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Collagen VI

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Last Updated: 02 July 2021

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General | Latest Info

Collagen VI-relate Myopathy is a group of disorders that affect skeletal muscles and connective tissue. Most affected individuals have muscle weakness and joint deformities called contractures that restrict movement of affected joints and worsen over time. Researchers have described several forms of Collagen VI-relate Myopathy, which range in severity: Bethlem Myopathy is mildest, intermediate form is moderate in severity, and Ullrich congenital muscular dystrophy is most severe. People with Bethlem Myopathy usually have loose joints and weak muscle tone in infancy, but they develop contractures during childhood, typically in their fingers, wrists, elbows, and ankles. Muscle weakness can begin at any age but often appears in childhood to early adulthood. Muscle weakness is slowly progressive, with about two-thirds of affected individuals over age 50 needing walking assistance. Older individuals may develop weakness in respiratory muscles, which can cause breathing problems. Some people with this mild form of Collagen VI-relate Myopathy have skin abnormalities, including small bumps called follicular hyperkeratosis on arms and legs; soft, velvety skin on the palms of hands and soles of feet; and abnormal wound healing that creates shallow scars. The intermediate form of Collagen VI-relate Myopathy is characterized by muscle weakness that begins in infancy. Affected children are able to walk, although walking becomes increasingly difficult starting in early adulthood. They develop contractures in ankles, elbows, knees, and spine in childhood. In some affected people, respiratory muscles weaken, requiring people to use machines to help them breathe, particularly during sleep. People with Ullrich congenital muscular dystrophy have severe muscle weakness beginning soon after birth. Some affected individuals are never able to walk and others can walk only with support. Those who can walk often lose ability, usually in adolescence. Individuals with Ullrich congenital muscular dystrophy develop contractures in their neck, hips, and knees, which further impair movement. There may be joint laxity in fingers, wrists, toes, ankles, and other joints. Some affected individuals need continuous mechanical ventilation to help them breathe. As in Bethlem Myopathy, some people with Ullrich congenital muscular dystrophy have follicular hyperkeratosis; soft, velvety skin on palms and soles; and abnormal wound healing. Individuals with Collagen VI-relate Myopathy often have signs and symptoms of multiple forms of this condition, so it can be difficult to assign a specific diagnosis. Overlap in disease features, in addition to their common cause, is why these once separate conditions are now considered part of the same disease spectrum. Mutations in COL6A1, COL6A2, and COL6A3 genes can cause various forms of Collagen VI-relate Myopathy. These genes each provide instructions for making one component of a protein called type VI Collagen. Type VI Collagen makes up part of the extracellular matrix that surrounds muscle cells and connective tissue. This matrix is an intricate lattice that forms in space between cells and provides structural support. Extracellular matrixs are necessary for cell stability and growth.

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Function

Colvi is one of the major components of muscle ECM and, thus, is involved in building the basement membrane of myofiber endomysium. Interstitial fibroblasts are the major cell type responsible for its deposition, whereas myogenic cells, which contain factors that can influence ColVI secretion, do not express it. The crucial role of ColVI in skeletal muscle is emphasized by the fact that mutations in genes encoding ColVI chains have a causative role in several forms of inherited human muscle diseases, including Bethlem myopathy, Ullrich congenital muscular dystrophy and myosclerosis myopathy. Interestingly, complete ablation of ColVI in COL6A1 / mice leads to an early-onset myopathic phenotype that is characterized by structural and functional defects of diaphragm and other skeletal muscles. Initial studies in COL6A1 / mice have also revealed cytoprotective role for ColVI, as ablation of gene triggers spontaneous apoptosis in muscle fibers that is associated with latent mitochondrial dysfunction and organelle alterations. More recent studies have demonstrated that the occurrence of dysfunctional organelles in COL6A1 / muscle is due to defects in regulation of autophagic pathway. Lack of ColVI causes impaired regulation of autophagic flux, defect that is accompanied by lower levels of Beclin 1 and BNIP3, which are key effectors in initiation of autophagy, and by persistent activation of Akt-mTOR pathway under fasting conditions. Notably, analysis of muscle biopsies of UCMD and Bethlem myopathy individuals revealed marked decrease in protein levels of Beclin 1 and BNIP3, thereby confirming a defect in autophagy regulation in the presence of mutated ColVI. Colvi has also been shown to be a key component of the niche of adult muscle stem cells and to be involved in proper regulation of muscle stiffness; this is in agreement with impaired self-renewal capabilities of satellite cells and defective muscle regeneration in COL6A1 / mice. Despite the dramatic impact of ColVI ablation on muscle fibers and on specific cell-survival pathways, such as apoptosis and autophagy, specific cell receptors accounting for these effects and thus mediating ColVI signals in muscle, remain unknown. Earlier in vitro studies identified several cell surface receptors that are capable of binding to ColVI-including 11 21 31 101 and v3 integrins, as well as chondroitin sulfate proteoglycan-4but it remains to elucidate how ColVI extracellular signals are transduce within muscle fibers.

