Molecular Communication from Skeletal Muscle to Bone: A Review for Muscle-Derived Myokines Regulating Bone Metabolism
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Besides the mechanical loading-dependent paradigm, skeletal muscle also serves as an endocrine organ capable of secreting cytokines to modulate bone metabolism. In this review, we focused on reviewing the myokines involved in communication from skeletal muscle to bone, i.e. (1) myostatin and myostatin-binding proteins including follistatin and decorin, (2) interleukins including interleukin-6 (IL-6), interleukin-7 (IL-7) and interleukin-15 (IL-15), (3) insulin-like growth factor 1 (IGF-1) and its binding proteins, (4) other myokines including PGC-1α-irisin system and osteoglycin (OGN). To better understand the molecular communication from skeletal muscle to bone, we have summarized the recent advances in muscle-derived cytokines regulating bone metabolism in this review.
KeywordsSkeletal muscle Bone Myokines
Skeletal muscles and bone are two largest tissues in musculoskeletal system. A close relationship between bone and muscle is observed during development and growth . The coupling of bones and skeletal muscles has been mainly viewed as a mechanical one in which bone provides the attachment sites and muscles apply load to bone . The mechanical coupling in many pathological conditions also implies that muscle atrophy would result in bone loss. Osteoporosis (decrease in bone mass) and sarcopenia (decrease in muscle mass) are major clinical problems in the aging population, and in many patients these two conditions occur concurrently, which may lead to abnormal physical function, decreased quality of life and increased patient mortality . However, it has been widely shown that muscle mass, measured as lean body mass, is related to bone mineral density (BMD) and could explain up to 20% of the variety in BMD at femoral neck . Therefore, the decreased mechanical loading caused by muscle atrophy alone cannot fully explain the totality of bone loss.
Besides mechanical coupling, there also is a biochemical coupling between muscle and bone. In a mice open tibial fracture model, Harry et al. demonstrated that in comparison with the fracture area covered with fasciocutaneous tissue (skin plus fascia), both the duration and quality of fracture healing were enhanced in the fracture area surrounded with muscle flaps, where the muscle was simultaneously injured and could not contract to supply load . These findings imply that skeletal muscle might secrete biochemical molecules to affect bone formation. Further investigation of the secretome from C2C12 cells, a cell mouse myoblast line, during muscle differentiation allowed to identify more than 600 proteins, including growth factors, cytokines and metallopeptidases . In 2003, Pedersen et al. firstly mentioned that those cytokines or peptides, which are produced, expressed and released by muscle fibers to exert auto-, para- and/or endocrine effects, are classified as myokines . Thus, skeletal muscle can be classified as an endocrine organ. These secreted myokines have potential regulating effects on far-away tissue and thus build a molecular regulatory network between the non-muscle tissues and skeletal muscles during physiopathological conditions. This review highlights the biological actions of myokines including cytokines and growth factors on bone tissue and the molecular communication from skeletal muscle to bone. These myokines will be classified as following categories in this review: (1) myostatin and myostatin-binding proteins, (2) interleukins, (3) insulin-like growth factor 1 and its binding proteins, and (4) other myokines.
Myostatin and Myostatin-Binding Proteins
Myostatin is known as growth differentiation factor 8 and specifically expressed in the developing and adult skeletal muscle, which was initially discovered in 1997 by McPherron, Lawler and Lee . Myostatin belongs to the highly structural conversed transforming growth factor β (TGF-β) superfamily and possesses the nine invariant cysteine residues, an “RXXR” furin-type proteolytic processing site, and a bioactive C-terminal domain, which are commonly existed in other members of TGF-β superfamily.
