Versican processing by a disintegrin-like and metalloproteinase domain with thrombospondin-1 repeats proteinases-5 and-15 facilitates myoblast fusion

Nicole Stupka, Christopher Kintakas, Jason D. White, Fiona W. Fraser, Michael Hanciu, Noriko Aramaki, Sheree Martin, Chantal Coles, Fiona Collier, Alister C. Ward, Suneel S. Apte, Daniel R. McCulloch

Research output: Contribution to journalArticle

32 Citations (Scopus)

Abstract

Background: Skeletal muscle fiber formation requires myoblast cell-cell membrane contact and fusion. Results: A versican-rich pericellular matrix surrounding myoblasts is proteolytically cleared by ADAMTS versicanases facilitating myoblast contact and fusion. Conclusion: Versican processing by ADAMTS versicanases contribute to muscle fiber formation. Significance: Targeting versican remodeling could enhance the regenerative capacity of muscle by improving muscle fiber fusion during regeneration. Skeletal muscle development and regeneration requires the fusion of myoblasts into multinucleated myotubes. Because the enzymatic proteolysis of a hyaluronan and versican-rich matrix by ADAMTS versicanases is required for developmental morphogenesis, we hypothesized that the clearance of versican may facilitate the fusion of myoblasts during myogenesis. Here, we used transgenic mice and an in vitro model of myoblast fusion, C2C12 cells, to determine a potential role forADAMTSversicanases. Versican processing was observed during in vivo myogenesis at the time when myoblasts were fusing to form multinucleated myotubes. Relevant ADAMTS genes, chief among them Adamts5 and Adamts15, were expressed both in developing embryonic muscle and differentiating C2C12 cells. Reducing the levels of Adamts5 mRNA in vitro impaired myoblast fusion, which could be rescued with catalytically active but not the inactive forms of ADAMTS5 or ADAMTS15. The addition of inactive ADAMTS5, ADAMTS15, or full-length V1 versican effectively impaired myoblast fusion. Finally, the expansion of a hyaluronan and versican-rich matrix was observed upon reducing the levels of Adamts5 mRNA in myoblasts. These data indicate that these ADAMTS proteinases contribute to the formation of multinucleated myotubes such as is necessary for both skeletal muscle development and during regeneration, by remodeling a versican-rich pericellular matrix of myoblasts. Our study identifies a possible pathway to target for the improvement of myogenesis in a plethora of diseases including cancer cachexia, sarcopenia, and muscular dystrophy.

Original languageEnglish
Pages (from-to)1907-1917
Number of pages11
JournalJournal of Biological Chemistry
Volume288
Issue number3
DOIs
Publication statusPublished - 2013 Jan 18
Externally publishedYes

Fingerprint

Versicans
Thrombospondin 1
Disintegrins
Myoblasts
Metalloproteases
Peptide Hydrolases
Fusion reactions
Muscle
Muscle Development
Processing
Skeletal Muscle Fibers
Hyaluronic Acid
Regeneration
Muscles
Cell Fusion
Fibers
Proteolysis
Skeletal Muscle
Messenger RNA
Sarcopenia

ASJC Scopus subject areas

  • Biochemistry
  • Cell Biology
  • Molecular Biology

Cite this

Versican processing by a disintegrin-like and metalloproteinase domain with thrombospondin-1 repeats proteinases-5 and-15 facilitates myoblast fusion. / Stupka, Nicole; Kintakas, Christopher; White, Jason D.; Fraser, Fiona W.; Hanciu, Michael; Aramaki, Noriko; Martin, Sheree; Coles, Chantal; Collier, Fiona; Ward, Alister C.; Apte, Suneel S.; McCulloch, Daniel R.

In: Journal of Biological Chemistry, Vol. 288, No. 3, 18.01.2013, p. 1907-1917.

