Wnt signaling in skeletal muscle dynamics: Myogenesis, neuromuscular synapse and fibrosis
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(2) Mol Neurobiol (2014) 49:574–589. like cells. All of these factors lead to tissue disorganization and to a progressive failure in muscle regeneration that culminates with a decrease in muscle activity [13, 14]. Recent studies suggest that the activation of Wnt signaling promotes muscle fibrosis [13, 14]. Particularly, the so-called canonical Wnt/βcatenin pathway has been described as profibrotic as it relates with changes in the expression of some ECM components. However, based on the fact that muscle fibers rely in calcium for most of their functions, we will also consider the potential and still unexplored role of noncanonical Wnt/Ca+2 signaling in this process [13–16]. In addition, the suggested profibrotic effect of Wnt signaling could be explained by its interaction with other pathways previously involved in the onset of fibrosis. For instance, the connective tissue growth factor (CTGF) and the transforming growth factor β (TGF-β) signaling cascades have been described in several organs as profibrotic including liver, kidney and skeletal muscle [17–19]. However, the molecular effects of Wnt signaling pathway on the activity of TGF-β and CTGF, as well as the effect of these interactions on the onset of muscle fibrosis are not well understood. The aim of this review is to describe the role of the Wnt pathway on skeletal muscle dynamics including myogenesis, NMJ formation, and muscle fibrosis.. Wnt Signaling Pathways Wnt ligands belong to a conserved family of cysteine rich glycoproteins, which are essential to a variety of biological processes. In humans, 19 Wnt genes have been described, each one with a different expression pattern and function [20–22]. The Wnt signaling can be divided into two types: canonical or βcatenin-dependent and noncanonical or β-catenin-independent pathways (Fig. 1) [21, 23]. Canonical or β-Catenin-Dependent Wnt Signaling Pathway The canonical Wnt pathway begins with the binding of the Wnt ligand to the widely expressed seven-transmembrane Frizzled (Fzd) receptors, of which ten members have been described in vertebrates [24]. The Wnt–Fzd interaction requires the LDL-receptor-related proteins 5/6 (LRP5/6), which act as co-receptors of Fzd [25]. Intracellulary, the canonical Wnt pathway requires the intracellular protein β-catenin. In the absence of Wnt ligands, β-catenin levels remain relatively low by the action of a so-called “destruction complex” formed by the scaffold protein Axin, adenomatous polyposis coli (APC) and the enzyme glycogen synthase kinase 3β (GSK3 β), that phosphorylates β-catenin stimulating its destruction by the proteosomal pathway [25]. Upon Wnt–Fzd interaction, the scaffold protein Dishevelled (Dvl) is recruited, causing the dissociation of the β-catenin destruction complex by a series of phosphorylations that inhibit GSK-3β. Under these conditions,. 575. β-catenin is accumulated in the cytoplasm and then translocated to the nucleus where interacts with the T-cell specific transcription factor (TCF) and the lymphoid enhancer-binding factor (LEF), inducing the expression of Wnt target genes (Fig. 1a) [21, 26, 27]. Noncanonical or β-Catenin-Independent Wnt Signaling Pathway At least two noncanonical pathways are also activated by Wnt ligands. In the planar cell polarity pathway (Wnt/PCP), the Wnt–Fzd dependent recruitment of Dvl leads to activation of small GTPases proteins, such as Rho and Rac, which subsequently activate the c-Jun N-terminal kinase. This protein can either signal to the nucleus and it also can modify the cytoskeleton stability, as it affects the phosphorylation of microtubule associated proteins and is also able to interact with actinregulator proteins (Fig. 1b) [28]. In turn, in the Wnt/Ca+2 pathway, signaling downstream of Dvl stimulates trimeric G proteins and the enzyme phospholipase C, which increase the production of inositol triphosphate (IP3), thus triggering an increase in intracellular Ca+2. As a consequence Ca+2-dependent proteins, such as protein kinase C (PKC), calciumcalmodulin-dependent protein kinase II (CaMKII), and the phosphatase calcineurin are activated. Some of these enzymes regulate the transcription factor NF-AT, promoting the expression of specific target genes (Fig. 1c) [20, 29, 30].. Wnt Signaling in Myogenesis Skeletal muscle tissue in vertebrates originates from the first germination plate of the mesoderm [31, 32]. Normal muscle differentiation involves the expression of several MRFs, such as Myf5, MyoD, and Pax3/7, which participates in the early stages of the patterning of mesoderm-derived multipotential cells [33–35]. The relationship between the Wnt signaling and the myogenesis is supported by in vivo studies using knockout mutants for Fzd receptors as well as for some Wnt ligands (for a comprehensive review, see von Maltzahn et al. [36, 37]). In these studies, the lack of some crucial Wnt effectors led to pronounced tissue damage, and poor muscle development leading to mice death, suggesting that the Wnt pathway is critical for prenatal myogenic development [36]. For instance, in studies using mutant Wnt10b−/−, the activation of canonical Wnt signaling by GSK-3β inhibition or the overexpression of Wnt10b in myoblasts, accelerates myoblast differentiation and promotes muscle development [38, 39]. In prenatal myogenesis, activation of Wnt pathways generates diverse effects. For instance, in chicken embryos, the somite myogenesis in presegmented paraxial mesoderm can be stimulated by activators of Shh pathway together with some Wnt ligands, including Wnt1, Wnt3, and Wnt4. Indeed,.