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Expression in Various Tissues

Five genes coding FOR ColVI chains were identified in Zebrafish 25 27 30 31, one ortholog each FOR 1, 2 and 3 chains and two FOR 4 chain. Two orthologs coding FOR 4 chain are designated col6a4a and col6a4b and are located on chromosome 16 and 13, respectively. However, it has not been determined how col6a4a and col6a4b evolve. Therefore, we performed phylogenetic analysis based on PROTEIN PARSIMONY and PROTEIN DISTANCE Methods and confirmed earlier results 27 indicating that two Zebrafish 4 chains do not belong to the 5 / 6 chain branch. The question remains whether duplication of two 4 genes is the result of whole genome duplication 32 that occurs in teleost linage, or if these two genes were independently duplicate. Close inspection of gene loci revealed that col6a4a, but not col6a4b, is in synteny with the locus coding FOR 4 chain in other vertebrates. In amphibians, reptiles, birds and mammals, genes ldlrap1b and fndc5a that flank col6a4b on Zebrafish chromosome 13 lack neighboring gene coding FOR ColVI chain. Moreover, synteny of orthologue col6a4b genes with ldlrap1b or fndc5a is only present in cyprinids, also commonly called carp family, clearly indicating that these ColVI 4 chains are unique to this family. Genomes of other teleosts, like salmon, fugu or medaka, and that of spotted gar 33, which belong to infraclass of holostei, do not contain col6a4b gene. Consequently, in carps, col6a4a and col6a4b are paralogue genes independently of teleost whole genome duplication. Interestingly, in Cyprinus carpio and Carassius auratus, col6a4b is further duplicate in tandem. The existence of an extra ColVI chain unique to carps may point to the specific function of this chain in this family of fish. To assess expression of ColVI genes during fish development, we perform qRT-PCR at different developmental stages from 12 hpf to 4 dpf. Colvi transcripts were first detected at 1 dpf and then they increased throughout development. Notably, COL6A1 and COL6A2 mRNA levels were most abundant at all developmental stages included in the analysis. Moreover, among transcripts encoding longer chains, levels of COL6A3 and col6a4b mRNAs gradually increased between 1 dpf and 3 dpf, whereas col6a4a mRNA was barely detectable before 3 dpf. To further investigate spatio-temporal expression of ColVI transcripts during development, we performed in situ hybridization in Zebrafish embryos and larvae from 1 dpf to 3 dpf, using digoxigenin-label antisense riboprobes FOR COL6A1, COL6A2 and COL6A3. Interestingly, at 1 dpf all three ColVI transcripts were restricted to the surface of myotome and pectoral fin buds. Of note, although ColVI is generally described as dermal Collagen, COL6A1 transcripts were clearly detected in cuboid epithelial cells of developing fish epidermis. Moreover, at 2 dpf, strong signals FOR ColVI transcripts were displayed by myosepta, pectoral fins, axial vasculature and gut.