Myostatin may be the first identified muscle-derived peptide fulfilling the above myokine criteria. It is secreted from muscle and negatively regulates myogenesis via its transmembrane activin receptor IIB (ActRIIB) in autocrine manner . Myostatin knockout mice demonstrated a massive muscle hypertrophy that is featured by the increase in both fiber cross-sectional area and fiber number. The muscle phenotype of the hyperplasia in the mentioned animal model was caused by accelerated primary and secondary myogenesis . These similar hypertrophy phenotypes were also found in cattle, sheep and dog [8, 9]. For human, a male child having a mutation in the myostatin gene has been reported demonstrated extraordinary muscularity . The myostatin in muscle and circulation is also regulated by physical activities. Several lines of evidence demonstrated that the exercise training in both humans and animals can reduce myostatin expression within muscles and blood, which is different to other TGF-β family members that are elevated by exercise [11, 12].
Recently, the relationship of myostatin and bone is also actively being examined. Animal studies demonstrate that inhibition of the myostatin pathway increases bone turnover and leads to bone mass increase . The ActRIIB has also been found on the cell membrane in osteoblasts (a type of bone cell forming bone tissue), and its inhibition leads to increased bone formation in mice . Besides the direct effects, myostatin/ActRIIB inhibition also increases muscle mass/force and subsequently increases bone mass due to the increased mechanotransduction applied to bone [15, 16]. In humans, there appears to be a relationship of myostatin genetic polymorphisms and peak BMD, suggesting that different levels of myostatin expression might be correlated with higher (or lower) BMD . Myostatin has been further identified as an important regulator of RANKL-induced osteoclast development in vitro . Myostatin exerts its effects through promoting the expression of SMAD2-dependent nuclear translocation of nuclear factor of activated T cells, cytoplasmic, calcineurin-dependent 1 (NFATC1) and subsequently upregulating the differentiation genes in osteoclasts (a type of bone cell resorbing bone tissue) . Interestingly, the loss or pharmacological inhibition of myostatin strongly reduces osteoclast formation and bone destruction in the human tumor necrosis factor (TNF)-α transgenic mouse model of RA . Thus, myostatin is a negative regulator of bone formation but positive regulator of bone resorption.
Follistatin is a myostatin-binding glycoprotein that can capable of binding directly to myostatin to inhibit myostatin’s receptor binding activity and subsequently promote muscle growth . Follistatin also showed high affinity to type IIA activin receptor (ActRIIA) and involved in regulating bone mass . Follistatin not only inhibits myostatin activity, but also blocks activin A activity, as indicated by that the follistatin-overexpressing mice showed a more significant phenotype in skeletal muscle than that in mice lacking myostatin alone [21, 22]. Although liver is the major source of follistatin, which may be mainly responsible for the increased plasma follistatin levels after exercise, skeletal muscles can also release follistatin and may involve in molecular communication from skeletal muscle to bone [23, 24]. It was reported that follistatin can be secreted from gastrocnemius muscle after hind-limb ischemic surgery . Later, it further reported that follistatin can increase mineralization and stimulate osteoblastogenesis, whereas activin A can inhibit mineralization by osteoblasts in vitro . Therefore, the activin A–myostatin–follistatin system is thought to play an important role in the regulation of muscle and bone mass.
Decorin is another more recently discovered myokine that is secreted from myotubes in response to muscle contraction . Decorin belongs to small leucine-rich repeat proteoglycans (SLRPs) class I and is involved in the regulation of collagen fibrillogenesis . Decorin directly binds to myostatin in a paracrine manner and thereby inhibits the action of myostatin . It was reported that Decorin could bind to mature myostatin with its core protein in the presence of Zn2+ in extracellular matrix, by which the Decorin traps myostatin to inhibit the activities of myostatin . It has been demonstrated that a short sequence of the N terminus of decorin is sufficient for the binding to myostatin. This binding is dependent on the presence of a physiologic concentration of zinc (i.e., around 15 μM), and the cysteine cluster present in the CX3CXCX6C motif is of crucial importance for keeping the capacity of interaction with myostatin . Therefore, decorin acts as an antagonist to myostatin. Decorin secreted from myotubes in response to contraction and the serum levels of decorin increase after exercise in human . Subsequently, decorin can promote the formation of bone matrix and calcium deposition to control bone morphogenesis . Further studies showed that decorin binds to collagen type I via a short SYIRIADTNIT sequence in leucine-rich repeat to promotes osteoblast collagen mineralization. In addition, it was also reported that decorin can bind to TGF-beta 1 with high affinity via its core protein and subsequently enhances TGF-beta 1 binding to its receptors in osteoblasts . Thus, the underlying mechanism for the decorin acting on bone is needed to further explored.
