The inhibition of lactate/Gpr81 signalling driven by moderate-intensity continuous training protects against...

Osteoarthritis (OA) is among the most prevalent chronic diseases worldwide. However, currently employed pharmacological therapies for OA are associated with various reported side effects. Exercise therapy represents a potentially safer and more effective strategy for OA treatment, although its underlying mechanism remains unclear. Here, we demonstrate that compared with high-intensity continuous training, moderate-intensity continuous training (MICT) has greater therapeutic potential for OA. Notably, these beneficial effects of MICT were abrogated following gut microbiota depletion. Moreover, transplantation of the gut microbiota from MICT-treated mice inhibited OA progression. Akkermansia was identified as the most significantly altered microbiota in response to MICT, and supplementation with Akkermansia in destabilization of the medial meniscus mice also alleviated OA. Mechanistically, MICT protects against OA by reducing plasma lactate levels. Production of high levels of lactate by numerous microbiotas was identified as a risk factor induced by destabilization of the medial meniscus. Consistent with these findings, our genetic data revealed that both the knockout of the lactate receptor Gpr81 and the knockdown of Gpr81 in articular cartilage with adeno-associated virus 2 mitigated OA progression by increasing anabolic metabolism and suppressing catabolic metabolism. The Gαi-CREB/NF-κB axis was further identified as the primary downstream pathway mediating the biological effects of Gpr81 in chondrocytes. Clinically, we validated a negative correlation between Akkermansia abundance and both synovial fluid lactate levels and GPR81 expression in the articular cartilage of OA patients. Collectively, the results of this study not only reveal the mechanism underlying the protective effects of exercise against OA but also identify a novel therapeutic target for OA treatment. Moderate-intensity continuous training remodelled the gut microbial composition in destabilization of the medial meniscus mice, which in turn decreased blood lactate levels, further alleviated destabilization of the medial meniscus-induced hyper-lactate and Gpr81 overactivation, ultimately ameliorating osteoarthritis by coordinating the Gαi-CREB/NF-κB signalling pathway.