Introduction

Ucmd was initially described in a series of papers in the 1930s by Otto Ullrich, who referred to the condition as atonic-sclerotic muscular dystrophy because of characteristic occurrence of weakness and striking joint hypermobility in conjunction with significant and evolving contractures. Ullrich's disease was maintained as a distinct diagnostic entity mainly in Japanese and European literature. After collagen VI mutations had been identified in BM, it was realised by Enrico Bertini and Mimma Pepe in 2001 in Italy that some of clinical features in UCMD were reminiscent of BM, that led to the first discovery of collagen VI mutations in this condition as well. Bm was initially reported in 1976 by Bethlem and van Wijngaarden in the Netherlands as autosomal dominant early-onset but relatively benign myopathy associated with development of characteristic contractures. Several others then reported similar cases, including reports of large French-Canadian kindred, authors of which then suggested the name Bethlem myopathy. A Linkage to collagen VI genes was first established in larger families in Holland and the USA, leading to identification of collagen VI mutations in these original families in 1996 and 1998. Genetic analysis in many patients with clinically convincing UCMD and BM has now clarified that the majority of patients with these phenotypes have underlying dominant or recessive mutations in three known collagen VI genes, COL6A1, COL6A2, and COL6A3. This has been true in particular for clinically more distinct phenotype of UCMD. There is, however, definite number of patients with convincing clinical features who have no detectable mutations in these three collagen VI genes, indicating that there is some degree of genetic heterogeneity underlying the otherwise fairly typical phenotype. This number may indeed be larger in sometimes less distinct clinical phenotype of Bethlem. Prevalence numbers are slowly emerging. In population followed by Muscle Centre in Newcastle upon Tyne, UK, prevalence of UCMD has been calculated as 0. 13 per 100 000 and that of BM as 0. 77 per 100 000. In other populations, it is now emerging that collagen VI-related muscle disorders are one of the most common entities subsumed under the category of congenital muscular dystrophy. Collagen type VI is microfibrillar collagen found in many extracellular matrices, including those of muscle, skin, tendon,ss and vessels. It is composed of three chains encoded by three independent genes on chromosomes 2 and 21. Mutations in these three genes have been found to underlie group of muscle disorders that are now referred to as collagen VI-related myopathies. Collagen VI-related myopathies encompass a spectrum of disorders ranging from more severe Ullrich congenital muscular dystrophy through phenotypes of transitional severity to milder Bethlem myopathy. An additional, mostly contractural, phenotype, referred to as myosclerosis, has also been delineated and associated with mutations in COL6A2.


5.16.2.7 Type VI Collagen

Type VI collagen, is highly unusual collagen consisting of collagenous and noncollagenous domains that assemble into beaded filaments. 7 35 Type VI collagen microfibrils have been located in the vascular subendothelium. 35-37 Type VI collagen microfibrils exhibit unique adhesive properties to other ECM components, such as other collagens, heparin, and VWF, and may be involved in adhesion of platelets and smooth muscle cells. In medial layer, Type VI collagen facilitates interaction between smooth muscle cells and elastin by bridging elastic fibers and cells. The 38 Type VI collagen molecule is a 400-kDa triple-helical molecule that contains globular domains of about 150 kDa each at both its NH 2 and COOH ends. Intact molecule has been difficult to isolate owing to its exquisite sensitivity to nonspecific proteases. Its molecular structure consists of heterotrimer of three different chains, 1, 2 and 3, encoded by unique genes. Several 2 and 3 chain variants, generated by alternate splicing of mRNAs, have also been document. 2 3 aggregates that Type VI collagen forms are relatively unusual; triple-helical monomeric units form dimers in antiparallel fashion. These staggered aggregates contain 75-nm overlap regions held together in supratwist by disulfide bonds. Tetramers are formed from dimers and held together by disulfide bonds in scissors-like regions. Types XV and XVIII collagens, identified as chondroitin sulfate and heparan sulfate proteoglycans, respectively, comprise unique subfamily of collagens. As shown in Figure 3-9, these two collagens have distinct structures, with central triple helical domains interrupted several times and noncollagenous fragments on their NH 2 and COOH termini. 39 Degradation of Type XV and Type XVIII collagens by various MMPs generates biologically active fragments capable of regulating motility, angiogenesis, and branching morphogenesis in vitro and in vivo.