Interleukin-6 (IL-6) has originally been classified as a prototypical pro-inflammatory cytokine and expresses in a number of cells including monocytes/macrophages, vascular endothelial cells and fibroblasts . It is further reported that skeletal muscle fibers also produce IL-6 and release into the circulation in response to muscle contractions . Thus, IL-6 also fulfilled the criteria of myokine which could secrete into the circulation in response to muscle contractions . At first, macrophages were thought mainly responsible to exercise-induced IL-6 expression ; however, several reported studies confirmed that IL-6 is actually produced in muscle fibers instead of monocytes without any signs of muscle injury . In skeletal muscle, IL-6 signals through a gp130Rβ/IL-6Rα homodimer leading to an increase in glucose uptake and fatty acid oxidation . Furthermore, a series studies indicated that IL-6 can also stimulate hepatic gluconeogenesis, glycogenolysis and glucose release . IL-6 also stimulates the secretion of glucagon-like peptide-1 (GLP-1) from intestinal L-cells and pancreatic α-cells, which results in an enhanced secretion of insulin . Therefore, the circulated IL-6 works as an energy sensor to modulate glucose and fatty acid metabolism and mediated the cross talk among several organs/tissues including muscle, liver, adipose tissue and pancreas .
With regard to the bone tissue, IL-6 shares the common receptor transducer gp130 with other myokines, such as Leukemia inhibitory factor (LIF) and Ciliary neurotrophic factor (CNTF) . In 1993, the IL-6 was firstly reported to mediate the bone loss induced by estrogen-withdrawal in mice . The in vivo studies with IL-6 transgenic mice showed overexpression of IL-6 resulted in increased osteoclastogenesis . IL-6 and tumor necrosis factor (TNF)-α have a synergistic effect on osteoclastogenesis , while IL-6 possibly upregulates the expression level of receptor activator of nuclear factor-kappaB ligand (R) to indirectly stimulate osteoclastogenesis . Furthermore, it has been reported that the potency of induction of matrix metalloproteinases (MMPs) by IL-1 and IL-6 is closely linked to the respective bone-resorbing activity, suggesting that MMP-dependent degradation of bone matrix plays a key role in bone resorption induced by these cytokines . Following studies revealed that IL-6 could also promote osteoblast differentiation . Thus, IL-6 has stimulatory effects on both osteoblasts and osteoclasts. In another study, it showed that the conditioned medium of IL-6-treated MLO-Y4 osteocytes could enhance Ki67 expression and lower expression level of Runt-related transcription factor 2 (RUNX2) in osteoblasts at day 5, in spite of the fact that IL-6 alone or conditioned medium from static osteocytes cultured without IL-6 has no direct effects on the expression of RUNX2 and Ki67 in osteoblasts . Thus, it reveals that IL-6 may modulate the communication from osteocyte toward osteoblasts. Although IL-6 is expressed in osteoblasts, osteoclasts and osteocytes and involved in regulating both bone formation and bone resorption , circulating IL-6 may play a dominant role in osteoclast formation as evidenced by the increased osteoclast and bone-resorption parameters are dampen by IL-6 antibody treatment in an ex vivo wild-type calvarial bones cultured with sera from MDX mice (a mouse model as a surrogate for Duchenne muscular dystrophy) .
