Resolution of Skeletal Muscle Inflammation: Role of Specialized Pro-resolving Lipid Mediators in the Recovery from Exercise, Injury, and Disease.

Abstract

This chapter examines the resolution biology and pharmacology of skeletal muscle inflammation across the physiological contexts of exercise, acute injury, and chronic musculoskeletal disease. Central to these processes are specialized pro-resolving lipid mediators (SPMs), bioactive metabolites of omega-6 (n-6) arachidonic acid (ARA), omega-3 (n-3) eicosapentaenoic acid (EPA), and n-3 docosahexaenoic acid (DHA), formed by the coordinated action of mammalian lipoxygenase (LOX) enzymes. Unlike traditional anti-inflammatory mechanisms that passively dissipate, SPMs actively coordinate resolution by limiting polymorphonuclear neutrophil (PMN) infiltration, stimulating efferocytosis, and orchestrating the macrophage (MΦ) transition from a pro-inflammatory to a reparative phenotype. We explore how physical activity serves as a natural stimulus for these pathways, as acute resistance or endurance exercise triggers transient SPM biosynthetic circuits, while chronic training primes the immune system for enhanced resolution. A critical focus is placed on "resolution-interference" caused by nonsteroidal anti-inflammatory drugs (NSAIDs), which may delay repair by suppressing endogenous mediators and impairing muscle stem cell (satellite cell) activity. Furthermore, we review a significant paradigm shift involving the discovery that lipid mediator class switching is an intrinsic requirement for the myogenic differentiation program. By evaluating preclinical models of "resolution deficit," including sarcopenia, muscular dystrophy, and volumetric muscle loss, we highlight the therapeutic potential of pharmacological "immunoresolvents." Ultimately, leveraging these pathways represents a sophisticated therapeutic frontier that moves beyond simple inflammation suppression to directly drive stem cell-mediated muscle regeneration and functional recovery.