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Associated Disorders

Defects in Collagen VI are associated with Ullrich congenital muscular dystrophy and Bethlem myopathy. Phenotypes associated with Ullrich congenital muscular dystrophy are typically more severe than phenotypes associated with Bethlem myopathy. Rare cases of Collagen VI related Myopathies with phenotypes of intermediate severity have been report. Whole genome sequencing reveals that these intermediate phenotypes most likely result from premature translation termination codon caused by variation in COL6A3 Gene, as well as amino acid substitution in the N2-terminal domain caused by nonsense-mediate decay. Biopsied muscle tissue samples in individuals with Ullrich congenital muscular dystrophy and Bethlem myopathy show significant decrease in protein levels of Beclin1 and VNIP3, demonstrating that mutated ColVI causes defect in regulation of autophagic pathways. There are few treatments that have been developed to treat Ullrich congenital muscular dystrophy or Bethlem myopathy at genetic level; primary methods of treating these disorders are surgery and physical therapy.

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Summary

Collagen VI comprises three peptide chains 1, 2, and 3. 1 and 2 chains are encoded by genes COL6A1 and COL6A2, respectively, which are situated head-to-tail on chromosome 21q22. 3 and separated by 150 kb of genomic DNA. Col6a3, Gene encoding 3 chain, is on chromosome 2q37. All three chains contain a central short triple helical domain of 335-336 amino acids with repeating Gly-Xaa-Yaa sequences flanked by large N-and C-terminal globular domains consisting of motifs of approximately 200 amino acids each homologous to von Willebrand factor type domains. For detailed summary of Gene and protein information, see Table, Gene. Give high number of variants that result in benign amino acid changes described for three genes encoding three collagen VI peptide chains, it is difficult to be sure about the pathogenicity of missense variants other than glycine substitutions within the triple helical domain. Normal Gene product. Extracellular matrix molecules are critical for skeletal muscle stability, regeneration, and muscle cell matrix adhesion. Collagen VI is an ubiquitous extracellular matrix protein that forms a microfibrillar network in close association with basement membrane around muscle cells and interacts with several other matrix constituents. Assembly of collagen VI is a complex multistep process. Association of three genetically distinct subunits 1, 2, and 3 to form triple helical monomer is followed by staggered assembly into disulfide-bond antiparallel dimers, which then align to form tetramers, also stabilized by disulfide bonds. Outside of the cell, tetramers, secrete form of collagen VI, associated end to end to form characteristic bead microfibrils.


DIAGNOSIS, DIFFERENTIAL DIAGNOSIS, GENETIC COUNSELING, AND TREATMENT

Differential diagnosis of two major phenotypes observed in collagen VI-related disorders is discussed below. Of note, normal to mildly elevated CK, suggestive findings on muscle MRI, and lack of cardiac phenotype generally distinguish collagen type VI-related disorders from these other disorders. Bethlem myopathy. When contractures are subtle or miss, major differential diagnoses are limb-girdle muscular dystrophies. When contractures are a prominent feature, major differential diagnoses are X-link or autosomal dominant Emery-Dreifuss muscular dystrophy, both of which are associated with serious cardiac complications. Immunohistochemical testing performed on muscle biopsy and / or molecular genetic testing can help to establish diagnosis of some LGMD subtypes such as sarcoglycanopathy, calpainopathy, and dysferlinopathy as well as X-link or autosomal dominant Emery-Dreifuss muscular dystrophy. Ullrich congenital muscular dystrophy. In neonatal period, differential diagnosis includes the following:

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Ullrich Congenital Muscular Dystrophy

