Exercise induces dynamic changes in intra-articular metabolism and inflammation associated with remodeling of the infrapatellar fat pad in mice.

We hypothesized that daily exercise promotes joint health by upregulating anti-inflammatory mediators via adaptive molecular and metabolic changes in the infrapatellar fat pad (IFP). We tested this hypothesis by conducting time-resolved analyses between 1 and 14 days of voluntary wheel running exercise in C57BL/6J mice. IFP structure and cellularity were evaluated by histomorphology, picrosirius red collagen staining, and flow cytometry analysis of stromal vascular fraction cells. Joint inflammation and metabolism were evaluated by multiplex gene expression analysis of synovium-IFP tissue and synovial fluid metabolomics, respectively. Exercise transiently increased cytokine and chemokine gene expression in synovium-IFP tissue, resolving within the first 5 days of exercise. The acute inflammatory response was associated with decreased adipocyte size and elevated CD45Gr1 myeloid cells, increased collagen content, and oxidized phospholipids. Exercise acutely altered synovial fluid metabolites, characterized by increased amino acids, peptides, bile acids, sphingolipids, dicarboxylic acids, and straight medium chain fatty acids and decreased hydroxy fatty acids and diacylglycerols. Between 5 and 14 days of exercise, inflammation, collagen, and adipocyte size returned to pre-exercise levels, and CD206 immuno-regulatory macrophages increased. Thus, although the onset of new daily exercise transiently induced synovium-IFP inflammation and altered tissue structure, sustained daily exercise promoted IFP homeostasis.