Collagen VI

Collagen VI (ColVI) is a type of collagen primarily associated with the extracellular matrix of skeletal muscle. ColVI maintains regularity in muscle function and stabilizes the cell membrane. It is synthesized by a complex, multistep pathway that leads to the formation of a unique network of linked microfilaments located in the extracellular matrix (ECM). ColVI plays a vital role in numerous cell types, including chondrocytes, neurons, myocytes, fibroblasts, and cardiomyocytes. ColVI molecules are made up of three alpha chains: α1(VI), α2(VI), and α3(VI). It is encoded by 6 genes: COL6A1, COL6A2, COL6A3, COL6A4, COL6A5, and COL6A6.Collagen VI at a glance

Matilde Cescon, Francesca Gattazzo, Peiwen Chen, Paolo Bonaldo

J Cell Sci 2015 128: 3525-3531; doi: 10.1242/jcs.169748 The chain lengths of α1(VI) and α2(VI) are about 1,000 amino acids. The chain length of α3(VI) is roughly a third larger than those of α1(VI) and α2(VI), and it consists of several spliced variants within the range of 2,500 to 3,100 amino acids.

The first two alpha chains subunits of ColVI have a molecular weight of 140-150 KDa and the third polypeptide chain is larger with a molecular weight of 250-300kDa. ColVI is also found in the skin, lungs, blood vessels, cornea and intervertebral disc. It also forms part of the peripheral nerves, brain, myocardium and adipose tissue.

Function Collagen VI plays many different roles in the cell depending on which tissue in which it is expressed. ColVI maintains a mechanical function in the cell, which is typical of most types of Collagen, by providing stability and structural support in the ECM. ColVI allows muscle cells to connect with the ECM by interacting with perlecan in the basal lamina.Kuo, H.-J., Maslen, C. L., Keene, D. R. and Glanville, R. W. (1997). Type VI collagen anchors endothelial basement membranes by interacting with type IV collagen. J. Biol. Chem. 272, 26522-26529. doi:10.1074/jbc.272.42.26522 ColVI also functions as a cytoprotective agent:

ColVI plays an important role in cancer by acting as a chemotherapy resistance modulator. ColVI inhibits oxidative damage and apoptosis. ColVI regulates cell differentiation and autophagic machinery. With the assistance of other collagens, proteoglycans, matrilineal, fibronectins, and glycoproteins, ColVI anchors the basement membrane of the skin to the extracellular matrix.

Expression in various tissues

Muscle tissue ColVI is one of the primary components of muscle extra cellular matrix. It has been shown to play an integral role in building the basement membrane of myofiber endomysium.Bönnemann, C. G. (2011). The collagen VI-related myopathies: muscle meets its matrix. Nat. Rev. Neurol. 7, 379-390. doi:10.1038/nrneurol.2011.81 The crucial role of ColVI in skeletal muscle can be seen by the fact that mutations in the genes responsible for encoding ColVI cause diseases affecting the function of skeletal muscle, including Ullrich congenital muscular dystrophy and Bethlem myopathy.Jöbsis, G. J., Keizers, H., Vreijling, J. P., de Visser, M., Speer, M. C., Wolterman, R. A., Baas, F. and Bolhuis, P. A. (1996). Type VI collagen mutations in Bethlem myopathy, an autosomal dominant myopathy with contractures. Nat. Genet. 14, 113-115. doi:10.1038/ng0996-113Camacho Vanegas, O., Bertini, E., Zhang, R.-Z., Petrini, S., Minosse, C., Sabatelli, P., Giusti, B., Chu, M.-L. and Pepe, G. (2001). Ullrich scleroatonic muscular dystrophy is caused by recessive mutations in collagen type VI. Proc. Natl. Acad. Sci. USA 98, 7516-7521. doi:10.1073/pnas.121027598Merlini, L., Martoni, E., Grumati, P., Sabatelli, P., Squarzoni, S., Urciuolo, A., Ferlini, A., Gualandi, F. and Bonaldo, P. (2008). Autosomal recessive myosclerosis myopathy is a collagen VI disorder. Neurology 71, 1245-1253. doi:10.1212/01.wnl.0000327611.01687.5e Absence of ColVI in muscle cells results in muscle cell dysfunction due to defects in the regulation of the autophagic pathway.Grumati, P., Coletto, L., Sabatelli, P., Cescon, M., Angelin, A., Bertaggia, E., Blaauw, B., Urciuolo, A., Tiepolo, T., Merlini, L., et al. (2010). Autophagy is defective in collagen VI muscular dystrophies, and its reactivation rescues myofiber degeneration. Nat. Med. 16, 1313-1320. doi:10.1038/nm.2247 ColVI is also a key component of muscle cell generation, and has been shown to have the ability to regenerate itself.Urciuolo, A., Quarta, M., Morbidoni, V., Gattazzo, F., Molon, S., Grumati, P., Montemurro, F., Tedesco, F. S., Blaauw, B., Cossu, G. et al. (2013). Collagen VI regulates satellite cell self-renewal and muscle regeneration. Nat. Commun. 4, 1964. doi:10.1038/ncomms2964