(3) 576. Mol Neurobiol (2014) 49:574–589. Fig. 1 Wnt signaling pathways. a In the absence of Wnt, GSK-3β protein promotes the phosphorylation and subsequent degradation of β-catenin. In the canonical Wnt signaling, Fzd and LRP 5/6 activation by Wnt ligand binding leads to the accumulation and migration of β-catenin to the nucleus where it could interact with transcription factors LEF/ TCF family and they potentiate transcription of Wnt target genes including Bcl2, axin-2 and ECM components. b Wnt/PCP signaling pathway, the Wnt ligand binding lead the activation of Fzd and Dvl and this complex activated smalls protein G such us Rho and Rac leading to activation of the JNK pathway and its interaction with the cytoskeleton. c Wnt/Ca+2 signaling, the activation of Fzd-Dvl complex lead to the generation of IP3 that activates the IP3 receptor and releases of intracellular Ca+2 , this activate several proteins including CamKII and calcineurin that regulate the gene expression via the transcription factors NF-AT. at early stages of differentiation, the expression of MyoD is dependent on the simultaneous activation of the Wnt and Shh pathways; in later stages of development, however, Wnt activity alone is able to stimulate the expression of MyoD,. suggesting that Wnt signaling is a key factor for late prenatal differentiation [40]. The distribution pattern of Fzd and Wnts ligands in different regions of chick embryo support a crucial role for Wnt signaling in early myogenesis, by showing a.
(4) Mol Neurobiol (2014) 49:574–589. direct correlation between the expression of some receptors and ligands; however, there is a clear overlapping expression pattern in an embryonic region that could activate both canonical and noncanonical Wnts pathways to regulate myogenesis. This includes somites, segmental plate mesoderm, and neural folds [41, 42]. In this regard, even though a crucial role has been well documented for the Wnt/β-catenin pathway during different steps of myogenesis, cumulative evidence suggest that other noncanonical pathways, such as the PCP or an alternative mTOR-dependent pathway, also play a role in the process [5]. Nevertheless, the precise mechanisms by which different Wnt ligands and pathways could interplay to regulate myogenesis require further studies.. Wnt Signaling in the Function of the Neuromuscular Junction The Neuromuscular Junction The vertebrate NMJ is a cholinergic synapse that controls skeletal muscle contraction. Unveiling how this peripheral synapse forms does not only represent a potential benefit to recover movement after pathological or traumatic conditions but also provides valuable information to understand central synapses; indeed, the NMJ has been widely used as an archetypical model to identify signaling molecules secreted at both sides of the synapse that potentially play positive or negative roles to shape functional synapses (for reviews, see [43–45]). An early hallmark of postsynaptic differentiation at the NMJ is the aggregation of several postsynaptic proteins, including the acetylcholine receptors (AChRs), in discrete domains of the sarcolemma [44]. Even though it was originally believed that only nerve-derived molecules induced AChR aggregation, the existence of an early prepattern of AChR clusters before inervation has been demonstrated to be crucial for the subsequent positioning of motor axons for NMJ assembly [46–48]. Later on, upon nerve–muscle contact, most of these prepatterned AChR clusters are disassembled by the inhibitory effect of acetylcholine (ACh), which signals through a Cdk5dependent pathway [49–51]. In turn, those aggregates located in close apposition with the motor axon are stabilized by the anti-inhibitory role of agrin, a motor neuron-derived proteoglycan originally believed to induce the aggregation of postsynaptic proteins [50–52]. Agrin signals through the musclespecific tyrosine kinase receptor MuSK [53–55] forming a membrane complex with a low density lipoprotein receptorrelated protein 4 (Lrp4) [56–58] and the cytosolic proteins rapsyn, which binds to AChRs, as well as to the MuSKbinding proteins Dok-7 and Tid1 [59–61]. In support of their crucial role, mice deficient in MuSK, Lrp4, rapsyn, Dok-7, or Tid1 show no signs of postsynaptic differentiation [53, 56,. 577. 