A possible physiological role of sclerostin in aging-associated skeletal muscle atrophy

Sarcopenia has a significant impact on quality of life by inhibiting the ability of daily living. Further, sarcopenia is a well-known risk factor for fall-associated fracture and frailty. Therefore, prevention of sarcopenia is an important issue for healthy life. Recently, it has been revealed that sclerostin (Sost) is a novel target for the treatment of aging-associated bone weakness, so-called osteoporosis, However, the physiological role of Sost in skeletal muscle is unknown. The purpose of this study was to investigate the effect of Sost for skeletal muscle mass. In order to investigate the effect of Sost on myogenic differentiation, we carried out cell culture experiment using mouse myoblast-derived cell line C2C12 cells. During differentiation, Sost (0, 10, 100, 1000 ng/ml) was administrated to the cell culture medium. Effects of anti-sclerostin antibody romosozumab (0, 2, 20, 200 μg/ml) on myotube formation of C2C12 was also investigated. Myotube diameter and the fusion index (FI) and evaluated. Furthermore, we also investigated the expression level of Sost in skeletal muscles of young (10-week old) and aged (100-week old) male mice (C57BL/6J). The effects of hindlimb unloading on the expression level of Sost in skeletal muscle was also investigated. All animal experimental procedures were carried out in accordance with the Guiding Principles for the Care and Use of Animals in the Field of Physiological Sciences by Japan Physiological Society, and approved by the Animal Use Committee of Toyohashi SOZO University. Soleus muscle (SOL) and plantaris muscle (PLA) were dissected before and after 2 weeks of hindlimb suspension. Expression level of Sost was evaluated by Western blotting. The relationship between Sost expression level in each muscle and muscle wet weight was analyzed using Pearson correlation coeffcient. The differences between groups were considered statistically significant at p < 0.05. Sost suppressed myogenic differentiation of C2C12 cells in a dose-dependent manner. On the other hand, romosozumab stimulated C2C12 differentiation in a dose-dependent manner. Expression level of Sost in SOL and PLA of aged mice was significantly higher than that in young animals. In SOL and PLA, a negative correlation was observed between the expression level of Sost and muscle weight was observed. Unloading-associated up-regulation of Sost was observed in PLA of aged mice. We demonstrated aging-associated up-regulation of Sost in mouse slow and fast skeletal muscles. Further, skeletal muscle weight was negatively correlated with the expression level of Sost in skeletal muscle. Therefore, it is suggested that skeletal muscle-derived Sost may play a role in aging-associated skeletal muscle atrophy. Sost may be a novel therapeutic target for sarcopenia. This work was supported by KAKENHI (18H03160, K.G.; 19K22825, K.G.; 19KK0254, K.G.;22H03474, K.G.; 22K19722, K.G.; 22H03319, K.G.; 22K18413, K.G.; 20K11221, T.K) from the Japan Society for the Promotion of Science, and a grant from DAIKO FOUNDATION (K.G.), Graduate School of Health Science, Toyohashi SOZO University (K.G.), and a research grant from Toyohashi SOZO university (K.G.). This is the full abstract presented at the American Physiology Summit 2024 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.