Research output: Contribution to journalArticle

Stupka, N, Kintakas, C, White, JD, Fraser, FW, Hanciu, M, Aramaki, N, Martin, S, Coles, C, Collier, F, Ward, AC, Apte, SS & McCulloch, DR 2013, 'Versican processing by a disintegrin-like and metalloproteinase domain with thrombospondin-1 repeats proteinases-5 and-15 facilitates myoblast fusion', Journal of Biological Chemistry, vol. 288, no. 3, pp. 1907-1917. https://doi.org/10.1074/jbc.M112.429647
Stupka, Nicole ; Kintakas, Christopher ; White, Jason D. ; Fraser, Fiona W. ; Hanciu, Michael ; Aramaki, Noriko ; Martin, Sheree ; Coles, Chantal ; Collier, Fiona ; Ward, Alister C. ; Apte, Suneel S. ; McCulloch, Daniel R. / Versican processing by a disintegrin-like and metalloproteinase domain with thrombospondin-1 repeats proteinases-5 and-15 facilitates myoblast fusion. In: Journal of Biological Chemistry. 2013 ; Vol. 288, No. 3. pp. 1907-1917.
@article{ef63c6dd763f4cc69f7a18e1ee04e661,
title = "Versican processing by a disintegrin-like and metalloproteinase domain with thrombospondin-1 repeats proteinases-5 and-15 facilitates myoblast fusion",
abstract = "Background: Skeletal muscle fiber formation requires myoblast cell-cell membrane contact and fusion. Results: A versican-rich pericellular matrix surrounding myoblasts is proteolytically cleared by ADAMTS versicanases facilitating myoblast contact and fusion. Conclusion: Versican processing by ADAMTS versicanases contribute to muscle fiber formation. Significance: Targeting versican remodeling could enhance the regenerative capacity of muscle by improving muscle fiber fusion during regeneration. Skeletal muscle development and regeneration requires the fusion of myoblasts into multinucleated myotubes. Because the enzymatic proteolysis of a hyaluronan and versican-rich matrix by ADAMTS versicanases is required for developmental morphogenesis, we hypothesized that the clearance of versican may facilitate the fusion of myoblasts during myogenesis. Here, we used transgenic mice and an in vitro model of myoblast fusion, C2C12 cells, to determine a potential role forADAMTSversicanases. Versican processing was observed during in vivo myogenesis at the time when myoblasts were fusing to form multinucleated myotubes. Relevant ADAMTS genes, chief among them Adamts5 and Adamts15, were expressed both in developing embryonic muscle and differentiating C2C12 cells. Reducing the levels of Adamts5 mRNA in vitro impaired myoblast fusion, which could be rescued with catalytically active but not the inactive forms of ADAMTS5 or ADAMTS15. The addition of inactive ADAMTS5, ADAMTS15, or full-length V1 versican effectively impaired myoblast fusion. Finally, the expansion of a hyaluronan and versican-rich matrix was observed upon reducing the levels of Adamts5 mRNA in myoblasts. These data indicate that these ADAMTS proteinases contribute to the formation of multinucleated myotubes such as is necessary for both skeletal muscle development and during regeneration, by remodeling a versican-rich pericellular matrix of myoblasts. Our study identifies a possible pathway to target for the improvement of myogenesis in a plethora of diseases including cancer cachexia, sarcopenia, and muscular dystrophy.",
author = "Nicole Stupka and Christopher Kintakas and White, {Jason D.} and Fraser, {Fiona W.} and Michael Hanciu and Noriko Aramaki and Sheree Martin and Chantal Coles and Fiona Collier and Ward, {Alister C.} and Apte, {Suneel S.} and McCulloch, {Daniel R.}",
year = "2013",
month = "1",
day = "18",
doi = "10.1074/jbc.M112.429647",
language = "English",
volume = "288",
pages = "1907--1917",
journal = "Journal of Biological Chemistry",
issn = "0021-9258",
publisher = "American Society for Biochemistry and Molecular Biology Inc.",
number = "3",

}

TY - JOUR

T1 - Versican processing by a disintegrin-like and metalloproteinase domain with thrombospondin-1 repeats proteinases-5 and-15 facilitates myoblast fusion

AU - Stupka, Nicole

AU - Kintakas, Christopher

AU - White, Jason D.

AU - Fraser, Fiona W.

AU - Hanciu, Michael

AU - Aramaki, Noriko

AU - Martin, Sheree

AU - Coles, Chantal

AU - Collier, Fiona

AU - Ward, Alister C.

AU - Apte, Suneel S.

AU - McCulloch, Daniel R.

