Collagen VI

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Collagen VI (ColVI) is a type of collagen primarily associated with the extracellular matrix of skeletal muscle. [1] ColVI maintains regularity in muscle function and stabilizes the cell membrane. [2] 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. [3] ColVI molecules are made up of three alpha chains: α1(VI), α2(VI), and α3(VI). [4] It is encoded by 6 genes: COL6A1, COL6A2, COL6A3, COL6A4, COL6A5, and COL6A6. [3] 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. [5]

Contents

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. [5] 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. [5]

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. [6] ColVI also functions as a cytoprotective agent: [3]

  1. ColVI plays an important role in cancer by acting as a chemotherapy resistance modulator. [5]
  2. ColVI inhibits oxidative damage and apoptosis. [3]
  3. ColVI regulates cell differentiation and autophagic machinery. [3]
  4. With the assistance of other collagens, proteoglycans, matrilineal, fibronectins, and glycoproteins, ColVI anchors the basement membrane of the skin to the extracellular matrix. [7]

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. [8] 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. [9] [10] [11] Absence of ColVI in muscle cells results in muscle cell dysfunction due to defects in the regulation of the autophagic pathway. [12] ColVI is also a key component of muscle cell generation, and has been shown to have the ability to regenerate itself. [13]

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. [14] ColVI has also been linked to the development of Alzheimer's disease. [15] 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. [15] 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. [16]

Peripheral nervous system

ColVI is expressed by Schwann cells in the peripheral nervous system. [17] It is present in the connective tissue of the endoneurium, perineurium, and epineurium. [18] 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. [19] ColVI also plays a key role in the peripheral nervous system myelination and maintains proper functioning of the sciatic nerve. [18]

Adipose tissue

ColVI also plays a key role in the extracellular matrix of white adipose tissue. [20] Lack of ColVI in the extracellular matrix of white adipose tissue leads to molecular characteristic notably seen in obese individuals. [21] Endotrophin, a peptide generated by ColVI in white adipose tissue, has been shown to promote the growth of breast cancer cells. [22] Further, therapeutic transplantation of adipose-derived stem cells has been shown to secrete and assemble ColVI microfibrils. [23]

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. [24]    

Associated disorders

Defects in Collagen VI are associated with Ullrich congenital muscular dystrophy and Bethlem myopathy. [1] [25] [26] [27] 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. [28] 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. [28] 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. [13] In the absence of any proven therapeutic agents for treatment, [27] a global registry is intended to facilitate matching people living with the conditions with potential clinical trials. [29] At present the primary methods of treating these disorders are surgery and physical therapy. [30]

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. [31] The most common pattern of inheritance for UCMD is autosomal recessive, although an autosomal dominant pattern of inheritance is observed in rare cases. [31]

Symptoms

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

[31]

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. [30]

Bethlem myopathy

Bethlem myopathy is the mildest form of Collagen VI related myopathies. Related symptoms include ligamentous laxity, hypotonia in infancy, and difficulty breathing due to weakness in respiratory muscles. Bethlem myopathy affects approximately 1 in 200,000 people. [32]

Related Research Articles

<span class="mw-page-title-main">Extracellular matrix</span> Network of proteins and molecules outside cells that provides structural support for cells

In biology, the extracellular matrix (ECM), also called intercellular matrix (ICM), is a network consisting of extracellular macromolecules and minerals, such as collagen, enzymes, glycoproteins and hydroxyapatite that provide structural and biochemical support to surrounding cells. Because multicellularity evolved independently in different multicellular lineages, the composition of ECM varies between multicellular structures; however, cell adhesion, cell-to-cell communication and differentiation are common functions of the ECM.

<span class="mw-page-title-main">Muscle biopsy</span> Medical exam

In medicine, a muscle biopsy is a procedure in which a piece of muscle tissue is removed from an organism and examined microscopically. A muscle biopsy can lead to the discovery of problems with the nervous system, connective tissue, vascular system, or musculoskeletal system.

<span class="mw-page-title-main">Laminin</span> Protein in the extracellular matrix

Laminins are a family of glycoproteins of the extracellular matrix of all animals. They are major constituents of the basement membrane, namely the basal lamina. Laminins are vital to biological activity, influencing cell differentiation, migration, and adhesion.

<span class="mw-page-title-main">Congenital muscular dystrophy</span> Medical condition

Congenital muscular dystrophies are autosomal recessively-inherited muscle diseases. They are a group of heterogeneous disorders characterized by muscle weakness which is present at birth and the different changes on muscle biopsy that ranges from myopathic to overtly dystrophic due to the age at which the biopsy takes place.

<span class="mw-page-title-main">Decorin</span> Protein-coding gene in humans

Decorin is a protein that in humans is encoded by the DCN gene.

