Sex-Based Transcriptomic Differences

Chronic fatigue syndrome, also known as myalgic encephalomyelitis (ME/CFS), is a complex and debilitating disorder characterized by persistent fatigue, cognitive impairments, and post-exertional malaise (PEM). While the exact cause of ME/CFS remains unclear, recent research has highlighted the potential influence of sex on the pathophysiology of the disease. A groundbreaking new study conducted by researchers at Nova Southeastern University's Kiran C. Patel College of Osteopathic Medicine has shed light on the sex-specific differences in transcriptomic profiles of ME/CFS patients during and after exercise. These findings provide valuable insights into the underlying molecular mechanisms of the disease and may pave the way for the development of targeted therapies.

About the study: Methods and Cohort

The pilot project involved 24 clinically diagnosed female ME/CFS subjects, along with 11 male ME/CFS subjects, and their respective control groups of healthy individuals (HCs). The participants were recruited from the Miami/Fort-Lauderdale area as part of an ongoing study by the Institute for Neuro-Immune Medicine. The subjects underwent a comprehensive evaluation, including the use of the SF-36 questionnaire to assess physical and mental health. Blood samples were collected at multiple time points: before exercise (T0), at the point of maximal exertion (T1), and four hours after exertion (T2). RNA sequencing was performed on isolated peripheral blood mononuclear cells (PBMCs) to analyze the transcriptomic profiles.

Participants ate a uniform breakfast (yogurt and banana) and rested for 30 min in reclining chairs before blood was drawn (T0). Subsequently, a standard maximal graded exercise test (GXT) was conducted using McArdle’s protocol [61]. This protocol was used as part of a larger ongoing study to investigate the biological mechanisms underlying neuroimmune diseases. The GXT involved participants pedaling at 60 W for two minutes, with an increase of 30 W every two minutes until they reached their maximum exertion. The second blood draw was taken at the point of maximal exertion (T1) and the third blood draw was collected four hours after maximal exertion (T2).
Gamer, J.; Van Booven, D.J.; Zarnowski, O.; Arango, S.; Elias, M.; Kurian, A.; Joseph, A.; Perez, M.; Collado, F.; Klimas, N.; et al. Sex-Dependent Transcriptional Changes in Response to Stress in Patients with Myalgic Encephalomyelitis/Chronic Fatigue Syndrome: A Pilot Project. Int. J. Mol. Sci. 2023, 24, 10255.

Key Findings: Sex-based differences in gene expression patterns

The study's results demonstrated significant differences in the transcriptomic profiles of male and female ME/CFS patients during and after exercise, particularly during the period of post-exertional malaise (PEM). The analysis revealed sex-based differences in gene expression patterns, highlighting the importance of considering sex as a critical factor in understanding ME/CFS pathophysiology.

  • In male ME/CFS patients, pathways related to immune-cell signaling and natural killer cell cytotoxicity were activated during exertion, while female ME/CFS patients did not show significant changes in gene expression.

  • During recovery from the exercise challenge, male ME/CFS patients exhibited distinct changes in the regulation of specific cytokine signals, while female ME/CFS patients showed significant alterations in gene networks related to cell stress, response to herpes viruses, and NF-κβ signaling.

  • The study highlights the sex-specific differences in the pathophysiology of ME/CFS and provides insight into the molecular mechanisms underlying the condition. These findings contribute to a better understanding of ME/CFS and suggest the need for sex-based diagnostics and therapeutics in the future.

Implications and Future Directions: Integrating other omics data

The identification of sex-based transcriptomic differences in ME/CFS patients has important implications for personalized medicine and the development of targeted therapies. The findings suggest that tailored treatment approaches may be necessary to address the unique molecular signatures associated with the disease in males and females. However, the study also acknowledged certain limitations, such as the need for larger-scale cohorts and multiple time points to comprehensively evaluate transcriptomic profiles and identify potential biomarkers associated with disease progression. Integrating other omics data and developing standardized assays to measure PEM accurately are also crucial for a comprehensive understanding of ME/CFS.


The recent study from Nova Southeastern University sheds light on the sex-specific differences in transcriptomic profiles of ME/CFS patients during and after exercise. These findings provide valuable insights into the underlying molecular mechanisms of the disease and highlight the need for personalized treatment strategies. With further research and larger-scale studies, including multi-omics approaches and standardized PEM measurement, we may unlock the full potential of understanding and managing ME/CFS, ultimately improving the lives of millions of individuals affected by this debilitating condition.