58–61], whereas agrin null mice fail to maintain AChR clusters [47, 51]. In contrast, and according to its inhibitory role, mice rendered unable to synthesize ACh, display more and wider postsynaptic densities than wild-type littermates [50, 51]. The identity and function of proteins regulating the presynaptic differentiation of motor neurons have not been extensively described; however, genetic in vivo studies have identified important regulators of the process. For instance, transgenic mice for members of the ephrin family of bidirectional signaling molecules revealed an essential in vivo role for these axonal guidance regulators on the formation of properly positioned NMJs [62]. Regarding neuromuscular synaptogenesis, it has been shown that whereas FGF signaling induces early presynaptic differentiation, laminin-2 affects the maturation and function of active zones, while collagen IV plays a later maintenance role [63]. Remarkably, mice null for Lrp4 or MuSK, key regulators of postsynaptic assembly, also display defects on presynaptic differentiation [53, 57]. According to this observation, Lrp4 has been recently shown to bind motor axons to induce key features of presynaptic differentiation, such as the clustering of presynaptic and active zone components, through a mechanism independent of MuSK and agrin [64]. Together, the confluence of multiple signals originated at both sides of the synapse refine the building of functional NMJs. Wnt Signaling on Postsynaptic Development at the Vertebrate NMJ Several lines of evidence have shown that Wnt pathways affect postsynaptic differentiation at the vertebrate NMJ in vivo. For instance, chick muscles exposed to the Wnt-binding inhibitor secreted Frizzled related protein (Sfrp1) display impaired AChR clustering [65], suggesting that endogenous Wnt ligands regulate postsynaptic assembly. In support of this notion, mutant mice for Dvl, a common mediator of several Wnt pathways, display abnormal postsynaptic development at the NMJ [65], a phenotype consistent with previous in vitro data showing that Dvl regulated the function of MuSK to induce AChR clustering [66]. In zebrafish, the Wnt11r ligand, expressed by tissues adjacent to the newly formed muscle fibers, interacts with the ligand-binding domain of MuSK to induce the prepatterning of AChR clusters and the guidance of motor axons [46] (Fig. 2a). Accordingly, mutant fish for Wnt11r or MuSK display similar severe defects in AChR prepatterning and axonal branching [46, 67]. Consistent with these findings, the mouse muscle-derived ligand Wnt4 binds to and phosphorylates MuSK [68]. Wnt4 null mice have less AChR than control littermates just before inervation, whereas cultured muscle cells exposed to Wnt4 display increased AChR clustering [68]. Similarly, the mouse-derived ligands Wnt9a and Wnt11 induce AChR clustering in cultured myotubes through a mechanism dependent on MuSK and.
(5) 578. Mol Neurobiol (2014) 49:574–589. Fig. 2 Wnt signaling in the vertebrate neuromuscular synaptogenesis. a Wnts induce aneural AChR clustering. Several muscle-derived Wnt ligands activate MuSK-dependent AChR clustering in cultured myotubes. In zebrafish, Wnt11r and Wnt4a induce the internalization of MuSK to endosomes located in the middle region of the myofiber. MuSK assemble a complex with the scaffolding proteins diversin, Daam1 and RhoA to position aneural AChR clusters in a central muscle band (gray stripe), which will guide the incoming motor axons for subsequent NMJ assembly. b. Wnts are positive signals for postsynaptic differentiation. Wnt3 and agrin released from the presynaptic terminal collaborate to promote the formation of AChR clusters. Wnt3 induces the formation of AChR microclusters via Rac1, which are aggregated into fullsize clusters by the Rhodependent effect of agrin. c Wnt/ β-catenin pathways inhibit AChR clustering but promote presynaptic behavior. Wnt3a, secreted by muscle cells at the stages of NMJ formation, activates a β-catenin pathway that induces the dispersal of AChR clusters through the inhibition of rapsyn expression. Specific ablation or stabilization of βcatenin in muscles, but not in motor neurons, result in presynaptic defects, suggesting that muscle β-catenin induces the expression of a still unknown retrograde signal for presynaptic differentiation. Lrp4 [69]. Remarkably, recent findings obtained in zebrafish show that Wnt11r and Wnt4a induce a localized endocytosis of MuSK to recycling endosomes which, in turn, accumulates AChRs at the sites where motor axons will be guided to assemble functional NMJs [70] (Fig. 2a). Together, these. findings reveal a novel key MuSK-dependent mechanism by which Wnt ligands induce the aneural clustering of AChRs on newly formed muscle cells. Wnt ligands can also regulate neuromuscular synaptogenesis [12, 71, 72]. On the one hand, transplantation of chick wings.
