Role of Irisin on the bone–muscle functional unit

Abstract

Irisin was originally recognized as a hormone-like myokine secreted as a product of fibronectin type III domain containing 5 from skeletal muscle in response to exercise both in mice and humans. The first role attributed to Irisin was its ability to induce trans-differentiation of white adipose tissue into brown, but we recently demonstrated that Irisin also has a central role in the control of bone mass, even at lower concentration than required to induce the browning response. Considering how physical exercise is important for the development of an efficient load-bearing skeleton, we can now consider this myokine as one of the molecules responsible for the positive correlation between exercise and healthy bone, linking to the well-established relationship between muscle and bone. Recombinant Irisin (r-Irisin), administered at low dose in young mice, increases cortical bone mineral density and positively modifies bone geometry. Irisin exerts its effect prevalently on osteoblast lineage by enhancing differentiation and activity of bone-forming cells, through the increase in activating transcription factor 4 expression. Low-dose r-Irisin also increases osteopontin and decreases sclerostin synthesis but did not affect Uncoupling protein 1 expression in white adipose tissue, whose upregulation is known to cause browning of fat, when Irisin is administered at a higher dose. These findings offer an explanation to the positive outcome on the skeleton triggered by skeletal muscle during physical activity and prove that the bone tissue is more sensitive than the adipose tissue to the Irisin action.

Crosstalk Between Muscle and Bone Via the Muscle-Myokine Irisin

“…Moreover, tibiae of mice treated with r-Irisin showed higher expression of osteopontin (OPN), one of the most abundant bone matrix proteins that is well known as mechanically responsive protein [17], as several studies showed that OPN expression was modulated in response to mechanical stimulation [18,19]. In accordance with the loading-mimetic function of Irisin, this myokine might be the mediator of the loading-induced increase of OPN expression [12].…”

“…Accordingly, Robling et al, showed that sclerostin expression was decreased by loading, resulting in increased bone formation, suggesting that it may be a key protein involved in mechanical loading [12,23]. Despite in vivo data indicating that r-Irisin, by downregulating sclerostin expression, participates in the signal-transduction pathway induced by mechanical loading, its direct effect on osteocyte is still unknown.…”

“…Furthermore, the increase of polar moment of inertia, an index of long bone resistance to torsion, provided evidence that Irisin treatment improves the quality of bone that becomes more structurally efficient for resisting torsional forces, in order to ameliorate stress transfer and physical performance. Accordingly, tibia from Irisin-treated mice displayed higher bending strength and energy to fracture than matching control, as demonstrated by three-point bending tests [12]. Dynamic histomorphometry of the tibial cortical bone using timed injections of xylenol orange and calcein showed a significant increase in bone formation parameters, including bone formation rate (BFR) and mineral apposition rate (MAR) [11••].…”

<p>Delivery vehicle of muscle-derived irisin based on silk/calcium silicate/sodium alginate composite scaffold for bone regeneration</p>

“…[8][9][10][11] The bioactive molecules involved in muscle-bone connection should be stressed due to the close relationship between skeletal muscle and bone. 12 Physical exercise, which is utilized as a nonpharmacological intervention in treatment protocols for some diseases, has been considered as being advantageous to metabolic and bone health. 13,14 Numerous studies have been designed to detect the molecules involved in the link between physical activity and bone acquisition and maintenance.…”

Irisin and musculoskeletal health

“…Studies have shown that different bone‐derived signals affect skeletal muscle; some of them, such as osteocalcin, insulin‐like growth factor 1 (IGF‐1), prostaglandin E2, and FGF‐23, display positive effects, while others, such as activin or TGF‐β, cause negative responses . Additionally, some muscle‐derived signals, such as interleukins (IL‐6, IL‐8, IL‐15), indirectly target bone through actions on other tissues, while other myokines, such as irisin, can affect bone directly …”