Behavioral and molecular characterization of fatigue-like manifestations triggered by acute restraint stress and LPS or saline

Fatigue is characterized as a feeling of exhaustion or lack of energy, is a common symptom of multiple chronic illnesses and interferes with daily activities and quality of life. There is a limited availability of animal models to examine potential underlying mechanisms, ultimately limiting development of potential therapeutic strategies. The primary purpose of this study was to develop a mouse model of persistent fatigue. A secondary purpose was to characterize potential measures of "fatigue-like" behaviors. An exploratory goal was to examine for immune and metabolic changes in the model. We examined voluntary wheel running and open field as measures of physical fatigue, and muscle and paw sensitivity as measures of pain. We also examined immune cell phenotype and plasma metabolite profiles after development of persistent fatigue. Acute stress paired with LPS or saline reduced wheel running compared to LPS alone or stress alone. Animals that received acute stress and LPS, showed a decreased ratio of T-helper to T-cytotoxic cells and reduced fatty acid metabolites 10 days after induction; there were no changes in the other groups. Thus, we characterized two unique methods, each requiring multiple stressors, to induce long-lasting fatigue-like behaviors that were associated with different mechanistic changes.