High-intensity running exercise promotes knee meniscal damage via the PI3K/AKT/mTOR axis.

Aims: To examine cellular and molecular mechanisms of meniscal degeneration, including matrix degradation and inflammation, and identify therapeutic targets for osteoarthritis interventions. Methods: Meniscal tissue samples were collected from a total of ten patients. Using a small animal running platform, a mouse model of meniscal injury was established via running training, and the extent of the damage was assessed using histological and immunohistochemical staining. Human meniscal cells and tissues obtained from ten patients undergoing arthroscopic surgery or joint replacement arthroplasty were exposed to mechanical stimuli, mimicking the forces experienced during human running activity using a cyclic stretching system. Western blot and quantitative reverse transcription polymerase chain reaction (qRT-PCR) analyses were performed to evaluate the responses. Transcriptome sequencing was conducted to determine gene expression changes associated with meniscal injuries, and functional alterations were analyzed using the Metascape platform. Rapamycin was administered via knee injections to evaluate its therapeutic effects on meniscal damage. Results: Histological staining showed progressive meniscal tissue degeneration over time in the high-intensity running group. Transcriptome analysis revealed that the phosphoinositide 3-kinase/protein kinase B (PI3K/AKT) pathway was markedly enriched in mechanically overstressed meniscal cells. Downstream activation of the mammalian target of rapamycin (mTOR) pathway was confirmed via western blot and immunofluorescence, consistent with the results of the mouse chronic overload model. The subsequent intra-articular administration of rapamycin, a well-established mTOR inhibitor, substantially mitigated meniscal degeneration in mice, a finding corroborated in experiments using human meniscal cells. Conclusion: These observations demonstrate that prolonged and excessive mechanical stress may contribute to meniscal damage or degeneration through activation of the phosphoinositide 3-kinase/protein kinase B/mammalian target of rapamycin (PI3K/AKT/mTOR) axis.