PY - 2013/1/18

Y1 - 2013/1/18

N2 - Background: Skeletal muscle fiber formation requires myoblast cell-cell membrane contact and fusion. Results: A versican-rich pericellular matrix surrounding myoblasts is proteolytically cleared by ADAMTS versicanases facilitating myoblast contact and fusion. Conclusion: Versican processing by ADAMTS versicanases contribute to muscle fiber formation. Significance: Targeting versican remodeling could enhance the regenerative capacity of muscle by improving muscle fiber fusion during regeneration. Skeletal muscle development and regeneration requires the fusion of myoblasts into multinucleated myotubes. Because the enzymatic proteolysis of a hyaluronan and versican-rich matrix by ADAMTS versicanases is required for developmental morphogenesis, we hypothesized that the clearance of versican may facilitate the fusion of myoblasts during myogenesis. Here, we used transgenic mice and an in vitro model of myoblast fusion, C2C12 cells, to determine a potential role forADAMTSversicanases. Versican processing was observed during in vivo myogenesis at the time when myoblasts were fusing to form multinucleated myotubes. Relevant ADAMTS genes, chief among them Adamts5 and Adamts15, were expressed both in developing embryonic muscle and differentiating C2C12 cells. Reducing the levels of Adamts5 mRNA in vitro impaired myoblast fusion, which could be rescued with catalytically active but not the inactive forms of ADAMTS5 or ADAMTS15. The addition of inactive ADAMTS5, ADAMTS15, or full-length V1 versican effectively impaired myoblast fusion. Finally, the expansion of a hyaluronan and versican-rich matrix was observed upon reducing the levels of Adamts5 mRNA in myoblasts. These data indicate that these ADAMTS proteinases contribute to the formation of multinucleated myotubes such as is necessary for both skeletal muscle development and during regeneration, by remodeling a versican-rich pericellular matrix of myoblasts. Our study identifies a possible pathway to target for the improvement of myogenesis in a plethora of diseases including cancer cachexia, sarcopenia, and muscular dystrophy.

AB - Background: Skeletal muscle fiber formation requires myoblast cell-cell membrane contact and fusion. Results: A versican-rich pericellular matrix surrounding myoblasts is proteolytically cleared by ADAMTS versicanases facilitating myoblast contact and fusion. Conclusion: Versican processing by ADAMTS versicanases contribute to muscle fiber formation. Significance: Targeting versican remodeling could enhance the regenerative capacity of muscle by improving muscle fiber fusion during regeneration. Skeletal muscle development and regeneration requires the fusion of myoblasts into multinucleated myotubes. Because the enzymatic proteolysis of a hyaluronan and versican-rich matrix by ADAMTS versicanases is required for developmental morphogenesis, we hypothesized that the clearance of versican may facilitate the fusion of myoblasts during myogenesis. Here, we used transgenic mice and an in vitro model of myoblast fusion, C2C12 cells, to determine a potential role forADAMTSversicanases. Versican processing was observed during in vivo myogenesis at the time when myoblasts were fusing to form multinucleated myotubes. Relevant ADAMTS genes, chief among them Adamts5 and Adamts15, were expressed both in developing embryonic muscle and differentiating C2C12 cells. Reducing the levels of Adamts5 mRNA in vitro impaired myoblast fusion, which could be rescued with catalytically active but not the inactive forms of ADAMTS5 or ADAMTS15. The addition of inactive ADAMTS5, ADAMTS15, or full-length V1 versican effectively impaired myoblast fusion. Finally, the expansion of a hyaluronan and versican-rich matrix was observed upon reducing the levels of Adamts5 mRNA in myoblasts. These data indicate that these ADAMTS proteinases contribute to the formation of multinucleated myotubes such as is necessary for both skeletal muscle development and during regeneration, by remodeling a versican-rich pericellular matrix of myoblasts. Our study identifies a possible pathway to target for the improvement of myogenesis in a plethora of diseases including cancer cachexia, sarcopenia, and muscular dystrophy.

UR - http://www.scopus.com/inward/record.url?scp=84872692374&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84872692374&partnerID=8YFLogxK

U2 - 10.1074/jbc.M112.429647

DO - 10.1074/jbc.M112.429647

M3 - Article

VL - 288

SP - 1907

EP - 1917

JO - Journal of Biological Chemistry

JF - Journal of Biological Chemistry

SN - 0021-9258

IS - 3

ER -