Haugen et al. identified IL-7 as another myokine, which can be detected in the media of primary cultures of human myotubes differentiated from satellite cells and increased with the incubation time . Generally, IL-7 stimulates the differentiation of multipotent (pluripotent) hematopoietic stem cells into lymphoid progenitor and regulates the differentiation of T cell and B cell . Moreover, IL-7 could upregulate T cell cytokines including receptor activator of nuclear factor-kappaB ligand (RANKL), which might be responsible for the IL-7-induced osteoclastic bone resorption. Interestingly, overexpression of IL-7 induced by ovariectomy not only induces bone resorption but also inhibits bone formation . Therefore, it indicates that IL-7 may be an important myokine participating in bone metabolism.
Interleukin-15 (IL-15) is another pro-inflammatory cytokine having similar structure with IL-2 . IL-15 can bind to the IL15Rαβγ complex, which is upstream of the Janus kinases 1 and 3 (JAK1, 3) and signal transducer and activator of transcription 3 and 5 (STAT3, 5) . Besides that IL-15 regulates T and natural killer cell activation and proliferation, IL-15 can be detected in several human tissues including heart, lung, liver and kidney, but most abundantly in placenta and skeletal muscle .
Recently, IL-15 has been described as another anabolic factor in skeletal muscle. IL-15 can stimulate the expression of contractile proteins and subsequent muscle cell hypertrophy . Moreover, IL-15 can antagonize cancer cachexia in rats, which indicated its therapeutic potential in muscle wasting disorders . In addition, transgenic overexpression of IL-15 or muscle-specific ablation of the IL-15 receptor α could promote skeletal fatty acid oxidation and muscle glucose uptake .
IL-15 not only induces proliferation and activation of T cells, but also directly acts on bone remodeling by stimulating pre-osteoclast differentiation . Indeed, osteoclasts express the high-affinity IL-15Rα chain and IL-15 influences osteoclastogenesis both directly, by co-stimulating RANKL-induced differentiation and activation processes in osteoclasts, and indirectly, by inducing proliferation and activation of T cells and their production of IFNγ and RANKL . However, it was also reported that IL-15-activated nature kill cells can trigger osteoclast apoptosis in a dose-dependent manner, resulting in drastically decreased bone erosion . In turn, IL-15Rα-deficient (IL-15Rα−/−) mice present a high bone mass phenotype and improved bone microarchitecture in both the cancellous and cortical bone compartments . Therefore, IL-15 maybe exerts the controversial effects on osteoclast-mediated bone resorption under different pathological conditions.
Insulin-Like Growth Factor 1 and its Binding Proteins
The insulin-like growth factor 1 (IGF-1) is localized to the muscle–bone interface in vivo and abundant in homogenized muscle tissue and conditioned medium from cultured myotubes . It is reported that muscle hypertrophy is associated not only with the increase in IGF-1 from liver, but also with the increase in IGF-1 in skeletal muscle . IGF-1 is also an important myokine for bone, since it stimulates bone formation both in vitro and in vivo, and its receptors are abundantly localized to periosteum at the muscle–bone interface . Paracrine interactions at the muscle–bone interface might be important in the establishment of a cross talk between these two tissues, both in physiologic conditions and in regeneration after a musculoskeletal injury. In these settings, muscle-derived IGF-1, released by muscle fibers near the periosteum depending on muscle hypertrophy, may act on nearby osteoblasts expressing the specific receptor (IGF-1R), thus promoting bone formation . Therefore, the muscle-derived IGF-1 may regulate bone formation via endocrine/paracrine and autocrine mechanisms. IGF-1 can bind to IGF1R chondrocytes, osteoblasts and osteocytes and cause phosphorylation of IGF1R and phosphorylate protein kinase B (AKT), subsequently activates downstream substrates including Forkhead group of transcriptional factors (FoxO1,3,4) and mTOR [60, 61].
