Abstract
Specialized proresolving mediators (SPMs) actively limit inflammation and expedite its resolution by modulating leukocyte recruitment and function. Here we profiled intramuscular lipid mediators via liquid chromatography-tandem mass spectrometry–based metabolipidomics following myofiber injury and investigated the potential role of SPMs in skeletal muscle inflammation and repair. Both proinflammatory eicosanoids and SPMs increased following myofiber damage induced by either intramuscular injection of barium chloride or synergist ablation–induced functional muscle overload. Daily systemic administration of the SPM resolvin D1 (RvD1) as an immunoresolvent limited the degree and duration of inflammation, enhanced regenerating myofiber growth, and improved recovery of muscle strength. RvD1 suppressed inflammatory cytokine expression, enhanced polymorphonuclear cell clearance, modulated the local muscle stem cell response, and polarized intramuscular macrophages to a more proregenerative subset. RvD1 had minimal direct impact on in vitro myogenesis but directly suppressed myokine production and stimulated macrophage phagocytosis, showing that SPMs can modulate both infiltrating myeloid and resident muscle cell populations. These data reveal the efficacy of immunoresolvents as a novel alternative to classical antiinflammatory interventions in the management of muscle injuries to modulate inflammation while stimulating tissue repair.
Highlights
Skeletal muscle damage induces an acute inflammatory response [1]
Intramuscular barium chloride (BaCl2) injection resulted in widespread myofiber damage and local appearance of both Polymorphonuclear cells (PMNs) (Ly6G+ cells) and macrophages (CD68+ cells) (Figure 1A)
By day 3, there was progressive PMN clearance and robust macrophage infiltration, and many small, regenerating myofibers with characteristic centrally located nuclei appeared by day 5
Summary
Skeletal muscle damage induces an acute inflammatory response [1]. Polymorphonuclear cells (PMNs) appear first within injured muscle, followed by blood monocyte–derived macrophages that invade within necrotic myofibers to engulf and clear tissue debris [2]. Clearance of PMNs from regenerating muscle is important for the inflammatory response to be successfully resolved. Demonstration of the production of distinct families of specialized proresolving lipid mediators (SPMs) during the resolution phase of the inflammatory response suggests that it is actively regulated [6]. SPMs are a superfamily of bioactive metabolites of essential fatty acids, including the lipoxins, resolvins, protectins, and maresins [7]. These autocoids actively limit PMN influx, while simultaneously stimulating macrophage functions essential for timely resolution of inflammation [8]. Emerging evidence suggests that SPMs can exert important biological actions on nonimmune cell populations (e.g., stem cells) that may contribute to their physiological effects [9]
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