(6) Mol Neurobiol (2014) 49:574–589. with cells secreting the Wnt3 ligand, which is expressed by motor neurons at the time of NMJ formation [73], led to increased AChRs clustering [65]. In cultured myotubes, Wnt3 activates the small GTPase Rac1 to induce the formation of AChR microclusters, which only coalesce into bigger clusters after agrin-dependent activation of Rho [65] (Fig. 2b). These findings reveal a potential neural-dependent cross-talk of Wntand agrin-mediated pathways to induce postsynaptic differentiation at the vertebrate NMJ. On the other hand, the highly identical ligand Wnt3a impairs agrin-induced AChR clustering and disassemble preformed aggregates [74, 75]. Wnt3a is expressed by developing skeletal muscles and mediates its dispersal activity by down-regulating rapsyn expression via a β-catenin-dependent, but TCF-independent, pathway [75] (Fig. 2c). Even though these findings reveal an inhibitory effect for β-catenin on AChR clustering, the in vivo role of this crucial effector of the Wnt canonical pathway at the NMJ is rather complex. Thus, even though specific ablation of βcatenin in skeletal muscles, but not in motor neurons, gives rise to enlarged AChR clusters, this effect is primarily related to presynaptic defects in axonal branching and neurotransmission [74, 76]. In turn, specific stabilization of β-catenin in muscle but not in neuronal cells, resulted in excessive nerve branching and defasciculation, while NMJ formation or function were unaffected [77] (Fig. 2c). Taken together, these findings reveal that activation of different Wnt pathways control opposite but complementary roles on the assembly of postsynaptic densities at nascent neuromuscular synapses. Wnt Signaling on Presynaptic Differentiation Even though our current knowledge regarding the potential role of Wnt signaling on presynaptic differentiation of vertebrate motor neurons is virtually null, the function of diverse Wnt pathways on several steps of presynaptic behavior in central synapses, from the establishment of neuronal cell polarity to synaptogenesis, has been well documented. In primary cultures of hippocampal neurons, it has been described that Wnt5a actives axonal differentiation in a βcatenin-independent manner via the activation of the protein complex Par6-Par3-atypical protein kinase C (aPKC) [78, 79]. Wnt5a signaling is also involved in regulating polarity via aPKC activation in a Dvl-dependent manner; however, in Drosophila , aPKC mutants do not show failures in neuronal polarity [80]. Other studies indicate that gradients of Wnt1 and Wnt5a expressed in the dorsal spinal cord in an anterior– posterior direction attracts ascending somatosensory axons projecting from the spinal cord to the brain, while the same gradient repels descending corticospinal tracts in the opposite direction, from the brain to the spinal cord [81, 82]. In addition, the repulsive signal of Wnt/Ca+2 signaling has been reported in mutants for CaMKII; indeed, this mutation causes severe failures in axonal guidance given the lack of a repulsive. 579. Wnt mediated signal [83]. Together, these data support the participation of Wnt signaling in the axonal guidance with repulsive and attractive effects depending of the Wnt ligand (Table 1). However, the molecular mechanism of the effect and the interaction networks of Wnt signaling are still to be fully underscored. Regarding presynaptic differention, Wnt7a stimulates the maturation of neuronal connections and the presence of the Wnt antagonist sFRP-1 blocks the growth of axons in the cerebellum [84–86]. Similarly, in hippocampal neurons, Wnt7a stimulates the clustering of the presynaptic protein synaptophysin and increases the mEPSC frequency [87]. Altogether, these data expose the critical role of Wnt signaling on presynaptic assembly at the central nervous system, modulating several processes, which lead to the correct formation of synapses (Table 2). However, the advance in the central synapse is not proportional to our knowledge of the differentiation of the presynaptic component at the vertebrate NMJ.. Wnt Signaling in Muscle Fibrosis Fibrosis in Skeletal Muscle Fibrosis is characterized by the aberrant deposition of ECM components including fibronectin and collagen type I or III. This accumulation of ECM components leads to the tissue disorganization and to the loss of muscle activity and eventually to death [15, 88, 89]. Several organs are susceptible to fibrosis including lung, kidney, liver, and skeletal muscle; however, all fibrotic reactions share common underlying cellular and molecular mechanisms, including tissue degeneration, macrophage infiltration, inflammation, and proliferation of fibroblast-like cells [15, 89–93]. The loss of organ architecture and the activation of leukocytes and fibroblasts increase the production of several molecules, such as growth factors, proteolytic enzymes, angiogenic factors, and fibrogenic cytokines. Together, these molecules lead to the accumulation of ECM components [16, 94, 95]. Table 1 Effect of Wnt ligands in axonal guidance Type of signal. Wnt1 Wnt3 Wnt4 Wnt5 Wnt5a Wnt7b Wnt8b Wnt11r. References. Attractive. Repulsive. + + + +. +. + + +. + +. [81, 155] [49] [54] [56, 155] [83] [76] [61] [46].
