A Pilot project: Examining gender-specific transcriptional alterations in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome patients under stressful conditions.

Background Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) is characterized by symptoms such as profound fatigue, cognitive difficulties, muscle and joint pain, gastrointestinal disturbances, neurological impairments, and hormonal irregularities. The precise mechanisms involved in the development and advancement of this disorder are not yet fully understood. Objectives This pilot research project aims to assess how sex differences in individuals with ME/CFS impact their response to stress, specifically through an exercise challenge. Additionally, it highlights the importance of considering sex differences in the diagnosis and treatment of ME/CFS. Methods We utilized RNA-seq to examine the differential gene expression (DG) in peripheral blood mononuclear cells of 20 female ME/CFS patients, 14 male ME/CFS patients, and 40 healthy controls (HC) who were matched in for sex, age, and BMI. We evaluated the gene expression changes at three time points: T0 (baseline), T1 (at maximal exertion), and T2 (4 hours into recovery after T1). To ensure consistency, we excluded genes located on the sex chromosomes and performed separate analyses for men and women. Our focus was to compare the response to exercise within each group (ME/CFS patients and HC) between different time points. Results In the male ME/CFS cohort, pathways associated with immune cell signaling, particularly IL-12, and natural killer cell cytotoxicity were activated during exercise. However, the female ME/CFS patients did not exhibit significant changes in gene expression that met the study's criteria for inclusion. During the recovery period after exercise, male ME/CFS patients demonstrated distinct alterations in the regulation of specific cytokine signals, including IL-1β. On the other hand, female ME/CFS patients displayed significant changes in gene networks related to cell stress, response to herpes viruses, and NF-kβ signaling. These functional pathways and differentially expressed genes identified in this pilot project provide valuable insights into the sex-specific pathophysiology of ME/CFS. Conclusion The identification of sex-specific biomarkers and therapeutic targets in ME/CFS holds great potential for understanding the distinct onset and progression of this disease in different sexes.