Vitamin D Receptor Attenuates Osteo-sarcopenia by Suppressing the Ferroptosis

Objective: Vitamin D deficiency is associated with a range of skeleton and muscle disorders, including osteoporosis and sarcopenia, but its functional role and the underlying mechanism in skeleton and muscle physiology remain unclear. We investigated the effect of vitamin D receptor (VDR) deletion on skeleton and muscle using a mice model with dexamethasone-induced osteo-sarcopenia (OS). Methods: The wildtype and VDR(-/-) mice were treated with vehicle and dexamethasone (i.p., once daily) for 14 consecutive days. The murine myoblast cell line C2C12 and bone mesenchymal stem cells (BMSCs) were used as an in vitro model in this study. Results: After challenging to dexamethasone, VDR-null mice exhibited more severe amyotrophy and bone rarefaction compared with wildtype counterparts, manifested by marked weight loss and significant decrease in muscle wet weight coefficient of the tibialis anterior muscle and gastrocnemius, accompanying with a decrease in bone mineral density (BMD). In addition, the limb grip and weight-loading swimming time were also fall off. Similarly, dystrophin fluorescence staining and haematoxylin eosin staining showed the decrease in cross-sectional area of skeletal muscle in the VDR-null mice. Alizarin red staining and TRAP staining showed that the differentiation of osteoblasts was significantly decreased, while the activity of osteoclasts was significantly increased in the VDR-null mice. VDR knockout mice significantly accelerated protein degradation and bone destructions, but inhibited protein synthesis and bone construction in skeleton and muscle tissue. In addition, we further assessed whether increased Fe2+ level and decreased GPX4 in VDR knockout muscle accelerated the muscle injury, since the deletion of VDR activated ferroptosis, giving rise to the accumulated of Fe2+ in mice and Depleting GSH and inhibiting GPX4 expression. Treatment with the inhibitor of ferroptosis Ferrostatin-1 eliminated dexamethasone-induced atrophy and osteoporosis of myotube cells and BMSCs, reflected by alleviating myotube cell atrophy and BMSCs bone rarefaction via MHC fluorescent staining, Alizarin red staining and TRAP staining. It is suggested that ferroptosis may be one of the pathogenesis of OS. Conclusion: These results provided evidence that VDR attenuated dexamethasone-induced OS at least in part by suppressing the ferroptosis. This work was sponsored by the Program of Natural Science Foundation of China (81973889), the Program of Shaanxi Education Department (19JC013 to FY & 22JK0346 to WL), Youth Innovation Team in Shaanxi universities, and the Program of Health Commission of Shaanxi Province (2022B002). This is the full abstract presented at the American Physiology Summit 2023 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.