(7) 580. Mol Neurobiol (2014) 49:574–589. Table 2 Effect of Wnt ligands in synaptogenesis Wnt Ligand. Effect in synaptogenesis. References. Wnt3a Wnt4 Wnt5a. Stimulates AChR clustering Stimulates AChR clustering Stimulates PSD95 clustering Stimulates LTP Decreases the number of presynaptic presynaptic terminals Stimulates synaptophysin clustering Stimulates mEPSC frequency Stimulates neuronal connection Stimulates AChR clustering. [65] [68] [30, 156, 157]. Wnt7a. Wnt11, 11r, 9a, 10b, 16. [84, 87]. [69]. Several models have been described to study the regenerative capacity of the skeletal muscle, almost all the models use acute injury induced by injection of a toxin or myofiber destruction. These studies have allowed the description of all stages of the regenerative process including the inflammatory response, which follows an ordered pattern [96–98]. Early after injury, the damaged area is infiltrated by inflammatory cells. In the mdx mice, the model animal for Duchenne's muscle dystrophy (DMD, see below), these inflammatory cells are critical to promote the survival and proliferation of myogenic precursor cells, promoting the repair of the skeletal muscle [16, 95, 99, 100]. The innate immune response is activated by the release to the extracellular space of several factors from the damaged fiber. These factors lead to the infiltration of the damage area by monocytes and neutrophils [99, 101]. The neutrophils play a key role in repair facilitating phagocytosis and the recruitment of monocytes by the release of cytokines [102]. Proinflammatory macrophages, observed experimentally in the context of muscle repair, are phenotypically similar to classically activated M1 macrophages and are usually found at early stages after muscle injury. These cells also release proinflammatory cytokines, such as interleukin-1 beta (IL-1β) and tumor necrosis factor alpha (TNF-α). In a chronic muscle damage, the M1 macrophages release several ECM remodelers like urokinase-type plasminogen activator (uPA), plasminogen activator inhibitor-1 (PAI-1), plasmin, matrix metalloproteinases and tissue inhibitors of metalloproteinases (TIMPs). The role of these molecules is to modulate the proliferation of myoblasts and to promote the excessive ECM production/accumulation and the replacement of muscle fiber with fibrotic tissue [103, 104]. After the activation of M1 macrophages, it has been described the activation of the M2c phenotype, so-called because of their role in deactivating M1 macrophages. These cells release antiinflammatory factors including the interleukin-10 (IL-10). The activity of these cells is important to regulate the end of the inflammatory response [105]. In skeletal muscle, fibrosis is commonly related with muscle dystrophies, a molecularly heterogeneous group of diseases,. characterized by skeletal muscle wasting, weakness, decrease in the fiber size, and muscle necrosis that compromises patient mobility, leading to death [106–108]. One of these diseases is the DMD [15, 91, 109]. The clinical manifestation of DMD includes an onset during childhood with progressive weakness and death in early adulthood [91, 108]. The DMD is caused by a failure in the gene coding for the cytoskeletal protein dystrophin, which is required for the proper interaction between the plasma membrane and the ECM. The absence of dystrophin leads to the loss of function in the normal muscle regeneration cycle, leading to an increase in the production of ECM components [107, 108, 110]. In normal conditions, the skeletal muscle have a great capacity to repair itself after injury; however, under chronic injury conditions such as DMD, the skeletal muscle progressively loses its capacity to regenerate, likely by the decrease in the number of satellite cells, the skeletal muscle stem cells, which are unable to repair the damaged tissue. As a consequence, the muscle tissue is progressively replaced by adipose and especially fibrotic tissue [4, 95, 111, 112]. Currently, no effective clinical treatment to combat or attenuate muscle fibrosis in DMD patients is available; however, recent studies using the mdx mouse have focused more attention on elucidating the cellular and molecular mechanisms underlying skeletal muscle fibrosis associated with dystrophin deficiency. These studies have tested several pharmacological agents that target muscle fibrosis and strongly suggest that combating fibrosis could ameliorate DMD progression and increase the success of new cell- and gene-based therapies [113, 114]. In fibrotic skeletal muscle, several pathways are turning on by different cells such as fibroblasts, macrophages and leukocytes. Despite the complex mixture of signaling implicated in the onset of skeletal muscle fibrosis until now two key molecules have been described as critical in the development of the disease: the TGF-β and the CTGF [15, 17, 110, 115–117]. TGF-β is a potent inducer of CTGF, and most models postulate that CTGF acts as a downstream mediator of TGF-β activity; by contrast, other studies support the independent action of each molecule [19, 118–121]. TGF-β Signaling in Fibrosis and its Possible Cross-Talk with the Wnt Signaling There are three TGF-β isoforms, TGF-β1, TGF-β2, and TGF-β3. The activation of these signaling relies on the binding of the ligand to a heterodimeric receptor complex which includes one TGF-β type I receptor molecule, termed activin linked kinase 5 (ALK5) [122–124]. In the canonical TGF-β signaling, ligand binding leads ALK5 to phosphorylate Smad2/3, which in turn, activates Smad4 and this protein complex translocates into the nucleus to activate transcription factors and lead to the expression of target genes including fibronectin, CTGF and PAI-1 (Fig. 3) [122, 123]..
