Exercise increases bone mass by lactate/Gpr81 signaling pathway.

Exercise is an effective intervention to promote bone mass by regulating bone homeostasis, but the specific mechanism is ambiguous. Here this study shows that high-intensity interval training (HIIT) was more effective than low-intensity continuous training (LICT) in promoting bone mineral density (BMD). Lactate, a major by-product of HIIT, emerges as a focal point in our investigation of bone homeostasis regulation. In vitro experiments revealed that lactate promotes osteoblast differentiation while inhibiting osteoclast differentiation. However, this effect is markedly suppressed in Gpr81-deficient osteoblasts and osteoclasts. We next found lactate inhibits osteoclast differentiation via the activation of the Gpr81-TAK1-p65 signaling pathway, while promoting osteoblast differentiation through activation of the Gpr81-Wnt/β-catenin pathway. Subsequently, HIIT interventions were performed using ovariectomized (OVX) mice with osteoporosis. It was found that HIIT not only attenuated bone resorption but also promoted bone formation, thereby partially rescuing the low bone mass phenotype of OVX mice. Furthermore, administering lactate in a mouse model of osteoporosis induced by ovariectomy effectively prevented bone loss. Our results provided a potential drug target for osteoporosis treatment, the activation of Gpr81 holds promise as a potential strategy for preventing osteoporosis.