<span class="mw-page-title-main">Emery–Dreifuss muscular dystrophy</span> Medical condition

Emery–Dreifuss muscular dystrophy (EDMD) is a type of muscular dystrophy, a group of heritable diseases that cause progressive impairment of muscles. EDMD affects muscles used for movement, causing atrophy, weakness and contractures. It almost always affects the heart, causing abnormal rhythms, heart failure, or sudden cardiac death. It is rare, affecting 0.39 per 100,000 people. It is named after Alan Eglin H. Emery and Fritz E. Dreifuss.

<span class="mw-page-title-main">Bethlem myopathy</span> Medical condition

Bethlem myopathy is predominantly an autosomal dominant myopathy, classified as a congenital form of limb-girdle muscular dystrophy. There are two types of Bethlem myopathy, based on which type of collagen is affected.

<span class="mw-page-title-main">NIM811</span> Chemical compound

NIM811 is a mitochondrial permeability transition inhibitor. Also known as N-methyl-4-isoleucine cyclosporin, it is a substituted cyclosporine analog that binds to cyclophilin; however, this binary complex cannot bind to calcineurin, and therefore lacks immunosuppressive activity.

<span class="mw-page-title-main">Fukutin-related protein</span> Mammalian protein found in Homo sapiens

Fukutin-related protein (FKRP) is also known as FKRP_HUMAN, LGMD2I, MDC1C, MDDGA5, MDDGB5, and MDDGC5. FKRP can be located in the brain, cardiac muscle and skeletal muscle, and in cells it is found in the Golgi apparatus. Fukutin is expressed in the mammalian retina and is located in the Golgi complex of retinal neurons.

<span class="mw-page-title-main">Collagen, type VI, alpha 1</span> Protein found in humans

Collagen alpha-1(VI) chain is a protein that in humans is encoded by the COL6A1 gene.

<span class="mw-page-title-main">Laminin, beta 1</span> Protein-coding gene in the species Homo sapiens

Laminin subunit beta-1 is a protein that in humans is encoded by the LAMB1 gene.

<span class="mw-page-title-main">Laminin subunit alpha-2</span> Protein-coding gene in the species Homo sapiens

Laminin subunit alpha-2 is a protein that in humans is encoded by the LAMA2 gene.

<span class="mw-page-title-main">Collagen, type VI, alpha 2</span> Protein found in humans

Collagen alpha-2(VI) chain is a protein that in humans is encoded by the COL6A2 gene.

<span class="mw-page-title-main">Integrin alpha 7</span>

Alpha-7 integrin is a protein that in humans is encoded by the ITGA7 gene. Alpha-7 integrin is critical for modulating cell-matrix interactions. Alpha-7 integrin is highly expressed in cardiac muscle, skeletal muscle and smooth muscle cells, and localizes to Z-disc and costamere structures. Mutations in ITGA7 have been associated with congenital myopathies and noncompaction cardiomyopathy, and altered expression levels of alpha-7 integrin have been identified in various forms of muscular dystrophy.

<span class="mw-page-title-main">Collagen, type VI, alpha 3</span> Mammalian protein found in humans

Collagen alpha-3(VI) chain is a protein that in humans is encoded by the COL6A3 gene. This protein is an alpha chain of type VI collagen that aids in microfibril formation. As part of type VI collagen, this protein has been implicated in Bethlem myopathy, Ullrich congenital muscular dystrophy (UCMD), and other diseases related to muscle and connective tissue.

<span class="mw-page-title-main">Collagen, type XII, alpha 1</span> Protein found in humans

Collagen alpha-1(XII) chain is a protein that in humans is encoded by the COL12A1 gene.

<span class="mw-page-title-main">Muscle contracture</span> Permanent shortening of a muscle

Muscle contractures can occur for many reasons, such as paralysis, muscular atrophy, and forms of muscular dystrophy. Fundamentally, the muscle and its tendons shorten, resulting in reduced flexibility.

<span class="mw-page-title-main">Ullrich congenital muscular dystrophy</span> Medical condition

Ullrich congenital muscular dystrophy (UCMD) is a form of congenital muscular dystrophy. There are two forms: UCMD1 and UCMD2.

<span class="mw-page-title-main">Pseudohypertrophy</span> False enlargement of muscle due to infiltration of fat or other tissue

Pseudohypertrophy, or false enlargement, is an increase in the size of an organ due to infiltration of a tissue not normally found in that organ. It is commonly applied to enlargement of a muscle due to infiltration of fat or connective tissue, famously in Duchenne muscular dystrophy. This is in contrast with typical muscle hypertrophy, in which the muscle tissue itself increases in size. Because pseudohypertrophy is not a result of increased muscle tissue, the muscles look bigger but are actually atrophied and thus weaker. Pseudohypertrophy is typically the result of a disease, which can be a disease of muscle or a disease of the nerve supplying the muscle.

