The myokine irisin increases cortical bone mass

Abstract

It is unclear how physical activity stimulates new bone synthesis. We explored whether irisin, a newly discovered myokine released upon physical activity, displays anabolic actions on the skeleton. Young male mice were injected with vehicle or recombinant irisin (r-irisin) at a low cumulative weekly dose of 100 µg kg(-1). We observed significant increases in cortical bone mass and strength, notably in cortical tissue mineral density, periosteal circumference, polar moment of inertia, and bending strength. This anabolic action was mediated primarily through the stimulation of bone formation, but with parallel notable reductions in osteoclast numbers. The trabecular compartment of the same bones was spared, as were vertebrae from the same mice. Higher irisin doses (3,500 µg kg(-1) per week) cause browning of adipose tissue; this was not seen with low-dose r-irisin. Expectedly, low-dose r-irisin modulated the skeletal genes, Opn and Sost, but not Ucp1 or Pparγ expression in white adipose tissue. In bone marrow stromal cell cultures, r-irisin rapidly phosphorylated Erk, and up-regulated Atf4, Runx2, Osx, Lrp5, β-catenin, Alp, and Col1a1; this is consistent with a direct receptor-mediated action to stimulate osteogenesis. We also noted that, although the irisin precursor Fndc5 was expressed abundantly in skeletal muscle, other sites, such as bone and brain, also expressed Fndc5, albeit at low levels. Furthermore, muscle fibers from r-irisin-injected mice displayed enhanced Fndc5 positivity, and irisin induced Fdnc5 mRNA expression in cultured myoblasts. Our data therefore highlight a previously unknown action of the myokine irisin, which may be the molecular entity responsible for muscle-bone connectivity

Role of Irisin on the bone–muscle functional unit

“…Accordingly, three-point bending tests on tibiae of Irisin-treated mice showed that bending strength and energy to fracture were increased by þ 65% and þ 9.5%, respectively. 19 Conversely, Irisin did not induce any change in trabecular bone, and this result was somewhat expected considering that young mice, used for this study, have a healthy trabecular pattern. However, this is also in line with previous literature data reporting that cortical bone is more sensitive to myokines or other anabolic factors released by muscle.…”

“…In fact, more recently, we demonstrated that Irisin also targets the bone tissue directly and, if administered at a lower dose than used to induce browning of white fat, it drives positive effects on cortical mineral density and improves bone strength and geometry in mice. 19 This recent result highlighted a new biological significance of Irisin, which might be a molecular link responsible for the yet poorly characterized bone-muscle unit ( Figure 1).…”

“…Consistently, ALP and collagen I mRNA expression were upregulated upon Irisin treatment in vitro. 19 In vivo data showed higher Atf4 expression in bone marrow of Irisin-treated mice, suggesting a substantial commitment of osteoblast precursor toward osteogenesis. 19 Accordingly, the expression of osteopontin (OPN), one of the most abundant bone matrix protein, was found higher in tibiae of mice treated with Irisin.…”

“…19 In vivo data showed higher Atf4 expression in bone marrow of Irisin-treated mice, suggesting a substantial commitment of osteoblast precursor toward osteogenesis. 19 Accordingly, the expression of osteopontin (OPN), one of the most abundant bone matrix protein, was found higher in tibiae of mice treated with Irisin. 19 In several studies, OPN expression was shown to be modulated in response to mechanical stimulation 30,31 and, therefore, it has been defined as a mechanically responsive gene.…”

“…We showed that tibiae of young male mice treated with r-Irisin exhibited a þ 7.15% increase in cortical BMD compared with those of mice injected with vehicle. 19 Moreover, the administration of Irisin also changed cortical bone geometry, as observed by the increase in mineral apposition rate, bone formation rate, periosteal circumference and polar moment of inertia. The increase in BMD and the improvement of bone geometrical architecture are recognized parameters used to define high bone quality.…”