Improvement of Cortical Bone Mineral Density associated with physical exercise is exerted through the myokine Irisin.

It has been recently reported that, after physical activity, the skeletal muscle releases Irisin, the newly identified myokine able of driving transition of white adipocytes into brown. This result supported the role of skeletal muscle as endocrine organ, suggesting that it could target other tissues besides adipose tissue. In our previous work, we demonstrated that conditioned media collected from primary myoblasts of exercised mice were able to increase OB differentiation and this effect was Irisin-mediated. Here we show that Irisin has positive effect on cortical mineral density and geometry in vivo. Young male mice were injected with r-Irisin and cortical bone adaptation was analyzed by micro-CT at tibial midshaft. Our results show that cortical tissue mineral density is significantly increased in Irisin-injected mice compared to vehicle-injected littermates (+8,16%; p<0,02). Furthermore, this higher density of calcium hydroxyapatite at cortical site is accompanied by increase in periosteal circumference (+7,5%; p<0,03) and polar moment of Inertia (pMOI +19,21%; p<0,01). A greater pMOI indicates stronger resistance of a long bone to torsion and, together with higher bone mineral density, suggests higher protection against fracture. The effect of Irisin is fully comparable to the effect of physical activity that is widely accepted method for increasing bone mineral density and bone size in healthy populations. In view of further proving the involvement of Irisin in bone metabolism, we validate its direct effect on osteoblasts in vitro. Phosphorylation of the MAP kinase ERK and the expression of Atf4 were significantly increased after Irisin treatment, as well as ALP and pro-Collagen I mRNA expression. Our data highlight a novel link in muscle-fat-bone axis demonstrating that Irisin targets bone tissue directly. Based on this study, future investigation could satisfy the ongoing research of exercise-mimetic therapies with anabolic action on the skeleton.