Nervous tissue ColVI is expressed in both the central nervous system and peripheral nervous system.

Central nervous system The presence of ColVI in the brain was originally discovered in meningeal cells.Sievers, J., Pehlemann, F. W., Gude, S. and Berry, M. (1994). Meningeal cells organize the superficial glia limitans of the cerebellum and produce components of both the interstitial matrix and the basement membrane. J. Neurocytol. 23, 135-149. doi:10.1007/BF01183867 ColVI has also been linked to the development of Alzheimer's disease.Cheng, J. S., Dubal, D. B., Kim, D. H., Legleiter, J., Cheng, I. H., Yu, G.-Q., Tesseur, I., Wyss-Coray, T., Bonaldo, P. and Mucke, L. (2009). Collagen VI protects neurons against Aβ toxicity. Nat. Neurosci. 12, 119-121. doi:10.1038/nn.2240 When treated with AB-peptides, mice without the COL6A1 gene were observed to have an increase in apoptosis compared to wild type mice, suggesting that ColVI plays a neuroprotective role against AB-peptide toxicity. Further, ColVI has been suggested to play an anti-apoptotic role in other parts of the nervous system, as seen in studies analyzing the effects of UV-induced apoptosis.Cheng, I. H., Lin, Y.-C., Hwang, E., Huang, H.-T., Chang, W.-H. Liu, Y.-L. and Chao, C.-Y. (2011). Collagen VI protects against neuronal apoptosis elicited by ultraviolet irradiation via an Akt/phosphatidylinositol 3-kinase signaling pathway. Neuroscience 183, 178-188. doi:10.1016/j.neuroscience.2011.03.057

Peripheral nervous system ColVI is expressed by Schwann cells in the peripheral nervous system.Braghetta, P., Fabbro, C., Piccolo, S., Marvulli, D., Bonaldo, P., Volpin, D. and Bressan, G. M. (1996). Distinct regions control transcriptional activation of the alpha1(VI) collagen promoter in different tissues of transgenic mice. J. Cell Biol. 135, 1163-1177. doi:10.1083/jcb.135.4.1163 It is present in the connective tissue of the endoneurium, perineurium, and epineurium.Chen, P., Cescon, M., Megighian, A. and Bonaldo, P. (2014a). Collagen VI regulates peripheral nerve myelination and function. FASEB J. 28, 1145-1156. doi:10.1096/fj.13-239533 ColVI has been shown to be expressed by immature Schwann cells when they begin to differentiate into myelinating cells, suggesting that ColVI plays an integral role in regulating Schwann cell differentiation.Vitale, P., Braghetta, P., Volpin, D., Bonaldo, P. and Bressan, G. M. (2001). Mechanisms of transcriptional activation of the col6a1 gene during Schwann cell differentiation. Mech. Dev. 102, 145-156. doi:10.1016/S0925-4773(01)00303-3 ColVI also plays a key role in the peripheral nervous system myelination and maintains proper functioning of the sciatic nerve.

