress encounters is stored in the form of altered mitochondrial and cellular macromolecule content, resulting in an increase in functional reserve capacity through a process known as mitocellular hormesis.

Association between vitamin D status and markers of vascular health in patients with chronic fatigue syndrome/myalgic encephalomyelitis (CFS/ME).
Witham M, Kennedy G, Belch J, Hill A, Khan F. Int J Cardiol. 2014
An association between vitamin D status and vascular health was found in CFS/ME patients.

Myalgic encephalomyelitis/chronic fatigue syndrome and encephalomyelitis disseminata/multiple sclerosis show remarkable levels of similarity in phenomenology and neuroimmune characteristics. [PDF] [ME-PEDIA]
Morris G, Maes M. BMC Med. 2013
Mitochondrial dysfunctions, including lowered levels of ATP, decreased phosphocreatine synthesis and impaired oxidative phosphorylation, are heavily involved in the pathophysiology of both MS and ME/CFS. The findings produced by neuroimaging techniques are quite similar in both illnesses and show decreased cerebral blood flow, atrophy, gray matter reduction, white matter hyperintensities, increased cerebral lactate and choline signaling and lowered acetyl-aspartate levels.

The role of mitochondrial dysfunctions due to oxidative and nitrosative stress in the chronic pain or chronic fatigue syndromes and fibromyalgia patients: peripheral and central mechanisms as therapeutic targets?
[Full Text]
Meeus M, Nijs J, Hermans L, Goubert D, Calders P. Expert Opin Ther Targets. 2013
The current evidence regarding oxidative and nitrosative stress and mitochondrial dysfunction in CFS and FM is presented in relation to chronic widespread pain.

Discriminative Validity of Metabolic and Workload Measurements for Identifying People With Chronic Fatigue Syndrome [PDF]
Snell CR, Stevens SR, Davenport TE, Van Ness JM. Physical Therapy. 2013

NMR metabolic profiling of serum identifies amino acid disturbances in chronic fatigue syndrome.
Armstrong CW, et al. Clin Chim Acta. 2012

[HIGHLIGHT] Mitochondrial dysfunction and the pathophysiology of Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS). [Full Text] [PDF]
Booth NE, Myhill S, McLaren-Howard J.  Int J Clin Exp Med. 2012
Researchers found that all CFS patients tested had measurable mitochondrial dysfunction, correlating with the severity of the illness. The patients divide into two main groups differentiated by how cellular metabolism attempts to compensate for the dysfunction. The major immediate causes of the dysfunction are lack of essential substrates and partial blocking of the translocator protein sites in mitochondria.

2005-2009

Coenzyme Q10 deficiency in myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is related to fatigue, autonomic and neurocognitive symptoms and is another risk factor explaining the early mortality in ME/CFS due to cardiovascular disorder.
Maes M, Mihaylova I, Kubera M, Uytterhoeven M, Vrydags N, Bosmans E. Neuro Endocrinol Lett. 2009
CFS patients have very low levels of CoQ10, a mitochondrial nutrient that acts as a cofactor for ATP production and has antioxidant effects.  This may be related to increased mortality from chronic heart failure in the disease.

(Psychology) Ventricular cerebrospinal fluid lactate is increased in chronic fatigue syndrome compared with generalized anxiety disorder: an in vivo 3.0 T (1)H MRS imaging study. [Full Text]
Mathew SJ, Mao X, Keegan KA, Levine SM, Smith EL, Heier LA, Otcheretko V, Coplan JD, Shungu DC.
NMR Biomed. 2009
Compared to healthy controls and sufferers of anxiety disorder, CFS patients have significantly raised concentrations of ventricular lactate in their spinal fluid.  This potentially related to decreased cortical blood flow, secondary mitochondrial dysfunction and oxidative stress abnormalities.