(8) Mol Neurobiol (2014) 49:574–589. 581. has been studied, it is possible a therapeutic approach, as the inhibition of this signaling has been reported to decrease the development of fibrosis. The relationship between canonical Wnt and TGF-β pathways has been described in several fibrotic models, and the evidence suggests a collaboration of both pathways in the fibrotic disease; indeed, the inhibition of both pathways prevents the development of fibrosis (Fig. 5) [131, 132]. Recent studies in vivo have shown that activation of the canonical Wnt pathway is required for the action of TGF-β, since the presence of dickkopf 1 (DKK1) (a Wnt signaling inhibitor) decreases the activity of TGF-β in a model of muscle fibrosis (Table 3) [123]. In this regard, in studies using chondrocytes as models, it has been reported that the TGF-β signaling inhibits the expression of axin-2, and this leads to an increases in the levels of β-catenin. This could be a negative feedback for the TGF-β signaling through the inhibition of Smad3 protein [133]. These data suggest a direct relationship between the TGF-β and Wnt/ β-catenin pathways in the establishment of the fibrotic disease, and that the effects of TGF-β needs the activation of the canonical Wnt signaling in the progress of the disease. Cross-Talk Between Wnt Signaling and CTGF in a Model of Muscle Disease Fig. 3 TGF-β signaling. Active TGF-β binds to its receptor type I/II this leads to the activation, via phosphorylation of Smad2/3 pathways, which regulates the transcription of several target genes involved in several cellular functions like CTGF and ECM proteins. TGF-β can also activate other signaling in Smad-independent manner. The expression of TGF-β has been described in normal skeletal muscle, mdx models and patients with DMD. Also, it has been described an over-expression of these ligands after muscle injury [125]. In skeletal muscle cells, TGF-β acts as a strong myogenic inhibitor. It is also known that TGF-β can inhibit myoblast differentiation in vitro, affecting the expression of muscle proteins, such as myosin heavy chain and creatine kinase [126, 127]. The profibrotic effect of TGF-β could be explained by the stimulation of fibroblasts to produce ECM proteins such as collagen and fibronectin. Furthermore, it has been described that the activation of TGF-β signaling leads to a decrease in the expression of metalloprotease like collagenase and to an increase in the expression of TIMPs. Together these effects could lead to the accumulation of ECM [121, 123, 124, 128, 129]. In fact, the injection of TGF-β in vivo in skeletal muscle stimulates the production of ECM in the injected area and the overexpression of TGF-β in myoblasts promotes the formation of myofibroblast cells, suggesting a critical role of the TGF-β in the onset of the fibrotic condition in the skeletal muscle [110, 130]. Since the critical role of these pathways. CTGF is a cysteine rich 36–38 kDa secreted protein, which belongs to CCN family (acronym for connective tissue growth factor, cysteine-rich-protein, and nephroblastoma-overexpressed). CTGF is expressed in various cell types including fibroblasts, chondrocytes, and leukocytes and is poorly expressed in the central nervous system [18, 134, 135]. The CTGF gene contains five exons. Exon 1 encodes a signal peptide (SP) for secretion, while exons 2–5 encode for modules 1–4 of the secreted CTGF protein which are homologous to other proteins including insulin-like growth factor binding protein (IGFBP) domain (module 1), a von Willebrand factor type C (VWC) domain (module 2), a thrombospondin type 1 (TSP1) domain (module 3), and a C-terminal (CT) module (Fig. 4) [134–136]. The modular structure of CTGF allows the interaction of CTGF with multiple molecules suggesting a role in several signaling downstream, including Notch1, LRPs, and growth factors such as BMP, TGF-β, and vascular endothelial growth factor. The interaction of CTGF and the receptors described previously allows the activation of several pathways downstream including PKC, MEK/ERK, and protein kinase B (PKB) [19, 137–140]. In physiological conditions, CTGF is involved in angiogenesis and cellular differentiation, but in pathological conditions, it has been described as a profibrotic molecule, stimulating the proliferation of fibroblasts, their differentiation towards myofibroblasts and ECM production [110, 115, 121, 134, 141]. In fact, in vivo studies have showed that the CTGF.
