Could the Chronic Fatigue Syndrome (and thus long covid) be linked to the transcription factor NFAT5? Some elements, which are described in the following post, could let think this is the case.
Response to osmotic stress
Ronald Davis, a famous CFS researcher, developed a test that works by submitting cells from a patient to osmotic stress and observing their caracteristics:
our experimental results on 40 ME/CFS individual patients and healthy controls revealed that ME/CFS hyperosmotic-stressed samples (PBMCs in plasma) display a unique characteristic in their impedance pattern, and one that is significantly different than what was observed in the controls.
The transcription factor NFAT5 is known, among other, for its role in the adaptation to osmotic stress, especially by increasing the influx of osmolytes or the production of proteins (Heat Shock Proteins) that can protect the structure of other proteins from the destructuring effect of osmotic stress.
Osmolytes are small molecules (for example betaine, aka trimethylglycine) that can help counter osmotic stress without disturbing the normal processes of the cell.
Could the abnormalities observed in cells of CFS patients, when an osmotic stress is set up, be the consequences of a dysfunction of NFAT5 and of the ability to accumulate osmolytes to prevent the damage done by osmotic stress?
Immune system
NFAT5 is also known to be tightly linked to the immune system:
NFAT5 is an important regulator of the immune response. NFAT5 haploinsufficiency has been described as an immunodeficiency syndrome affecting both innate and adaptive immunity. EBV susceptibility might be another manifestation in the spectrum of this disease.
Not enough by half: NFAT5 haploinsufficiency in two patients with Epstein-Barr virus susceptibility
Thus, a dysfunction of NFAT5 could be a cause of EBV reactivation. Some patients suffering from CFS are also suffering from EBV reactivation.
Glymphatic system
NFAT5 could also be linked to CFS as it has been hypothesized that the glymphatic system, which could be related to NFAT5 via the aquaporin AQP4, could be involved in CFS:
In the present paper, we speculate that glymphatic dysfunction, causing toxic build up within the central nervous system, may be responsible for at least some cases of chronic fatigue syndrome.
A dysfunction of NFAT5, having for consequences an impaired glymphatic flow, could cause some cases of the CFS.
Inflammatory Bowel Disease (IBD)
CFS seems to be associated with digestive troubles called Inflammatory Bowel Disease (because IBD could be associated with intestinal permeability and thus leak of pathogens and inflammatory substances like LPS?). A study had the following conclusion:
The findings from this population-based retrospective cohort study suggest that IBD, especially Crohn’s disease, is associated with an increased risk of subsequent CFS.
It is interesting to note that NFAT5 could also be involved in IBD:
Crohn's disease (CD) and ulcerative colitis (UC), which together comprise IBD, are believed to result from an aberrant immune response to commensal gut microbes, leading to chronic intestinal inflammation. Compared to healthy controls, we observed that NFAT5 mRNA expression was significantly reduced in patients with active UC and CD (Fig. 7), raising the possibility that NFAT5 and other components of the osmoadaptation pathway may be dysregulated in IBD.
Immunodeficiency and Autoimmune Enterocolopathy Linked to NFAT5 Haploinsufficiency
Could NFAT5 dysfunction be a common root cause of CFS and IBD?
Water homeostasis
Some studies demonstrated that CFS patients could have issues with water homeostasis. In particular, they seem to suffer from drastically lowered vasopressin (an antidiuretic hormone) compared with controls:
Therefore, it is proposed that altered water metabolism secondary to changes in AVP regulation is a pathophysiological component of certain chronic fatigue disorders. In support of this hypothesis are data demonstrating that low baseline levels and erratic secretion of AVP are present in individuals with post-viral fatigue syndrome (9). Individuals with chronic fatigue disorders appear to be more sensitive to fluctuating levels of AVP than non-fatigued individuals. For example, patients with chronic fatigue excreted 62% of a water load, compared with 97% in healthy subjects (9). Baseline plasma AVP levels in patients with post-viral fatigue syndrome were reported to be significantly lower (0.1 + 0.03 pmol/1) than in healthy controls (0.9 + 0.2 pmol/1) (9). A close correlation between serum osmolarity and plasma AVP levels was observed in healthy subjects but not in the chronic fatigue patients. The patients with post-viral fatigue syndrome also showed evidence of increased total body water content (9). Thus, these data are consistent with the hypothesis that chronic fatigue disorders may result from an exaggerated, or hyper-sensitive, response to AVP. Alterations in water metabolism are also a biologically plausible explanation for the observed lethargy, mental confusion, weight fluctuations and diffuse muscle and joint pain that is characteristic of CFS and related disorders such as fibromyalgia.
Chronic fatigue disorders: an inappropriate response to arginine vasopressin?
Another publication found that NFAT5 (aka TonEBP in the literature), seemed to be necessary for vasopressin production.
Therefore, our result support the idea that TonEBP is directly necessary, at least in part, for the elevation of AVP transcription in dehydration conditions.
Thus, an NFAT5 dysfunction in the area of the brain in charge of vasopressin production could lead to lowered levels of vasopressin, which is associated with CFS.
Post-exertional malaise
A hallmark symptom of CFS is called Post-exertional malaise (PEM). It refers to the sickness feeling which is caused by a physical or mental exertion. Regarding physical exertion, muscles themselves could be a part of the cause as inflammation can happen after physical activity and could, if not properly controlled, cause a sickness feeling. NFAT5 seems to play a role in muscles' recovery as it allows cells to take osmolytes so that they help fight the stress:
NFAT5+/- mice displayed a defect in muscle regeneration with fewer myofibers formed at early times after injury. NFAT5 has a muscle-intrinsic function because inhibition of NFAT5 transcriptional activity caused both a migratory and differentiation defect in cultured myoblasts.
Pro-inflammatory cytokines activated mitogen-activated protein kinases, nuclear factor κB as well as nuclear factor of activated T-cells 5 mRNA expression. In muscle biopsies from patients with polymyositis or sporadic inclusion body myositis, osmolyte pathway activation was observed in regenerating muscle fibers. In addition, the osmolyte carriers SLC5A3 and SLC6A12 localized to subsets of immune cells, most notably to the endomysial macrophages and T-cells. Collectively, this study unveiled that muscle cells respond to osmotic and inflammatory stress by osmolyte pathway activation, likely orchestrating general protection of the tissue.
Induction of Osmolyte Pathways in Skeletal Muscle Inflammation: Novel Biomarkers for Myositis
Could an issue with NFAT5 activation after physical activity lead to an inflammatory reaction which would be the cause of PEM?
Conclusion
There is a number of elements associating CFS and what we could expect from NFAT5 dysfunction, in particular related to the immune system, the resistance to osmotic stress, inflammatory bowel diseases, the glymphatic system efficiency, water homeostasis and inflammation following physical exertion.
This post’s ambition is not to prove a firm causality between NFAT5 and CFS but to present some intriguing associations.