Abstract
Accumulation of uric acid (UA) during muscular trauma is a factor involved in the development of muscle hyperalgesia. Neutrophil extracellular traps (NETs), DNA-based reticular structures to capture UA, play a central role in the pain onset of gout attacks; however, the involvement of NETs via the elevation of local UA level in muscle hyperalgesia due to injuries from muscle overuse remains unknown. The triceps surae muscles (TSMs) in the unilateral hindlimb of mice were electrically stimulated to induce excessive muscle contraction. Mechanical withdrawal thresholds, tissue UA levels, neutrophil recruitment, and protein amount of citrullinated histone 3 (citH3), a major marker of NETs, were investigated. Furthermore, whether neutrophil depletion, extracellular DNA cleavage, and administration of the urate-lowering agent febuxostat improved muscle hyperalgesia caused by NET formation was examined. CitH3 expression upon neutrophil recruitment was significantly increased in the stimulated TSMs with increased tissue UA levels, whereas febuxostat administration improved muscle hyperalgesia with decreased citH3 and tissue UA levels, as observed in neutrophil depletion and extracellular DNA digestion. The underlying mechanism of muscle hyperalgesia associated with locally recruited neutrophils forming NETs due to increased tissue UA levels potentially plays a significant role in creating a vicious circle of muscle pain.
Highlights
Accumulation of uric acid (UA) during muscular trauma is a factor involved in the development of muscle hyperalgesia
Compared to those of the control group, the mechanical nociceptive threshold (MNT) of the monosodium urate (MSU) group significantly decreased after the intramuscular injection of MSU (Fig. 1a)
IL-1β expression in the triceps surae muscles (TSMs) injected with MSU significantly increased on day 2 (Fig. 1d & Fig. S1b)
Summary
Accumulation of uric acid (UA) during muscular trauma is a factor involved in the development of muscle hyperalgesia. The underlying mechanism of muscle hyperalgesia associated with locally recruited neutrophils forming NETs due to increased tissue UA levels potentially plays a significant role in creating a vicious circle of muscle pain. Overuse trauma prompts muscle fibers to release extracellular adenosine triphosphate (ATP), which directly activates pain signaling through purinergic and metabotropic receptors via autocrine and paracrine functions[7–10] Both the serum and muscle tissue levels of uric acid (UA), an end product of purine nucleotides including ATP and dead cell DNA, are reportedly increased due to the production of damaged muscle fibers[11–15]. Our recent study using a muscle pain model by the repeated electrical stimulation of the triceps surae muscles (TSMs) revealed the marked recruitment of inflammatory cells, including neutrophils and macrophages, which produce proinflammatory cytokines, such as IL-1β and IL-18, due to inflammasome activation caused by the increase in tissue UA levels[11,15,17]. Research findings regarding the underlying mechanism of UA accumulation with a focus on NETs in damaged muscle tissues will facilitate the development of an integrative therapeutic strategy for chronic muscle pain
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