Ucmd, on other hand, is classically described as autosomal recessive condition. It is a clinically and genetically distinct entity within congenital muscular dystrophies. 30 UCMD was first described by Ullrich in 1930 31 32 and subsequent publications confirm likely autosomal recessive inheritance and recognisable pattern of disease. 33-42 hallmarks of UCMD are muscle weakness of early onset with proximal joint contractures and striking hyperelasticity of distal joints. Posteriorly protruding calcanei are commonly see. Weakness is profound and children typically either never achieve the ability to walk independently, or walk independently for short periods only. 43 44 Intelligence is normal. With progression of disease, there is typically development of spinal rigidity and scoliosis and Variable proximal contractures, while with time, distal hyperlaxity can give way to marked long finger flexion contractures and tight Achilles tendons. 45 Respiratory failure in the first or second decade is a common cause of death unless treated with nocturnal respiratory support, but cardiac involvement is not documented to date. 11 43 46 There is frequent failure to thrive. Other distinctive features observed in UCMD patients are congenital hip dislocations 42 43 and transient kyphotic deformity at birth as well as follicular hyperkeratosis over extensor surfaces of upper and lower limbs, soft velvety skin on palms and soles, and tendency to keloid or cigarette paper scar formation 30 45. Muscle MRI shows characteristic pattern with diffuse involvement of thigh muscles with relative sparing of sartorius, gracilis, adductor longus, and rectus. 47 as for BM, serum creatine kinase activity in UCMD patients is usually normal or mildly increased 42 43 and electromyography reveals action potentials of low amplitude and short duration. 42 Variable pathology, ranging from non-specific mild myopathic changes to more dystrophic-like changes, can be observed in muscle biopsies from UCMD Patients, spectrum including variation in fibre size, type 1 fibre predominance, increased endomysial connective tissue, increased numbers of internal nuclei, and focal areas of necrosis, along with more indirect evidence of Muscle fibre regeneration such as presence of fibres containing fetal myosin. 38 43 in neonatal period, differential diagnosis includes other forms of congenital muscular dystrophy, congenital myopathies, Spinal muscular atrophy, and forms of Ehlers-Danlos syndrome or Marfan syndrome. Other types of CMD do not generally present with distal hyperlaxity characteristic of UCMD and are usually associated with serum creatine kinase levels higher than those observed in UCMD. 30 48 Biochemical testing carried out on muscle biopsy, along with molecular genetic testing, can help to establish diagnosis of some CMD subtypes such as MDC1A or MDC1C. 30 48 in addition, brain MRI may show structural abnormalities or white matter changes in some CMD subtypes such as MDC1A, Walker-Warburg syndrome, Muscle-eye-brain disease, and Fukuyama CMD. 46 Spinal muscular atrophy can usually be diagnosed by demonstrating mutations in SMN gene 49 and muscle biopsy shows features of denervation rather than myopathic or dystrophic changes.

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Collagen VI and molecular pathogenesis

Collagens are major constituents of extracellular matrix, and are found in most connective tissues. They provide structural and mechanical stability to tissues, but they also play crucial roles in cell-ECM interactions through various receptors. In particular, Collagen Type VI, important component of skeletal muscle ECM, is involved in maintaining tissue integrity by providing structural link between different constituents of Connective-Tissue basement membranes and cells. In addition to its structural role, ColVI supports adhesion, spreading and migration of cells, and cell survival, as discussed later in this review. Colvi is a heterotrimeric molecule composed of three individual chains that display similar structure, with a triple helical domain characterized by repetition of Gly-XY amino acid sequence, flanked by globular domains homologous to von Willebrand factor domains. In addition to well-know 1 2 and 3 chains encoded in humans by COL6A1, COL6A2, and COL6A3 Genes, three novel chains, 4 5 and 6, have recently been identify. These chains have high structural homology to 3 chain. In humans, COL6A4, COL6A5 and COL6A6 genes are all located on chromosome 3q22. 1, with COL6A4 Gene being split by chromosome break and thus not coding for protein. Murine orthologs of these genes are organized in tandem on chromosome 9 and encode 4, 5 and 6 chains. The expression pattern of three novel chains differs between mice and humans, and also between fetal and adult tissues. Importantly, in the context of ColVI Myopathies, 6 chain is only one expressed at high levels in human skeletal muscle, at higher levels in fetal than adult tissue. In skin, detailed analysis of Expression of Human 5 and 6 chains reveals that both chains are express, albeit differently, and that they are variably altered in tissues from patients with mutations in COL6A1, COL6A2 and COL6A3 Genes. Interestingly, COL6A5 Gene had previously been reported as associated with atopic dermatitis under the name COL29A1, but this association has recently been question. Knee osteoarthritis susceptibility locus DVWA was shown to correspond to 5 parts of the split COL6A4 Gene. Although largely ubiquitous, expression of ColVI seems to be finely regulated in different cell types and tissues, as shown for murine COL6A1 Gene. Identification of transcriptional enhancer located in 5 -flanking sequence of Gene points to collaborative crosstalk between myogenic and mesenchymal / endomysial cells, enabling transcription of ColV in muscle Connective Tissue. 1, 2 and 3 chains assemble intracellularly as monomers, from their C-terminal ends, and subsequently form dimers and tetramers that are stabilized by disulfide bonds between cysteine residues of three chains. Colvi chains are subject to extensive post-translational modifications such as hydroxylation of lysine and proline residues, and glycosylation of hydroxylysines, which have been shown to be essential for tetramerization and further secretion of ColVI. Upon secretion, tetramers are further aligned end to end as microfibrils in extracellular space, with characteristic bead appearance.

