Damage-associated molecular patterns in skeletal muscle: a double-edged sword - from sterile inflammation initiation to precision targeted therapeutic strategies.

Skeletal muscle repair after injury depends on a tightly coordinated cascade of inflammatory and regenerative responses. Damage-associated molecular patterns (DAMPs) link tissue damage to innate immune activation, but their effects are highly context dependent. This review summarizes the major cellular sources of DAMPs, including nuclear, cytoplasmic, mitochondrial, and extracellular matrix-derived molecules, and discusses their release through regulated cell death pathways such as necroptosis, pyroptosis, ferroptosis, and apoptosis. We further examine major DAMP-sensing systems relevant to skeletal muscle, including TLR2/4/9, the NLRP3 inflammasome, and the cGAS-STING pathway. Transient DAMP signaling can support inflammatory recruitment, tissue clearance, and regenerative responses, whereas persistent or excessive signaling may contribute to chronic inflammation, fibrosis, and muscle wasting. Exercise-associated DAMP signaling is similarly context dependent and is influenced by exercise modality, intensity, duration, training status, and recovery. We also discuss major barriers to clinical translation, including spatiotemporal heterogeneity, pathway redundancy, limited muscle-specific pharmacology, and discrepancies between experimental models and chronic human muscle diseases. Emerging strategies include targeted nanodelivery, engineered extracellular vesicles, selective modulation of regulated cell death, immunometabolic remodeling, gene- and cell-based approaches, and precision exercise. Molecular docking analyses of representative pathway inhibitors are considered hypothesis-generating tools for proposing potential binding modes rather than evidence of target engagement or therapeutic efficacy. Overall, DAMP-directed intervention in skeletal muscle will likely require selective and context-dependent modulation that limits pathological inflammation while preserving physiological repair and regeneration.