Epigenetics of Post-exertional Malaise in Patients With ME/CFS
Condition: Fatigue Syndrome, Chronic
MeSH terms: Fatigue Syndrome, Chronic; Syndrome; Fatigue
Study type: Interventional

Summary: 
      Exploring epigenetic mechanisms of Myalgic Encephalomyelitis / Chronic Fatigue Syndrome
      (ME/CFS) is crucial to understand the mechanisms underlying its pathophysiology. Three
      potential candidates have been selected (BDNF, COMT, and HDAC genes). DNA methylation in the
      promoter regions of those genes will be explored.

      The investigators designed a randomised controlled trial and will enrol 70 patients with
      ME/CFS and 35 age-, sex-, and BMI-matched healthy controls. Both groups will be randomised in
      2 groups and receive either one session of aerobic exercise or a validated test designed to
      trigger mental stress and mental fatigue. The primary aim is to assess genetic and epigenetic
      mechanisms of BDNF, COMT and HDAC genes in response to exercise and the stress task.
    

Detailed description: 
      The only way to improve the diagnosis and treatment of Myalgic Encephalomyelitis / Chronic
      Fatigue Syndrome (ME/CFS) is to better understand the mechanisms underlying its
      pathophysiology. Central nervous system dysfunctions play a major role in ME/CFS and help
      explaining patients' symptoms, such as general malaise occurring after physical activity
      (i.e. post-exertional malaise). Therefore, post-exertional malaise in relation to three major
      candidates involved in central nervous system functioning - brain-derived neurotrophic factor
      (BDNF), catechol-O-methyltransferase (COMT) and histone de-acetylases (HDAC) - will be
      explored.

      BDNF is a protein involved in crucial functions such as nerve growth, memory and learning,
      and plays a role in neuronal sensitisation and pain. However, no study has explored the role
      of BDNF in ME/CFS. Our research group performed a preliminary study which focussed on BDNF in
      ME/CFS. In a previous study, the investigators assessed DNA methylation (an epigenetic
      mechanism that contribute to gene expression silencing), and protein expression in serum of
      the BDNF in patients with ME/CFS and healthy controls. Patients showed significantly less DNA
      methylation and significantly more BDNF protein. Given these exciting findings, further study
      is warranted.

      COMT is an enzyme encoded by its homonymous gene. The enzyme degrades catecholamines like
      dopamine, epinephrine and norepinephrine. Catecholamines have been repeatedly associated with
      pain, stress, and depression. Lower COMT activity increases catecholamines level, causes
      hyperalgesia, and has been associated with depressive symptoms.

      Similarly, research on histone acetylation shows that another group of enzymes (Histone
      de-acetylases, HDACs) are increased during neural sensitisation and pain. However, no
      research has been done on HDACs in patients with ME/CFS. Interestingly, aerobic exercise has
      been shown to increase BDNF release and decrease COMT and HDACs activity. Given the
      detrimental acute effects that exercise can have on patients with ME/CFS, investigators
      hypothesised that understanding the role of BDNF, COMT, and HDACs following exercise would
      help elucidating both mechanisms of post-exertional malaise and ME/CFS pathophysiology.

      A randomised controlled trial has been designed including 70 patients with ME/CFS and 35
      age-, sex-, and BMI-matched healthy controls. Both groups will be randomised in 2 groups. One
      group will undergo one session of aerobic exercise, and the other group undergoes a validated
      test designed to trigger mental stress and mental fatigue. All participants will undergo
      clinical assessments, measurements of pain thresholds, and blood withdrawal before and after
      the exercise/mental stress exposure. The aims are to assess genetic and epigenetic mechanisms
      of BDNF, COMT and HDAC genes, as well as the expression of these factors in blood and serum
      in patients with ME/CFS.
    

Intervention name(s): Exercise; Mental Stress Test
Intervention type(s): Behavioral; Other
Intervention description(s): Sub-maximal exercise test; Computerised mental arithmetic challenges and social evaluative threat tasks
Other intervention name(s): Aerobic Power Index; Montreal Imaging Stress Task
Allocation: Randomized
Intervention model: Parallel Assignment
Intervention model description: Randomised Controlled Trial
Masking: Single (Outcomes Assessor)
Primary purpose: Basic Science
Keywords: Chronic Fatigue Syndrome; Exercise; Epigenetics; DNA methylation