(9) 582. Mol Neurobiol (2014) 49:574–589. Table 3 Effect of different signaling components on fibrosis. Effect over fibrosis Decrease. Tissue. References. Liver/muscle/kidney/lung Liver/muscle/kidney/lung Muscle/kidney Muscle. [18, 125, 129] [19, 134] [17, 142, 143] [14, 147]. Kidney/liver Mammary epithelial cells Heart Chondrocytes. [158, 159] [160] [161] [144]. Dermal fibrosis Dermal fibrosis. [162] [163]. Increase. Treatment or drug TGF-β CTGF TGF-β+ CTGF Wnt3a Classical Wnt/β-catenin inhibitors DKK1 + sFRP1 + sFRP2 + Wif-1 + GSK-3β inhibitors PKF118-310 XAV-939. + + ++ ++. + +. injection stimulates the fibrosis and the coinjection of CTGF and TGF-β resulted in a persistent fibrosis [142, 143]. Together, this has led to the notion that CTGF plays an important role in tissue response to injury and fibrosis (Fig. 5). In chondrocytes, CTGF binds the Wnt inhibitory factor 1 (WIF-1), an antagonist of the Wnt pathway, through the CT domain of CTGF. It has been also described a direct relationship in the expression patterns of CTGF and WIF-1, and the presence of WIF-1 inhibits the expression of CTGF; however, CTGF is unable of interfering with the effect of WIF-1 on the canonical Wnt signaling [144]. Furthermore, it has been described that CTGF can also interact with the CT domain of LRP6, so CTGF is also able to affect the interaction of Wnt with their coreceptor [145, 146]. Other studies in human mesangial cells have been described suggesting that CTGF stimulates the canonical Wnt pathway in an LRP6-dependent manner, and this effect is inhibited in the presence of DKK1 (Table 3) [145]. Remarkably, studies in a fibroblast cell line show that the treatment with the Wnt3a ligand, which signals through the Wnt/β-catenin pathway, increases the expression of CTGF and TGF-β mRNAs, reinforcing the view that these signaling pathways may crosstalk in the context of fibrosis [147].. Fig. 4 CTGF signaling. The CTGF protein contains a signal peptide (SP) as well as four modules: IGFBP, VWC, TSP1, and CT. Through these domains CTGF can interact with several molecules including BMP, TGFβ, and possibly some Wnt ligands. CTGF interacts with several membrane proteins, including LRP proteins, integrins, TrkA, BMP, and Notch 1; these interactions trigger various pathways downstream including PKC, MEK, p38, and PKB JNK, and the activation of these signaling lead to several effects like proliferation, fibroblast differentiation, and production of ECM components, leading to the onset of fibrotic condition. Proposed Model for the Interaction Between Wnt/β-catenin, CTGF, and TGF-β Signaling in the Development of Skeletal Muscle Fibrosis The data presented above support an important role for the Wnt/β-catenin signaling pathway during the onset and development of the fibrotic condition in skeletal muscle. The effect of the Wnt pathway could be explained at least in part by the relationship between this signaling cascade with the signaling mediated by TGF-β and CTGF [17, 128, 144]. In addition,.
