Temporal changes in the muscle extracellular matrix due to volumetric muscle loss injury

Daniel B. Hoffman, Christiana J Raymond-Pope, Jacob R. Sorensen, Benjamin T. Corona, Sarah M. Greising

Research output: Contribution to journalArticlepeer-review

12 Scopus citations


Purpose/Aim: Volumetric muscle loss (VML) is a devastating orthopedic injury resulting in chronic persistent functional deficits, loss of joint range of motion, pathologic fibrotic deposition and lifelong disability. However, there is only limited mechanistic understanding of VML-induced fibrosis. Herein we examined the temporal changes in the fibrotic deposition at 3, 7, 14, 28, and 48 days post-VML injury. Materials and Methods: Adult male Lewis rats (n = 39) underwent a full thickness ~20% (~85 mg) VML injury to the tibialis anterior (TA) muscle unilaterally, the contralateral TA muscle served as the control group. All TA muscles were harvested for biochemical and histologic evaluation. Results: The ratio of collagen I/III was decreased at 3, 7, and 14 days post-VML, but significantly increased at 48 days. Decorin content followed an opposite trend, significantly increasing by day 3 before dropping to below control levels by 48 days. Histological evaluation of the defect area indicates a shift from loosely packed collagen at early time points post-VML, to a densely packed fibrotic scar by 48 days. Conclusions: The shift from early wound healing efforts to a fibrotic scar with densely packed collagen within the skeletal muscle occurs around 21 days after VML injury through dogmatic synchronous reduction of collagen III and increase in collagen I. Thus, there appears to be an early window for therapeutic intervention to prevent pathologic fibrous tissue formation, potentially by targeting CCN2/CTGF or using decorin as a therapeutic.

Original languageEnglish (US)
Pages (from-to)124-137
Number of pages14
JournalConnective Tissue Research
Issue number2
Early online dateFeb 15 2021
StatePublished - Feb 15 2021

Bibliographical note

Funding Information:
The authors gratefully acknowledge support from the University of Minnesota - University Imaging Centers, this work was completed using the TissueScope LE slide scanner and the C2 Nikon Confocal microscope.

Publisher Copyright:
© 2021 Informa UK Limited, trading as Taylor & Francis Group.


  • Collagen
  • fibrosis
  • neuromusculoskeletal injury
  • orthopedic trauma
  • skeletal muscle injury

PubMed: MeSH publication types

  • Journal Article
  • Research Support, N.I.H., Extramural
  • Research Support, U.S. Gov't, Non-P.H.S.


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