Defective energy metabolism in ME/CFS

ME/CFS is a disabling disease with an unknown mechanism and without standardized treatment. In a research collaboration between Haukeland University Hospital and the University of Bergen, the goal is to find out more about the molecular mechanisms behind ME/CFS. In this project, we investigated the hypothesis that cellular energy failure plays a role in ME/CFS. The findings of the project support the theory that errors in the cells' energy metabolism may be related to key symptoms of the disease, such as activity intolerance. Specifically, we now believe that an underlying mechanism associated with the immune system leads to a failing oxygen supply during excertion, which, among other things, will weaken the working capacity of the cells and provide an abnormally lowered anaerobic activity threshold. We did several studies where we measured metabolites in blood samples, and in total it has included about 250 ME/CFS patients and about 150 healthy controls. Some of the studies were aimed at specific parts of the metabolic machinery, and we found changes that may indicate that the normal energy metabolism is hindered, and that the cells increase the metabolism of amino acids and fatty acids. We were able to reproduce some aspect of such effects in laboratory studies with experimental cell models. We also did broad-spectrum measurement of about 1500 metabolites (metabolomics) in blood serum. Using exploratory data analyzes (bioinformatics), we found a pattern of changes, some of which may influence symptom picture and symptom pressure. Some changes were unambiguous and may point to common mechanisms within the patient group, while other differences were varied and could possibly be influenced by individual factors such as severity, genetics and other factors. This mapping of metabolic changes in ME/CFS could be an important resource for future searches for new biomarkers and treatment methods. The findings also support that metabolite measurements may be used as a tool to improve individual follow-up of ME/CFS patients.

Dette prosjektet har bidratt til viktig forskning på molekylære mekanismer ved ME/CFS Basert på funnene fremstår det mest sannsynlig at de metabolske endringene forårsakes av en underliggende sykdomsmekanisme som ofte utløses av en infeksjon. Disse metabolske svakhetene kan være avgjørende for forverring av symptomer. Denne forståelsen støttes av nyere internasjonal forskning. Resultatene peker på spesifikke deler av energiomsetningen som påvirkes, og dette kan forhåpentligvis utnyttes i utvikling av nye strategier for forbedret behandling og oppfølging av pasientene. Kunnskapen fra dette prosjektet vil kunne bidra til å forbedre forståelsen av ME/CFS som sykdom i samfunnet, og hvordan pasientene best kan ivaretas i helsevesenet og hos sosiale støtteinstanser.

This project builds on existing knowledge that has recently appeared concerning the ME/CFS disease, and adopts new methods and strategies to bring the field further ahead. By using a translational research approach our aim is to determine whether defective energy metabolism is a central cause of ME/CFS symptoms, and link this to the development of new potential treatment and innovative tools for patient diagnosis and stratification. Importantly, by enlightening the physiological causes and consequences of the disease, the new insights sought in these fields are essential to be able to improve the public health care service for ME/CFS patients. Recently, we reported that function of the enzyme pyruvate dehydrogenase (PDH) appears to be impaired in patients with ME/CFS, and we provided evidence that a ME/CFS-specific serum factor modulates energy metabolism in cultured muscle cells. These findings combined with the potential efficacy of immunomodulatory treatment in ME/CFS suggest the presence of an immuno-metabolic pathomechanism. In the proposed project we will investigate the hypothesis that ME/CFS is triggered by an abnormal immune response that ultimately leads to defective energy metabolism. Such a mechanism is likely to cause energy deficiency, excessive lactate production, and consumption of metabolic fuel reserves, which constitute metabolic hallmarks of fatigue and post-exertional malaise (PEM). The research strategy will be to combine metabolic profiling in patient samples with targeted laboratory studies to pursue the molecular mechanisms. This approach is enabled through the participation of clinical partners conducting clinical trials with immunomodulatory treatment in ME/CFS patients. The project is based on the close and already fruitful collaboration established between clinical and biomedical research groups at HUS/UiB focused on investigating ME/CFS, together with national and international partners.