Development Of a Mouse Model for Myalgic Encephalomyelitis/Chronic Fatigue Syndrome, Janowski et al, 2024

John Mac

John Mac

Senior Member (Voting Rights)
Not a recommendation :banghead:

Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) is a complex clinical condition characterized by overwhelming fatigue and associated symptoms like pain lasting greater than 6 months. ME/CFS is often initiated after an illness, exacerbated by stress, and associated with immune system changes.

The purpose of this study was to develop a clinically relevant mouse model of ME/CFS. We hypothesized that pairing stress with an illness-like immune stimulation would generate long-term fatigue and pain, and thus tested effects of combining one-day of acute restraint stress with the immune activator lipopolysaccharide (LPS, i.p.).

Fatigue was assessed using voluntary wheel running (RW) and open field testing. For pain, we assessed mechanical paw sensitivity and muscle withdrawal thresholds. Immune cell phenotype was assessed using spectral flow cytometry. C57BL6 mice were divided into 4 groups: (1) stress+LPS, (2) stress+saline, (3) stress+saline+1-day no-RW, (4) no intervention.

The stress+LPS group showed a short duration decrease in RW (p<0.001), open field activity (p<0.001), and muscle withdrawal threshold (p=0.005). Surprisingly, the stress and saline group ran significantly less over the 12-day period showing a long-lasting decrease in RW when compared to the other three groups (p=0.002) without changes in open field or pain behaviors long-term (day 10).

The stress+LPS group showed alterations in immune phenotypes: increased CD4+ T-cells (p<0.001), decreased CD8+ T-cells (p=0.007), and decreased CD25+ T-cells (p=0.02) compared to no intervention group.

Thus, stress with a mild insult produces a long-term reduction in activity that is not associated with alterations in immune cell phenotype. Funded by the Foundation for Physical Therapy Research: PODS I and II.

https://www.sciencedirect.com/science/article/abs/pii/S1526590024000671
 
By this point the whole mouse model would be laughably absurd if it weren't embraced for far darker things like serial passaging of different pathogens to achieve performance and symptoms goals (e.g. gain of function).
 

The Development of an Animal Model of Myalgic Encephalomyelitis/Chronic Fatigue Syndrome
by
Adam Janowski

A thesis submitted in partial fulfillment of the requirements for the Doctor of Philosophy degree in Physical Rehabilitation Science in the Graduate College of The University of Iowa
December 2024
Thesis Committee:
Kathleen Sluka, Thesis Supervisor
Laura Frey Law Ruth Chimenti Emine Bayman Chris Benson

Abstract​

Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) is a severe multisystem disease characterized by unexplained fatigue that is not alleviated by rest, is greater than 6 months in duration, and has a detrimental impact on function and quality of life. Further, ME/CFS is associated with several symptoms including pain, anxiety/stress, cognitive difficulties, and post-exertional malaise. The pathobiological mechanisms underlying the induction and maintenance of ME/CFS remain poorly understood. This is reflected in the small number of potential mouse models described in the literature, lack of available biomarkers, and multiple hypothesized mechanisms across body systems. Up to 80% of individuals with ME/CFS report their disease began with an acute infection suggesting an immune component as a trigger. In individuals with ME/CFS, there is considerable evidence for immune system dysfunction with a general increase in inflammatory cytokines and altered expression of immune cell phenotypes. However, prior studies have been small, only considered a few cytokines or immune cell types, and have not adequately assessed multiple variables across the biopsychosocial spectrum. Thus, the relationship between clinical symptoms and immune system changes are unknown. Stress is strongly associated with the development of ME/CFS. Acute stress can enhance the inflammatory response of the immune system, suggesting that stress could serve as a priming event to ME/CFS development. The overall goal of this work was to build a clinically relevant animal model of ME/CFS utilizing stress and immune activation. I proposed that stress combined with an acute infection leads to alterations in immune function resulting in elevated risk for the development of persistent fatigue.

Several steps are required for building an animal model. The goal of Chapter 2 was to characterize sex differences throughout three common animal activity assays including voluntary wheel running, forced treadmill running, and open field. Throughout those 3 assays female mice showed greater activity intensity as evidenced by differences in speed, similar frequency of activity evidenced by total bouts, and a large difference in duration of activity evidenced by total distance. I determined that females appear to be less fatigable but have similar maximum ability compared to males.

The goals of Chapter 3 were to (1) determine which activity assays could best measure “fatigue-like” reductions in activity with systemic injection of multiple immune activators and to (2) determine if pairing stress with an immune activator would recapitulate the primary symptom of ME/CFS, fatigue. I evaluated the response to systemic LPS injection in a range of animal activity assays. In voluntary wheel running and open field, I tested a dose-response for LPS and Poly I:C finding that LPS caused more robust activity reductions which were prevented by using a TLR4 antagonist. I then evaluated the impact of acute stress paired with LPS on activity, pain behaviors, and immune phenotype. Acute stress and LPS caused short-term (7 days) of reduced voluntary wheel running while surprisingly, acute stress and saline caused a longer-term reduction (12 days). When animals were forced to rest from wheel running for 24 hours after LPS, their voluntary wheel running behavior recovered normally, suggesting acute activity plays a role in long-term activity reductions. Increases in muscle sensitivity were demonstrated acutely only in the animals receiving acute stress and saline with 24 hours of rest after injection. Interestingly, alterations in immune phenotype were seen only in T cells in animals who received acute stress and LPS 10 days after model induction, while there were no changes in acute stress and saline animals despite their long-term activity reduction.

This work presents two unique mouse models of “fatigue-like” behaviors induced by multiple stressors. The first paired acute stress with LPS injection and the second paired acute stress with isotonic saline injection. Given the differences in model induction, severity of pain and fatigue, duration of recovery, and differences in immune phenotype, it is likely that the two models involve different underlying mechanisms.

animal activity animal model fatigue immune ME/CFS sex differences
 
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