The development of an animal model of Myalgic Encephalomyelitis/Chronic Fatigue Syndrome
Creators: name: Janowski, Adam
Publisher: name: University of Iowa
Year: 2024
Subjects: animal activity
animal model
fatigue
immune
ME/CFS
sex differences

description: 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.
description: 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.
description: 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.
description: 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.