Exploring the Role of Manganese and Mn-Dependent Metabolic Pathways in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome
Abstract
FY20 PRMRP Topic Area: Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) ME/CFS is a debilitating disease that affects up to 2.5 million Americans, including men, women, and children from all walks of life. This includes military Service Members and their families, retired military members and beneficiaries, and Veterans. In addition, a unique group of Veterans who served in the Gulf War conflict between 1990-1991 developed a ME/CFS-like illness known as Gulf War Illness. Fatigue is the main symptom, but the disease is also characterized by a hallmark symptom of post-exertional malaise. Normal individuals may experience fatigue after a heavy workload, but normal fatigue resolves after a brief period of rest. In ME/CFS, individuals experience a form of pathological fatigue that does not improve with rest. Individuals who overexert themselves may require days, weeks, or months to return back to the pre-existing level of function. Patients with ME/CFS also have difficulty sleeping, experience bouts of cognitive impairment or memory loss called brain fog, and may experience lightheadedness when standing up. Taken altogether, this constellation of symptoms prevents ME/CFS patients from engaging in occupational, educational, social, and personal activities. For many, the illness can persist for years or decades. Most people who are ill longer than 5 years never regain their pre-illness levels of health or functioning. This poses a substantial strain on families and relationships, as well as a financial burden for individuals who are unable to work or attend school. ME/CFS is an expensive illness, not only due to loss of income but also because of how ME/CFS patients must navigate the medical establishment to obtain a diagnosis. Currently, there is no approved diagnostic test or U.S. Food and Drug Administration (FDA)-approved treatment, and an extreme shortage of specialists. According to the insurer UnitedHealth Group, ME/CFS patients incur approximately $30,000 per year in medical expenses, a cost that is four times higher than for average consumers and 50% higher than for patients with diseases like lupus or multiple sclerosis. ME/CFS is an expensive illness because patients are often referred to a variety of specialists (neurologists, rheumatologists, cardiologists, gastroenterologists) and are subjected to a variety of unrevealing tests. Patients also visit the emergency room during flares of symptoms, and bedridden patients may be admitted due to the severity of their illness. Overall, the lack of diagnostic tests and treatments creates an expensive health disparity that burdens the patient as well as the healthcare system. Chronic, unrelenting fatigue is a defining characteristic of ME/CFS. Whereas a healthy individual may experience fatigue after excessive physical or cognitive effort, normal fatigue resolves after a brief period of rest. Pathological fatigue, in contrast, is commonly associated with disease processes that are known to affect energy production, including defects in mitochondrial oxidative respiration, substrate transport, uptake and metabolism, vascular hemodynamics and oxygen delivery, the availability of necessary cofactors, and the presence of inhibitors. The cause of ME/CFS is likely to involve one or more of these factors. Although mitochondria have been extensively studied using multiple different approaches, there is little evidence that cells from ME/CFS patients that are studied in culture have a reduced ability to synthesize adenosine triphosphate (ATP) for energy. Analysis of the metabolites in plasma tells a different story, pointing to a metabolic bottleneck at the level of pyruvate utilization. We are focused on this pathway as the potential molecular ballpark that causes the pathological fatigue in ME/CFS. This research project is based on a novel finding in our laboratory of reduced trace metals content in scalp hair from severely affected ME/CFS patients, primarily
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Dec 28, 2022
- Source ID
- W81XWH2210414
Entities
People
- Ronald W. Davis
Organizations
- Stanford University
- United States Army