Impaired microcirculation and tissue hypoxia as a possible mechanism in ME/CFS

Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) is a debilitating disease that usually occurs after an infection, also sometimes in patients with late effects after COVID-19 (Long-COVID). The mechanism of the disease is still unknown, and we lack biomarkers and effective treatments. However, there is a growing number of research reports documenting biological changes in ME/CFS patients, and recent findings suggest that limitations in blood supply may be an important factor. Based on these findings, we hypothesize that tissue hypoxia due to impaired blood flow in small blood vessels disrupts cellular energy metabolism in the patients. To test this hypothesis, we will analyze biochemical signatures of hypoxia in blood samples from ME/CFS and Long-COVID patients taken at rest or during exercise testing. We will also look at changes in cells of the blood and blood vessels, and small particles that they may release, which may reveal new details about the pathomechanism. Our project aims to investigate the mechanism of ME/CFS through hypothesis-driven investigations in patient samples and laboratory studies, using novel approaches. We will look for evidence of impaired microcirculation and tissue hypoxia that may be induced in an exertion-dependent manner. We will address research questions related to mechanisms in blood and blood vessels, which may be responsible for impaired tissue perfusion. This will also include mechanisms that may link impaired microcirculation to specific changes in the immune system. The findings may provide new insights into the mechanisms behind ME/CFS and Long-COVID, uncover new avenues for future research, and provide new opportunities for biomarker and treatment development. The project will involve collaboration with leading scientists with complementary expertise and resources in the field.

Myalgic Encephalomyelitis/ Chronic Fatigue Syndrome (ME/CFS) is a debilitating disease with a systemic clinical picture. A significant proportion of Long-COVID patients develop ME/CFS-like symptoms. There is no standardized treatment and the cost to society is high. A deeper understanding of the biological disease mechanisms and the establishment of scientifically based approaches to target them are needed to address this major health challenge. There is increasing evidence that the blood supply to tissues in ME/CFS patients is poorly regulated. Based on published and preliminary data, we hypothesize that tissue hypoxia due to impaired microcirculation is a key element that disrupts cellular energy metabolism in patients. To address this, we will analyze extracellular ATP and other biochemical signatures of hypoxia in the blood of ME/CFS and Long-COVID patients collected at rest and during exercise testing. We will also investigate changes in circulating endothelial microparticles, erythrocytes, and neutrophils, as possible novel mediators of the pathomechanism. We will pursue the mechanisms involved through hypothesis-driven approaches in patient samples and laboratory studies, using beyond state-of-the-art approaches. We will test the following hypotheses: (1) Impaired microcirculation and tissue hypoxia play a role in ME/CFS, in an exertion-dependent manner; (2) Endothelial dysfunction and erythrocyte alterations contribute to impaired microcirculation in ME/CFS; and (3) Altered neutrophil activity is associated with impaired microcirculation in ME/CFS. The results will provide new insights into the mechanism of ME/CFS and Long-COVID, identify new avenues for future research, and uncover possible opportunities for clinical translation. The project will involve collaboration with leading scientists with complementary expertise and resources in the field.