Muscle Symptoms Define a Stable Physiological Dysregulation Cluster in ME/CFS: Sex- and Menopause-Related Differences in Symptom Expression

Abstract Background : Muscle-related symptoms are among the most disabling manifestations of myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS), yet their position within the broader symptom architecture of the disease remains unclear. We hypothesized that muscle symptoms function as bridge symptoms linking multiple dysregulated physiological systems and that their symptom associations differ according to sex and menopausal status. Methods : Cross-sectional data from 745 individuals with physician-diagnosed ME/CFS enrolled in the APAV-ME/CFS registry were analyzed. Muscle problems served as the primary outcome variable. Associations with 14 symptom domains were examined using multivariable logistic regression. Pearson and tetrachoric correlations, exploratory factor analysis, and structural equation modeling (SEM) were used to identify latent symptom structures. Analyses were stratified by sex, menopausal status, and disease duration. Results : In the full multivariable model, breathing problems (β = 0.96, p = 0.001), flu-like symptoms (β = 0.65, p = 0.020), and temperature-regulation disorders (β = 0.63, p = 0.030) independently predicted muscle problems. A reduced physiological model additionally identified cardiovascular symptoms (β = 0.65, p = 0.017) and visual disturbances (β = 0.52, p = 0.046) as significant predictors. Tetrachoric correlations demonstrated substantial latent associations between muscle problems and breathing difficulties (ρ = 0.54), cardiovascular symptoms (ρ = 0.50), temperature-regulation disorders (ρ = 0.50), visual disturbances (ρ = 0.41), and flu-like symptoms (ρ = 0.39). Factor analysis and SEM supported a single latent physiological dysregulation factor with good model fit (RMSEA = 0.046, CFI = 0.972, TLI = 0.953, SRMR = 0.026). Sex-stratified analyses revealed distinct symptom architectures. In women, all five physiological symptoms independently predicted muscle problems, whereas in men only breathing problems and temperature-regulation disorders remained significant. Women classified as premenopausal showed strongest associations with cardiovascular symptoms, visual disturbances, and temperature dysregulation, while women classified as postmenopausal displayed a distinct symptom pattern characterized by breathing difficulties and flu-like symptoms. The latent physiological factor remained stable across disease-duration groups. Gastrointestinal complaints loaded substantially on the same latent factor despite lacking independent predictive value in regression analyses, whereas urogenital symptoms did not. Conclusions : Muscle symptoms occupy a central position within a stable physiological dysregulation cluster in ME/CFS encompassing respiratory, cardiovascular, thermoregulatory, visual, flu-like, and gastrointestinal manifestations. These findings provide evidence for a stable physiological symptom architecture that may improve clinical phenotyping and facilitate future biomarker-guided stratification The identified latent physiological factor remained stable across disease duration but showed distinct clinical expressions according to sex and menopausal status. Women classified as premenopausal were characterized primarily by cardiovascular, visual, and thermoregulatory symptom associations, whereas women classified as postmenopausal and men showed greater prominence of breathing-related symptoms. The persistence of flu-like symptoms in women classified as postmenopausal suggests that menopause modifies symptom expression without abolishing the underlying physiological dysregulation. More broadly, the findings are compatible with the hypothesis that this physiological dysregulation factor reflects a chronic PEM-associated multisystem response involving interacting autonomic, vascular, immunological, and metabolic pathways. Incorporating sex and menopausal status into ME/CFS phenotyping may improve patient stratification and facilitate the development of mechanism-based therapeutic approaches.