(10) Mol Neurobiol (2014) 49:574–589. 583. Fig. 5 Cross-talk between Wnt and TGF-β signaling. In fibrotic condition, the levels of TGF-β are increased, and this promotes the stimulation of the target genes of this pathway, like CTGF and ECM components such as type I collagen; this promote the accumulation of connective tissue in the extracellular space, the transcription effect of the TGF−β signaling, leading a down-regulation of axin-2 a protein part of the. complex destruction of β-catenin, and the activation of TGF-β leads to an increase in cytoplasmic β-catenin and an activation of canonical Wnt signaling and an increase in their target genes including fibronectin, leading to a major accumulation of ECM components promoting the development of muscle fibrosis. Wnt signaling could modulate early processes related to the regeneration of skeletal muscles after injury, and, in this way, it could trigger a deregulation of the regenerative capacity of the muscle, promoting the onset of fibrosis [14, 148]. Therefore, the activation of the Wnt/β-catenin signaling could stimulate the formation and activation of fibroblasts into myofibroblast derived from the satellite cells activated by injury. The activated fibroblasts could increase the expression and release of TGF-β to the environment. In turn, this ligand, in a autocrine form, could increase the expression of CTGF and together these ligands could activate downstream signaling leading to the over-expression of ECM components like fibronectin [149–152]. Furthermore, the activation of Wnt/β-catenin could itself stimulate the expression of fibronectin, and also there are. some reports suggesting that the CTGF could be a possible target gene of the canonical Wnt signaling [153]. Therefore, the Wnt/β-catenin signaling pathway could have a key role in triggering the activation of TGF-β and CTGF in activated fibroblasts and maybe in other cells of the fibrotic environment. The presence of several Wnt/β-catenin inhibitors, such as DKK1 and Sfrp1 and 2 inhibit the signaling of TGF-β and CTGF, leading to an inhibition of the fibrosis (Table 3 and Fig. 6). This new role of the Wnt/β-catenin signaling as a profibrotic factor makes this signaling pathway an interesting candidate for therapeutic interventions. In fact, there is evidence describing that inhibition of the Wnt/β-catenin pathway decreases the progression of the fibrosis [154]. Certainly, further studies are.
(11) 584. Mol Neurobiol (2014) 49:574–589. Fig. 6 Proposed model for the role of Wnt signaling in Fibrosis. After acute muscle injury, the damage area is infiltrated by macrophages and neutrophils; these cells release several cytokines and lead to the activation of the inflammation process. In normal postinjury muscle regeneration, these inflammation is acute and important for the correct replacement of the muscle fiber. In a second step, the satellite cells are activated and star the differentiation/proliferation to myoblast, and finally, these cells star the fusion process to form a new muscle fiber; in these normal cycle of regeneration has been described a low expression of Wnt ligands and a low activity of the Wnt/β-catenin pathway. By contrast, in a chronic muscle injury like DMD, the inflammation process is deregulated, and these lead to the deregulation of the regeneration processes stimulating. the differentiation of the fibroblast into myofibroblast. The activated myofibroblast cells increase the production of ECM components like fibronectin and collagen and also release profibrotic molecules like CTGF and TGF-β. In these chronic damage condition has been described an increase in the expression of Wnt ligands, and these lead to the activation of the Wnt/β-catenin pathway in the myofibroblast increasing the production of the ECM components and the release of profibrotic molecules; together, this lead to aberrant regeneration. Several inhibitors of Wnt/βcatenin signaling like DKK1 and Wif-1 block the TGF-β and CTGF profibrotic effect, suggesting the central role of the Wnt signaling in the progress of fibrosis. necessary to better define the effect of Wnt signaling inhibition on skeletal muscle fibrosis.. formation of the motoneuron-muscle synapse. In myogenesis, the effect of Wnt signaling leads to the progression of the differentation at early developmental stages and inhibition of this signaling leads to a poor skeletal muscle formation. In the maturation of the NMJ, the Wnt signaling modulates the localization of several proteins critical for the patterning of the synapse and for the precise control of the muscle contraction. In muscle fibrosis, apparently the Wnt signaling plays a critical. General Conclusions The Wnt signaling pathway plays a critical role in several processes including the development of muscle tissue and the.
(12) Mol Neurobiol (2014) 49:574–589. role, as it is able to functionally interact with other profibrotic molecules, such as CTGF and TGF-β. Understanding these interactions could be critical in the discovery of future treatments for this pathological condition. Acknowledgments This work was supported by grants from the Basal Center of Excellence in Aging and Regeneration (CONICYT-PFB 12/ 2007) and FONDECYT (no. 1120156 to N.C.I. and no. 1130321 to J.P.H.). PC was a postdoctoral fellow from the PFB (12/2007) grant to NCI and EB. Graphic work was carried out by Graphique-Science (http:// graphique-science.blogspot.com). Conflicts of Interest There is no conflict of interest.. References 1. Burden SJ (1998) The formation of neuromuscular synapses. Genes Dev 12(2):133–148 2. Fallon JR, Gelfman CE (1989) Agrin-related molecules are concentrated at acetylcholine receptor clusters in normal and aneural developing muscle. J Cell Biol 108(4):1527–1535 3. 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