Exercise-induced musclin enhances efferocytosis via metabolic reprogramming to alleviate periprosthetic joint infection.

BACKGROUND

In periprosthetic joint infection (PJI), impaired macrophage efferocytosis limits bacterial clearance and sustains inflammation. Clinical therapies for restoring macrophage efferocytosis in the infectious microenvironment are limited. Here, we elucidate the mechanistic links between regular exercise, musclin release, and macrophage efferocytosis.

METHODS

We established a murine PJI model to investigate the therapeutic potential of regular exercise. Agar plate colony counting, histological assessment, immunofluorescence staining, radiographic evaluation, and micro-CT were employed to assess bacterial burden, inflammation, tissue fibrosis, and the extent of osteolysis. Bulk RNA sequencing was performed to identify key exercise-responsive molecules. Flow cytometry, immunoprecipitation coupled with mass spectrometry, Seahorse metabolic analysis, and genetic overexpression and inhibition techniques were used to reveal the impacts on macrophage efferocytosis and metabolism. Finally, we evaluated the synergistic therapeutic effects of a key exercise-associated secretory protein combined with antibiotics in PJI mice.

RESULTS

Regular exercise significantly alleviated bacterial burden and inflammatory osteolysis in PJI mice. The exogenous administration of musclin-identified as a key exercise-responsive myokine-replicated the protective effects of exercise, with the core mechanism involving restoration and enhancement of macrophage efferocytosis. Mechanistically, musclin bound to formyl peptide receptor 2 (FPR2) on macrophages to reprogram their metabolic phenotype, significantly suppressing the glycolytic pathway while restoring oxidative phosphorylation. Therefore, FPR2-mediated metabolic reprogramming was crucial for enhancing efferocytotic capacity. Furthermore, combination therapy of musclin and oxacillin synergistically reduced bone destruction and tissue fibrosis, while being associated with partial restoration of adaptive immunity.

CONCLUSION

Musclin mitigates PJI by enhancing macrophage efferocytosis via FPR2-mediated metabolic reprogramming. By revealing the mechanism through which exercise ameliorates PJI and establishing musclin as a promising therapeutic candidate, this study provides new strategies for the prevention and treatment of PJI.