References

  1. 1 2 Merlini L, Angelin A, Tiepolo T, Braghetta P, Sabatelli P, Zamparelli A, Ferlini A, Maraldi NM, Bonaldo P, Bernardi P (April 2008). "Cyclosporin A corrects mitochondrial dysfunction and muscle apoptosis in patients with collagen VI myopathies". Proceedings of the National Academy of Sciences of the United States of America. 105 (13): 5225–9. doi: 10.1073/pnas.0800962105 . PMC   2278179 . PMID   18362356.
  2. ↑ Bernardi P, Bonaldo P (December 2008). "Dysfunction of mitochondria and sarcoplasmic reticulum in the pathogenesis of collagen VI muscular dystrophies". Annals of the New York Academy of Sciences. 1147: 303–11. doi:10.1196/annals.1427.009. PMID   19076452. S2CID   45028337.
  3. 1 2 3 4 5 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
  4. ↑ Pan TC, Zhang RZ, Arita M, Bogdanovich S, Adams SM, Gara SK, Wagener R, Khurana TS, Birk DE, Chu ML (April 2014). "A mouse model for dominant collagen VI disorders: heterozygous deletion of Col6a3 Exon 16". The Journal of Biological Chemistry. 289 (15): 10293–307. doi: 10.1074/jbc.M114.549311 . PMC   4036154 . PMID   24563484.
  5. 1 2 3 4 Chen P, Cescon M, Bonaldo P (July 2013). "Collagen VI in cancer and its biological mechanisms". Trends in Molecular Medicine. 19 (7): 410–7. doi:10.1016/j.molmed.2013.04.001. PMID   23639582.
  6. ↑ 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
  7. ↑ Lamandé SR, Bateman JF (October 2018). "Collagen VI disorders: Insights on form and function in the extracellular matrix and beyond". Matrix Biology. 71–72: 348–367. doi:10.1016/j.matbio.2017.12.008. PMID   29277723.
  8. ↑ 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
  9. ↑ 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/ng0996-113
  10. ↑ Camacho 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.121027598
  11. ↑ Merlini, 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
  12. ↑ 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
  13. 1 2 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
  14. ↑ 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
  15. 1 2 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
  16. ↑ 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
  17. ↑ 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
  18. 1 2 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
  19. ↑ 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
  20. ↑ 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
  21. ↑ 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
  22. ↑ Park, J. and Scherer, P. E. (2012). Adipocyte-derived endotrophin promotes malignant tumor progression. J. Clin. Invest. 122, 4243-4256. doi:10.1172/JCI63930
  23. ↑ 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
  24. ↑ Christensen, Susan E.; Coles, Jeffrey M.; Zelenski, Nicole A.; Furman, Bridgette D.; Leddy, Holly A.; Zauscher, Stefan; Bonaldo, Paolo; Guilak, Farshid (2012-03-20). "Altered Trabecular Bone Structure and Delayed Cartilage Degeneration in the Knees of Collagen VI Null Mice". PLOS ONE. 7 (3): e33397. doi: 10.1371/journal.pone.0033397 . ISSN   1932-6203. PMC   3308976 . PMID   22448243.
  25. ↑ Lampe AK, Flanigan KM, Bushby KM, Hicks D (August 9, 2012). "Collagen VI-Related Dystrophies". Collagen Type VI-Related Disorders. University of Washington, Seattle. NBK1503. In Adam MP, Ardinger HH, Pagon RA, Wallace SE, Bean LJ, Stephens K, et al., eds. (1993–2018). GeneReviews [Internet]. Seattle WA: University of Washington, Seattle.
  26. ↑ Lampe AK, Bushby KM (September 2005). "Collagen VI related muscle disorders". Journal of Medical Genetics. 42 (9): 673–85. doi:10.1136/jmg.2002.002311. PMC   1736127 . PMID   16141002.
  27. 1 2 Merlini L, Bernardi P (October 2008). "Therapy of collagen VI-related myopathies (Bethlem and Ullrich)". Neurotherapeutics. 5 (4): 613–8. doi:10.1016/j.nurt.2008.08.004. PMC   4514708 . PMID   19019314.
  28. 1 2 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
  29. ↑ McDonald, Sam. "Global Registry for COL6-related Dystrophies". ClinicalTrials.gov. NIH U.S.National Library of Medicine NCT04020159. Retrieved 27 August 2023.
  30. 1 2 Di Martino, Alberto; Cescon, Matilde; D’Agostino, Claudio; Schilardi, Francesco; Sabatelli, Patrizia; Merlini, Luciano; Faldini, Cesare (7 March 2023). "Collagen VI in the Musculoskeletal System". International Journal of Molecular Sciences. 24 (6): 5095. doi: 10.3390/ijms24065095 . ISSN   1422-0067. PMC   10049728 . PMID   36982167.
  31. 1 2 3 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
  32. ↑ Okada, M., Kawahara, G., Noguchi, S., Sugie, K., Murayama, K., Nonaka, I., . . . Nishino, I. (2007). Primary collagen VI deficiency is the second most common congenital muscular dystrophy in Japan. Neurology,69(10), 1035-1042. doi:10.1212/01.wnl.0000271387.10404.4e

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