Thread by @IsabelRamirezRD

Prof Karl J Tronstad - energy metabolism and associations to clinical data in ME

There is no unified hypothesis that everyone agrees on, but there are observations that are guiding research

Mechanism, treatments and biomarkers of #MECFS - investigating abnormalities in the clinic, biobank and lab

Samples from 2 interventional studies at Hukeland university hospital being used in rituxME and cycloME trials.

Main energy pathway - glucose-pyruvate-acetyl-CoA-O2-energy ATP

Hypoxic conditions shuts down the entire mito system and compensation with degration of glucose and pyruvate to lactate is required to keep the system going #theacidtest pts describe the feeling of lactate accumulation all the time.

PDH inhibition leads to more lactate, less energy, altered use in energy fuels, especially on exertion #theacidtest #IIMEC15

Energy fuels: sugars, amino acids, fatty acids (#remissionbiome). The system responds to the impairments and finds ways to compensate. We find decreased levels of amino acids, tca metabolites and changed redox status, changes in lipid metabolism leading to diff hypothesis

oxygen and fuel supply , PDH inhibition, organelle dysfunction, and kynurenine pathway are some of the basis for the hypothesis. Although a phenotype has not been found, we can use some of these signs of stressed energy metabolism to find impairment and treatment pathways.

Abnormal lactate levels in #mecfs pts found during exercise. These are related to blood supply and not related to deconditioning.

base levels of lactate are also higher in #mecfs patients compared to controls.

Something in ME stresses cellular energy metabolism: increased o2 consumption/increased lactate production. Fatty acid oxidation in PDK4 overexpressing cells.

Data supports a metabolic switch to an energy restricted state. This contributes both to symptoms and symptoms worsening under certain conditions.

Global metabolomics of mecfs pts showed 159 significant differences in me vs controls. One of the metabolites (m2) showed an association with severity of symptoms.

Sex, diet, medication, BMI, aging, fasting effects were evaluated to determine influence

consequences at cell level: chronic struggle with ATP among others

Struggle for energy, decreased o2 extraction, lactate over production, physical debilitation. Metabolic effects may promote exertion triggered "damage" Normal training to metabolic adaptations, excessive training to mitochondrial impairment.

That metabolic impairment may contribute to PEM. Mechanism can include: immune response, vascular dysregulation with both leading to adaptations

Energy metabolism

Knowing about the metabolic limitation of patients can help with interventions, which can include nutritional ones. There are limitations related to insulin regulation process, but targets can be derived within the considerations.