Sex-Dependent Transcriptional Changes in response to stress in patients with Myalgic Encephalomyelitis/Chronic Fatigue Syndrome
Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is a complex, multi-symptom illness characterized by debilitating fatigue and post-exertional malaise (PEM). Numerous studies have reported sex differences at the epidemiological, cellular, and molecular levels between male and female ME/CFS patients. To gain further insight into these sex-dependent changes, we evaluated differential gene expression by RNA-sequencing in 35 ME/CFS patients (24 female, 11 male) and 34 matched healthy control participants (21 female and 13 male) during and after an exercise challenge intended to provoke PEM. The effects of exertion in the male ME/CFS cohort highlighted pathways related to immune cell signaling (including IL-12) and NK cell cytotoxicity, while female ME/CFS patients did not have significant enough changes in gene expression to meet criteria for our study. Functional analysis during recovery from exercise showed that male ME/CFS patients had distinct changes in regulation of specific cytokine signals (including IL-1ß). Female ME/CFS patients had significant alterations in gene networks related to cell stress, response to herpes viruses and NF-kß signaling. The functional pathways and differentially expressed genes highlighted in this study provide insight into sex-specific predisposition and pathophysiology of ME/CFS. Overall design: Comparative gene expression analysis of RNA-seq data for female and male ME/CFS patients and matching female and male controls undergoing exercise challenge