Exercise suppresses osteoclastogenesis by increasing the secretion of muscle-derived L-β-aminoisobutyric acid
Zhiwei Huang, Yong-Peng Yu, Xinrong He, Yun-Biao Chen, Xin Xiang, Hongzhou Li, Zhihai Cai, Jiayi Zhang, Di-Zheng Wu, Guo-Zheng Zhu, Jia-Wen Gao, Guixing Cai, Sheng Yang, Chen Tu, Zhaoming Zhong
Abstract
BACKGROUND: Exercise is a key strategy for combating bone loss in individuals with postmenopausal osteoporosis (PMOP). L-β-aminoisobutyric acid (L-BAIBA), an exercise-responsive myokine, is secreted at elevated levels during physical activity. However, the role of exercise-induced L-BAIBA secretion in PMOP remains unclear. In this study, we aimed to evaluate the therapeutic efficacy of L-BAIBA in mitigating bone loss using an ovariectomized (OVX) mouse exercise-induced model. METHODS: An OVX mouse model was established to simulate PMOP. Primary bone marrow-derived macrophages, murine muscle satellite cells (MuSCs), and human peripheral blood mononuclear cells were isolated and cultured. We hypothesized that exercise-induced L-BAIBA release would attenuate PMOP by suppressing osteoclastogenesis. To test this hypothesis, we conducted the following experiments: (a) measured plasma L-BAIBA concentrations, femoral morphology and biomechanical properties, and bone resorption markers in OVX mice following 8 weeks of treadmill exercise, and assessed osteoclast induction in vitro using conditioned co-cultures of stretched primary MuSCs; (b) repeated the same measurements after 8 weeks of daily L-BAIBA administration (150 mg/kg) to OVX mice; (c) investigated molecular signaling pathways associated with L-BAIBA action; and (d) examined the correlation between L-BAIBA plasma concentration and bone mineral density (BMD) in women with PMOP. RESULTS: Exercise increased L-BAIBA secretion, suppressed osteoclastogenesis, and reduced bone loss in OVX mice. L-BAIBA supplementation similarly inhibited osteoclastogenesis both in vivo and in vitro. Mechanistically, L-BAIBA acted through the taurine transporter solute carrier family 6 member 6 (SLC6A6), downregulated phosphatidylinositol 3-kinase (PI3K)/serine/threonine-protein kinase (AKT)/nuclear factor kappa-B (NF-κB) signaling, and activated the nuclear factor erythroid 2-related factor 2 (NRF2) anti-oxidant system. L-BAIBA levels were significantly reduced in women with PMOP and positively correlated with BMD. CONCLUSION: Exercise suppresses osteoclastogenesis by enhancing L-BAIBA secretion. These findings provide new insights into the mechanisms underlying the skeletal benefits of exercise and highlight L-BAIBA's therapeutic potential as a novel agent for managing PMOP.