Exercise alleviates age-related osteoarthritis associated with PGC-1α activation to suppress chondrocyte senescence and aberrant glycolysis

Abstract

Background Age-related osteoarthritis (OA) is a leading global disability cause. Exercise is recommended as first-line therapy but poorly tolerated by elderly patients. This study elucidated the mechanism of low-intensity exercise in OA and develop a targeted exercise-mimetic nanotherapy. Methods The effects of low-intensity swimming exercise on age-related OA were investigated using aged mouse models. A senescence-targeted nanoparticle system (NP-B2M) was fabricated via a double-emulsion solvent evaporation method combined with EDC/NHS conjugation. The mechanisms underlying exercise and PGC-1α–mediated metabolic reprogramming were explored using transcriptomic sequencing, glycolysis analysis, RT-qPCR, and Western blotting in IL-1β–induced senescent ATDC5 chondrocytes. The therapeutic efficacy of intra-articular delivery of NP-B2M was systematically evaluated using micro-CT, histological staining, and immunohistochemistry in aged mice. Results Low-intensity swimming attenuated OA by suppressing chondrocyte senescence and pathological glycolysis via activating PGC-1α, effects that were recapitulated by ZLN005. NP-B2M enabled targeted intra-articular drug release and showed superior efficacy over free ZLN005. Conclusion This study demonstrates that low-intensity exercise alleviates age-related OA via PGC-1α–mediated metabolic reprogramming. NP-B2M provides a biocompatible, precisely targeted, long-acting platform that mimics exercise benefits, offering promising translational potential as a precision therapeutic strategy for immobile elderly OA patients. The translational potential of this article In this study, we developed NP-B2M, a PLGA-based nanoplatform, achieves prolonged joint retention and enhanced efficacy versus free drug, representing a promising targeted approach for OA patients with limited mobility.