Over the past decade, the myokine irisin has been identified as the main molecular mediator of physical exercise, with a remarkable effect on muscle and bone. Given its anabolic role, we sought to determine whether prolonged treatment with irisin could be a therapeutic option to counteract age-related osteosarcopenia. To this end, 12-month-old C57BL6 mice were treated with vehicle or irisin (s.c. 100 µg/kg/weekly) for 8 months. Femurs were analyzed by micro-computed tomography, 3-point-bending assay and histomorphometry. Vastus Lateralis muscles were subjected to histological and molecular analysis. To evaluate the effect of irisin on sclerostin, its expression was assessed in bone marrow, cortical bone and skeletal muscle ex vivo, and in C2C12 myoblasts in vitro. The mice treated with irisin showed increase in cortical tissue mineral density (TMD) ( p = 0.008 ), bone surface (BS) ( p = 0.036 ), bone volume/total volume (BV/TV) ( p = 0.02 ), and number of trabeculae (Tb. N) ( p = 0.0002 ) compared with vehicle-mice. Irisin decreased the number of osteoclasts ( p = 0.0056 ), tartrate-resistant acid phosphatase positive (TRAP+) osteocytes ( p = 0.0292 ), and Sost expression in the bone marrow ( p = 0.026 ) and cortical bone ( p = 0.032 ). Furthermore, irisin preserved the morphological organization of muscle fibers and decreased the expression of muscle atrophy genes, Atrogin ( p = 0.0168 ) and Muscle Ring-Finger Protein-1 ( Murf1 ) ( p = 0.0452 ). Notably, we observed a 2-fold lower sclerostin positivity in the muscle of irisin-treated mice than in vehicle mice ( p = 0.026 ). In vitro experiments demonstrated that Sost was downregulated in C2C12 myoblasts treated with irisin either for 8 h ( p = 0.0001 ) or intermittently for 1 week ( p = 0.0004 ). On the other hand, sclerostin treatment in myoblasts affected their differentiation marker genes and downregulated the irisin precursor Fibronectin domain-containing protein 5 (FNDC5) ( p = 0.009 ). Overall, this study demonstrates that irisin is a systemic mediator capable of counteracting the effects of aging on the musculoskeletal system. Furthermore, our study provides evidence of sclerostin expression in skeletal muscle and the negative effect of this osteokine on myoblast differentiation. Therefore, the ability of irisin to downregulate sclerostin expression in both bone and skeletal muscle highlights its functional versatility, which could find application as a therapeutic approach for the treatment of osteosarcopenia.
Suriano et al. (Sat,) studied this question.