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Collagen VI synthesis and interactions

Anchoring and adhesion complexes on the surface of cells link cytoskeleton to surrounding extracellular matrix, thus maintaining cell integrity and allowing signal transduction. These anchoring structures have a critical role in tissues undergoing extensive mechanical stress, like skeletal muscle; it comes as no coincidence that genetic defects of components of anchoring complexes cause human muscular dystrophies. Ecm is directly involved in molecular pathogenesis of various forms of Muscular Dystrophy, and there is accumulating evidence that ECM components, such as laminin-2 and collagen VI, play a critical role in maintaining muscle integrity and function. Colvi is the main ECM protein forming a distinct microfilamentous network with broad distribution in several organs, including skeletal muscle, skin, cornea, lung, blood vessels, intervertebral disks, and joints. It consists of three major chains, 1, 2, and 3, encoded by separate genes. 140-kd 1 and 2 chains are about 1000 amino acids long, while 3 chain is three times larger with several alternatively spliced variants ranging between 2500 and 3100 amino acids. Colvi is a multimodular protein made of several domains; each chain contains a short triple helical domain of 335-336 amino acids and two large amino-and carboxy-terminal globular ends composed of repeated domains of 200 amino acids each, sharing similarity with the von Willebrand factor type module. Three additional ColVI chains, 4, 5, and 6, were recently identify. These chains, cod by distinct genes, show high degree of similarity with 3, and their tissue distribution is more restricted, suggesting a specific role in assembly and / or function of ColVI. Colvi has complex pathway of intracellular assembly. The Association of-chains into triple helical monomers is followed by formation of dimers and tetramers, stabilized by disulfide bonds. After secretion into extracellular space, tetramers interact in an end-to-end fashion and form bead microfilaments with a typical 100-nm periodicity, which are deposited into ECM. Colvi microfilaments form extended networks particularly abundant in close periphery of several cell types, and they have been suggested to bridge the surface of cells with interstitial connective tissue. In skeletal muscle, ColVI is a major component of endomysium, where it is localized in the outer layer of the basement membrane. Different domains of ColVI are involved in a broad range of interactions with cell surface receptors and with other ECM components. The Triple helical region of ColVI is a major cell-binding domain, and it promotes adhesion through interaction with several integrins and with NG2 proteoglycan. Both the triple helical region and vWF-domains of ColVI bind various ECM proteins including fibrillar collagens, basal lamina collagen, decorin, biglycan, and fibronectin. These interactions and close association of beaded microfilaments with muscle basal lamina strongly suggest that ColVI provides an important mechanical link of muscle cells to surrounding ECM. Colvi is synthesize and secreted by cells organized ECM, such as fibroblasts and muscle cells.


