Immunoresolvents Support Skeletal Myofiber Regeneration via Actions on Myeloid and Muscle Stem Cells

Specialized pro-resolving mediators (SPMs) actively limit inflammation and expedite its resolution. Here we profiled intramuscular lipid mediators following injury and investigated the role of SPMs in skeletal muscle inflammation and repair. Both eicosanoids and SPMs increased following myofiber damage induced by intramuscular injection of barium chloride or functional overload. Daily systemic administration of resolvin D1 (RvD1) limited the degree and duration of inflammation, enhanced regenerating myofiber growth, and improved recovery of muscle strength. RvD1 suppressed inflammatory cytokines, enhanced polymorphonuclear cell clearance, modulated muscle stem cells, and polarized macrophages to a more pro-regenerative subset. RvD1 had minimal direct impact on in-vitro myogenesis but directly suppressed myokine production and stimulated macrophage phagocytosis, showing that SPMs influence modulate both infiltrating myeloid and resident muscle cells. These data reveal the efficacy of immunoresolvents as a novel alternative to classical anti-inflammatory interventions in the management of muscle injuries to modulate inflammation while stimulating tissue repair.