Chronic fatigue syndrome and mitochondrial dysfunction. [PDF]
Myhill S, Booth NE, McLaren-Howard J. Int J Clin Exp Med. 2009
We have demonstrated the power and usefulness of the “ATP profile” test in confirming and pin-pointing biochemical dysfunctions in people with CFS.

Our observations strongly implicate mitochondrial dysfunction as the immediate cause of CFS symptoms. However, we cannot tell whether the damage to mitochondrial function is a primary effect, or a secondary effect to one or more of a number of primary conditions, for example cellular hypoxia, or oxidative stress including excessive peroxynitrite.

What happens if some part of these cellular metabolic pathways goes wrong? If the mitochondrial source of energy is dysfunctional many disease symptoms may appear including the symptoms of CFS. Suppose that the demand for ATP is higher than the rate at which it can be recycled. This happens to athletes during the 100 meters sprint. The muscle cells go into anaerobic metabolism where each glucose molecule is converted into 2 molecules of lactic acid. This process is very inefficient (5.2% energy production compared to the 100% of complete oxidation) and can last for only a few minutes. The increased acidity leads to muscle pain. Also, when the concentration of ADP in the cytosol increases and the ADP cannot be recycled quickly enough to ATP, another chemical reaction takes place. This becomes important if there is any mitochondrial dysfunction. Two molecules of ADP interact to produce one of ATP and one of AMP (adenosine monophosphate). The AMP cannot be recycled and thus half of the potential ATP is lost. This takes some days to replenish and may account for the post-exertional malaise symptom experienced by patients.

Thus, mitochondrial dysfunction resulting in impaired ATP production and recycling is a biologically plausible hypothesis, and there is considerable evidence that it is a contributory factor in CFS, at least for a subset of patients. Our study may be considered to be a test of this hypothesis.

Transcription profile analysis of vastus lateralis muscle from patients with chronic fatigue syndrome. [Full Text]
Pietrangelo T, Mancinelli R, Toniolo L, Montanari G, Vecchiet J, Fanò G, Fulle S. Int J Immunopathol
Pharmacol. 2009
The expression of a number of genes in CFS are altered, including ones related to mitochondrial function and oxidative balance, energy production, muscular trophism, and neuromuscular transmission.

Treating Chronic Fatigue states as a disease of the regulation of energy metabolism. [Full Text]
Bains W. Med Hypotheses. 2008

PRE-2000

Vitamin B status in patients with chronic fatigue syndrome. [Full Text] [PDF]
Heap LC, Peters TJ, Wessely S. J R Soc Med. 1999
There is a reduced functional B vitamin status, particularly of pyridoxine, in CFS patients.

Serum levels of carnitine in chronic fatigue syndrome: clinical correlates.
Plioplys AV, Plioplys S. Neuropsychobiology. 1995
CFS patients have statistically significantly lower serum total carnitine, free carnitine and acylcarnitine levels. Higher serum carnitine levels correlated with better functional capacity. These findings may be indicative of mitochondrial dysfunction.

Acylcarnitine deficiency in chronic fatigue syndrome.
Kuratsune H, Yamaguti K, Takahashi M, Misaki H, Tagawa S, Kitani T. Clin Infect Dis. 1994
A group of CFS patients had a deficiency of serum acylcarnitine.

Serum folate and chronic fatigue syndrome.
Jacobson W, Saich T, Borysiewicz LK, Behan WM, Behan PO, Wreghitt TG. Neurology. 1993
Half of a group of CFS patients were deficient in folic acid.

Plasma and cerebrospinal fluid monoamine metabolism in patients with chronic fatigue syndrome: preliminary findings. [PDF]
Demitrack MA, Gold PW, Dale JK, Krahn DD, Kling MA, Straus SE. Biol Psychiatry. 1992
A group of CFS patients showed a significant reduction in basal plasma levels of MHPG and a significant increase in basal plasma levels of 5-HIAA.

Other

New Research Project Launches through SMCI’s Targeted Initiative Research Program.
SMCI. 2016