Introduction

Interactions between cells and extracellular matrix play key roles in tissues undergoing extensive mechanical stress, such as skeletal muscles 1. The major component of ECM of skeletal muscles is collagen VI, protein composed of three genetically distinct chains and forming a discrete network of beaded microfilaments in the basement membrane of Muscle endomysium 2 3. Collagen VI deposition in skeletal muscles is mainly provided by interstitial muscular fibroblasts 4. Moreover, expression of collagen VI genes is regulated by myogenic cells, whose presence is prerequisite for inducing deposition of collagen VI by fibroblasts 5. The critical role of collagen VI in skeletal muscles is supported by the fact that mutations of COL6 genes in humans cause various muscle disorders, including Bethlem myopathy and Ullrich congenital muscular dystrophy 2 3. Collagen VI null mice display mild myopathic phenotype associated with mitochondrial dysfunction, defective autophagy and spontaneous apoptosis of Muscle fibers 6-8. Satellite cells are located between basal lamina and plasma membrane of muscle fibers 9, and this anatomic localization represents their niche. This niche is characterized by asymmetric distribution of muscle components, where SCs contact myofibers through apical surface whereas ECM lies on their basal surface 9 10. Myogenic commitment and differentiation of SCs is under control of key transcription factors, such as paired box protein 7 and myogenic regulatory factors MyoD and Myogenin 11-15. During Muscle regeneration, SCs undergo proliferation, generating both stem cell population by self-renewal and more differentiated cells that give rise to myoblasts that undergo terminal differentiation and fusion 16. A growing body of evidence indicates that niche serves as an instructive environment in which SCs respond to extrinsic stimuli associated with muscle growth and repair 17-23. Changes in ECM composition provide regulatory cues to SCs, thus influencing their quiescence, activation, differentiation, and / or self-renewal 24. On the other hand, ECM composition affects mechanical properties of the tissue microenvironment, which in turn influences activity of various stem cells, including SCs 25 26. Here we demonstrate that collagen VI is a critical component of the SC niche that is required for preserving SC self-renewal and muscle regeneration. In vitro and in vivo data indicate that one key mechanism through which collagen VI regulates SC activity is modulation of muscle stiffness. Grafting with wild-type fibroblasts elicits extensive deposition of collagen VI and rescues SC self-renewal and Muscle stiffness in COL6A1-/ mice. Our findings provide novel insights into the relevance of collagen VI for skeletal muscles and reveal an unforeseen role for this ECM molecule in regulation of SC homeostasis.

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Significance

Colvi structure, assembly and mutations are linked to human nervous system diseases. Schematic representation of ColVI chains and their protein domains. Diagram displaying ColVI assembly and secretion. Summary of mutations in COL6 genes that were described to be linked to human disorders affecting CNS and PNS. Bm, Bethlem myopathy; ER, endoplasmic reticulum; FN-III, fibronectin type III;, triple-helical domain; vWFA, von Willebrand factor type. Colvi is found along neural crest cell migratory pathways and regulates Schwann cell differentiation. During embryonic development, neural crest cells originate from neural tube closure site. After clustering at dorsal apex of neural tube, they soon migrate along two alternative paths: dorsolateral or ventral. Along the dorsolateral path, ColVI is detectable in close proximity to the neural tube basement membrane, in the subectodermal basement membrane and surrounding dermatome. Nccs entering this route give rise to melanocytes, once they colonize developing dermis. At developmental stages following gangliogenesis, ColVI is found all around developing dorsal root ganglia and in ventral sclerotome. Indeed, NCCs can stop at the ventrolateral site of developing DRG or continue in more ventral direction towards sclerotome, where they will give rise to sympathetic ganglia. Involvement of ColVI in Schwann cell differentiation is depicted in the enlarged circular inset. Immature Schwann cells acquire competence to express ColVI via axon-derive neuregulin signals, and soon after that, ColVI expression becomes NRG independent. Once SCs develop their mature myelinating phenotype, they cease to express COL6. Pathological aspects of the brain relate to ColVI alterations. In the brain, ECM is associated with meningeal and vessel basement membranes or forms perineuronal nets and neural interstitial matrix. Alterations in ColVI deposition associated with basement membrane were reported in amyloid angiopathy and chronic hypertension. Moreover, ColVI displays cytoprotective roles against neuronal cell death induced by stress and aging. Mutations in ColVI were recently linked to defective neuronal pathfinding and altered synaptic plasticity, leading to dystonia and epilepsy, respectively.