The turnover, transport and half-life of circulating IGFs, including IGF-1, are regulated by IGF-binding proteins (IGFBPs) . IGFBPs are a family of secreted proteins that specifically bind IGF with affinities that are equal to or greater than those of the IGF-1R. Most IGFBPs, including IGFBP2, are expressed in skeletal muscle [63, 64]. Relative appendicular skeletal muscle mass (ASM) has been shown to be significantly inversely related to serum IGFBP-2 levels in both genders . Regarding bone tissue, IGFBP-2 binds to IGFs and prevents its fixation to IGF receptors . Indeed, high IGFBP-2 circulating concentrations were associated with lower BMD in men and women .
Irisin, as a new hormone-like myokine, is discovered in the presence of exercise-induced peroxisome proliferator-activated receptor gamma coactivator-1-alpha (PGC-1α) . Irisin is cleaved off from fibronectin type III domain-containing protein 5 (FNDC5), a membrane-bound protein in skeletal muscle that is induced by exercise and muscle shivering . Irisin may positively regulate muscle metabolism via autocrine manner. Myocytes treated with irisin in vitro express higher levels of PGC-1α, nuclear respiratory factor 1 (NRF-1), mitochondrial transcription factor A (TFAM), glucose transporter 4 (GLUT4), UCP-3 and irisin implying a positive auto-regulatory loop between PGC-1α and FNDC5 . Therefore, energy expenditure and oxidative metabolism in muscle cells is elevated by irisin. In addition to these autocrine effects, irisin may also exert its effects on adipocytes and osteoblasts via endocrine manner. It was reported that high dosage of irisin exerts its action on white adipose tissue cells to stimulate uncoupling protein (UCP)-1 expression and other brown fat-like genes thereby inducing browning and thermogenesis of white adipose tissue , while low dose of irisin increases cortical bone mineral density and positively modifies bone geometry . On the one hand, irisin upregulates the expression of osteogenic genes including Opn and Sost in bone tissues in vivo; on the other hand, irisin exerts its effect prevalently on osteoblast lineage by enhancing differentiation and activity of bone-forming cells in vitro . Further, it was reported that exercise training can induce the differentiation of osteoblasts and improve the expression of ALP and type I collagen in osteoblasts in an irisin-dependent manner, thereby confirming that irisin reveals a direct involvement in bone metabolism to accelerate the transformation of matured osteoblasts from bone marrow stromal cells . Thus, these findings offer an alternative explanation to the positive outcome on the skeleton triggered by skeletal muscle during physical activity and it provides a novel therapeutic strategy for skeletal disorders with impaired bone formation.
Recently, a doubt about the significance of irisin in human has been raised, regarding a FNDC5 signature has been identified at −20 kDa by mass spectrometry in human serum but not detected by the commercial ELISA kits that have been commonly used in the previous studies . As the polyclonal antibodies (pAbs) for detection of irisin in blood crossly reacted with other serum protein, so the data obtained with commercial ELISA kits were still be challenged [73, 74]. Thereafter, another study has identified and quantitated human irisin in plasma using mass spectrometry and confirmed that human irisin exists, circulates and is regulated by exercise .
Osteoglycin (OGN) is the seventh member of the small leucine-rich proteoglycans (PGs) and identified in the secretome components during skeletal myogenesis . It indicated that osteoglycin may play an inhibitory role by hindering myoblast migration and subsequent cell–cell contact during myogenesis . Fibrodysplasia ossificans progressiva characterized by postnatal progressive heterotopic ossification in skeletal muscle is caused by constitutive activation of bone morphogenetic protein (BMP) receptor due to a mutation causing constitutive activation (617G-A;R206H)/activin-like kinase 2 (ALK2). It indicates that some muscle-derived anabolic factors might trigger the heterotopic ossification in skeletal muscle during development of Fibrodysplasia ossificans progressive . Therefore, Tanaka et al. performed a comparative DNA microarray analysis between mouse myoblastic C2C12 cells transfected with either stable empty vector or ALK2 (R206H) and identified osteoglycin as an important anabolic factor produced by muscle-derived cells and secreted into blood that exhibits bone anabolic effects . Further study showed that OGN significantly decreased the levels of RUNX2 and Osterix in MC3T3-E1 cells, but significantly enhanced the levels of alkaline phosphatase (ALP), type I collagen (Col1) and osteocalcin (OCN) mRNA . Thus, OGN might be an important myokine secreted from muscle to induce heterotopic ossification in Fibrodysplasia ossificans patients.