Adipose tissue ColVI also plays a key role in the extracellular matrix of white adipose tissue.Divoux, A. and Clément, K. (2011). Architecture and the extracellular matrix: the still unappreciated components of the adipose tissue. Obes. Rev. 12, e494-e503. doi:10.1111/j.1467-789X.2010.00811.x Lack of ColVI in the extracellular matrix of white adipose tissue leads to molecular characteristic notably seen in obese individuals.Khan, T., Muise, E. S., Iyengar, P., Wang, Z. V., Chandalia, M., Abate, N., Zhang, B. B., Bonaldo, P., Chua, S. and Scherer, P. E. (2009). Metabolic dysregulation and adipose tissue fibrosis: role of collagen VI. Mol. Cell Biol. 29, 1575-1591. doi:10.1128/MCB.01300-08 Endotrophin, a peptide generated by ColVI in white adipose tissue, has been shown to promote the growth of breast cancer cells.Park, J. and Scherer, P. E. (2012). Adipocyte-derived endotrophin promotes malignant tumor progression. J. Clin. Invest. 122, 4243-4256. doi:10.1172/JCI63930 Further, therapeutic transplantation of adipose-derived stem cells has been shown to secrete and assemble ColVI microfibrils.Alexeev, V., Arita, M., Donahue, A., Bonaldo, P., Chu, M.-L. and Igoucheva, O. (2014). Human adipose-derived stem cell transplantation as a potential therapy for collagen VI-related congenital muscular dystrophy. Stem Cell Res. Ther. 5, 21. doi:10.1186/scrt411

Role of Collagen VI in knee function

Studies have revealed that the mutation or deletion of genes encoding for collagen VI can result in numerous musculoskeletal disorders, e.g. hip osteoarthritis, tissue fibrosis, tissue ossification, and muscular dystrophies. The deletion of the COL6A1 gene in mice was used to determine the function of collagen VI in the bone and cartilage of knee joints. The absence of collagen VI impacted the structure and shape of the knee joint, but did not critically affect physicality of the cartilage.   

Associated disorders Defects in Collagen VI are associated with Ullrich congenital muscular dystrophy and Bethlem myopathy. In 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 reported.Marakhonov, A. V., Tabakov, V. Y., Zernov, N. V., Dadali, E. L., Sharkova, I. V., & Skoblov, M. Y. (2018). Two novel COL6A3 mutations disrupt extracellular matrix formation and lead to myopathy from Ullrich congenital muscular dystrophy and Bethlem myopathy spectrum. Gene, 672, 165-171. doi:10.1016/j.gene.2018.06.026 Whole genome sequencing reveals that these intermediate phenotypes most likely result from a premature translation termination codon caused by a variation in the COL6A3 gene, as well as an amino acid substitution in the N2-terminal domain caused by nonsense-mediated decay. Biopsied muscle tissue samples in individuals with Ullrich congenital muscular dystrophy and Bethlem myopathy showed a significant decrease in protein levels of Beclin1 and VNIP3, demonstrating that mutated ColVI causes defect in the regulation of autophagic pathways. In the absence of any proven therapeutic agents for treatment, a global registry is intended to facilitate matching people living with the conditions with potential clinical trials. At present the primary methods of treating these disorders are surgery and physical therapy.

Ullrich congenital muscular dystrophy Ullrich congenital muscular dystrophy (UCMD) is a condition that primarily affects the function of skeletal muscles. UCMD has been associated with mutations in the COL6A1, COL6A2, and COL6A3 gene.Collagen VI involvement in Ullrich syndrome

E. Mercuri, Y. Yuva, S. C. Brown, M. Brockington, M. Kinali, H.Jungbluth, L. Feng, C. A. Sewry, F. Muntoni

Neurology May 2002, 58 (9) 1354-1359; DOI:10.1212/WNL.58.9.1354 The most common pattern of inheritance for UCMD is autosomal recessive, although an autosomal dominant pattern of inheritance is observed in rare cases.

Symptoms

Severe weakness and atrophy of skeletal muscles Contractures in knees and elbows Hyper-mobility in wrists and ankles Rigid spine

Treatments The most common treatment for individuals affected by Ullrich congenital muscular dystrophy is physical therapy, with an emphasis on the mobilization and stabilization of affected joints. Surgical interventions may be needed to correct contractures or scoliosis.

Bethlem myopathy