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Results

Finding that lack of ColVI causes autophagosome accumulation points to impairment of autophagy-lysosome machinery in COL6A1-/ fibroblasts, with defective off-rate of autophagic flux. Thus, we analyze lysosomes and their fusion with autophagosomes. Immunostaining with lysosomal marker LAMP-2 reveals high amounts of enlarged lysosomes in COL6A1-/ fibroblasts, whereas in WT cultures, lysosomes appear as smaller punctuate structures. Enlarge lysosomes were only detectable in WT fibroblasts after serum depletion or following CQ treatment. Moreover, increased number of enlarged lysosomes in COL6A1-/ fibroblasts appear to be independent of serum starvation. Interestingly, when compared to WT, COL6A1-/ fibroblasts also display decrease in LAMP-2 protein levels, which was not parallel by decrease in Lamp2 mRNA levels. We further analyze the final stages of fusion between autophagosomes and lysosomes, by performing co-immunostaining for LC3 and LAMP-2. In WT cultures, co-localization of autophagosomes with lysosomes was almost double upon serum depletion-induced autophagy, whereas in COL6A1-/ cultures, co-localization of LAMP-2 and LC3 was not affected by serum depletion, indicating defective autophagosome-lysosome fusion. Analysis of COL6A1 + /: GFP-LC3 and COL6A1-/: GFP-LC3 fibroblasts provide similar results. Proper cross-talk between autophagosomes and lysosomes is fundamental to ensure efficient completion of the autophagy process. Accumulation of autophagosomes and lysosomal abnormalities prompted us to investigate whether cellular clearance via lysosomes was affected in COL6A1-/ fibroblasts. One of the master regulators of lysosomal function and autophagy is TFEB. Extracellular signal-regulated kinase 2 and mTOR coordinate TFEB retention in cytosol, thus regulating its activity. Under nutrient depletion, TFEB rapidly shuttles to the nucleus and activates its translational program. Hence, we investigate TFEB cellular localization following transfection with GFP-TFEB construct. As expect, in WT fibroblasts serum depletion induces TFEB translocation from cytosol to nucleus, and indeed majority of cells show GFP-TFEB in nucleus after 3 H serum depletion. Conversely, in COL6A1-/ fibroblasts nutrient availability-dependent cellular localization of GFP-TFEB was strongly affect. Indeed, in complete medium, 59% of COL6A1-/ cells display GFP-TFEB already in the nucleus, whereas after 3 H serum depletion nuclear translocation of GFP-TFEB was markedly reduce, being present in 26% of cells Figures 3H, I.

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Discussion

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Introduction

Collagen VI is an unusual member of the collagen family and has been studied in the past few years within the context of a remarkably wide range of tissues. It is encoded by six different genes, and distinctive feature of this protein is its unique supramolecular assembly, which is driven by a multi-step process that leads to formation of characteristic bead microfilaments network in extracellular matrix. Colvi exerts different roles in tissues where it is express, spanning from mechanical roles, which are typical of collagen components of ECM, to more specific cytoprotective functions; these include inhibition of apoptosis and oxidative damage, promotion of tumor growth and progression, regulation of cell differentiation and of autophagic machinery, and maintenance of Cell stemness. Colvi-null mice, in which target inactivation of COL6A1 gene prevents assembly and secretion of the entire ColVI protein, have largely helped to unveil many of these roles in vivo, thereby shedding new light on the relevance of this matrix component, but also of ECM. In general, in regulating the number of key cellular pathways. Several human disorders have been linked to altered expression or mutations of genes encoding ColVI, emphasizing the importance of this protein for tissue homeostasis. In this Cell Science at Glance article and accompanying poster, we will summarize current knowledge of ColVI. We will first focus on the multi-step assembly process, before moving on to description of distribution and expression pattern. We will discuss in detail tissue-specific functions that have been revealed by studies in COL6A1 / mice and in related human disorders. We will close by highlighting how study of this collagen has stimulated research at intersections of different areas and fields of biomedical research.

* Please keep in mind that all text is machine-generated, we do not bear any responsibility, and you should always get advice from professionals before taking any actions.

* Please keep in mind that all text is machine-generated, we do not bear any responsibility, and you should always get advice from professionals before taking any actions

Sources

* Please keep in mind that all text is machine-generated, we do not bear any responsibility, and you should always get advice from professionals before taking any actions.

* Please keep in mind that all text is machine-generated, we do not bear any responsibility, and you should always get advice from professionals before taking any actions

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