Targeting Muscle–Bone Communication Network as a Potential Therapeutic Strategy for Musculoskeletal Diseases
Biological functions of myokines involved muscle to bone communication
Functions in muscle (ref.)
Effects on bone (ref.)
Negatively regulates myogenesis 
Upregulates RANKL-induced osteoclast development 
Inhibit myostatin’s receptor binding activity and subsequently promote muscle growth 
Increase mineralization and stimulate osteoblastogenesis 
Binds to mature myostatin in extracellular matrix and regulates muscle hypertrophy 
Promotes the formation of bone matrix and calcium deposition 
Increases in glucose uptake and fatty acid oxidation in myofibers 
Promote osteoblast differentiation 
Increases osteoclastogenesis 
Involves in muscle cell development 
Inhibits bone formation 
Upregulate receptor activator of nuclear factor-kappaB ligand (RANKL) 
(a) Stimulates the production of contractile proteins 
(b) Promotes skeletal muscle glucose uptake and fatty acid oxidation 
Dual effects on bone resorption
(a) Stimulates pre-osteoclast differentiation 
(b) Decreases bone resorption by inducing nature kill cells mediated osteoclast apoptosis 
Promotes muscle growth 
Stimulate bone formation 
Promotes oxidative metabolism in myofibers 
Promotes osteoblast differentiation in irisin-dependent manner 
Hinders myoblast migration and subsequent cell–cell contact during myogenesis 
Exhibits bone anabolic effects 
Musculoskeletal diseases are highly prevalent and great challenges to human health. The combined wasting of muscle (e.g., sarcopenia) and bone (e.g., osteoporosis)—both in normal aging and pathologic states—can lead to vastly compounded risk for fracture in patients. Until now, our therapeutic approach to the prevention of such fractures has focused solely on bone, but our increasing understanding of the interconnected biology of muscle and bone has begun to shift our treatment paradigm for musculoskeletal disease. Recently, skeletal muscle was considered as a secretory organ, which could secrete peptide/protein (myokines) to cross talk with bone and other tissue/organs including adipose tissue, liver, pancreas, brain and immune system. The conceptual basis will not only help to better understand the communication between muscle and bone, but also encourage us to develop efficient therapeutic approaches with dual beneficial effects on both muscle and bone. In 2013, Bialek et al.  reported that both muscle and bone mass were increased after administration of myostatin inhibitors in young adult mice. The dual activity of myostatin inhibitors represents a potential approach for the treatment of both muscle wasting and bone lose in aged people. Taken together, the putative existence of a musculoskeletal pleiotropy and a muscle–bone communication has fueled the idea to develop compounds able to target simultaneously muscle and bone in order to prevent and possibly reverse conditions of sarco-osteoporosis.
This work was supported by the Faculty Research Grant of Hong Kong Baptist University (FRG2/13-14/006), the Hong Kong General Research Fund (12136616, 12102914 and 478312), Interdisciplinary Research Matching Scheme (IRMS) of Hong Kong Baptist University (RC-IRMS/13-14/02 and RC-IRMS/13-14/03), the Research Committee of Hong Kong Baptist University (30-12-286, FRG2/14-15/021 and FRG2/12-13/027), the Science and Technology Innovation Commission of Shenzhen Municipality (SCM-2013-SZTIC-001), Natural Science Foundation Council (81272045, 81401833 and 81572195).
Conflict of interest
All the authors including Baosheng Guo, Zong-Kang Zhang, Chao Liang, Jie Li, Jin Liu, Aiping Lu, Bao-Ting Zhang and Ge Zhang declare that they have no conflict of interest.
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