Collagen VI

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]

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 endoymsium.[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] There are few treatments that have been developed to treat Ullrich congenital muscular dystrophy or Bethlem myopathy at the genetic level; 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.[29] The most common pattern of inheritance for UCMD is autosomal recessive, although an autosomal dominant pattern of inheritance is observed in rare cases.[29]

Symptoms[29]
  • 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

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.[30]

References
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  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.
  3. 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. 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. 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. 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. 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 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. 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. 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. 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
  30. 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

Further reading
  • Sparks SE, Quijano-Roy S, Harper A, Rutkowski A, Gordon E, Hoffman EP, Pegoraro E (2012-08-23). "Congenital Muscular Dystrophy Overview". In Adam MP, Ardinger HH, Pagon RA, Wallace SE, Bean LJ, Stephens K, Amemiya A, Lampe AK, Flanigan KM, Bushby KM, Hicks D (eds.). Gene Reviews. Seattle: University of Washington. NBK1291.
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