Anterior Cruciate Ligament Tear Promotes Skeletal Muscle Myostatin Expression, Fibrogenic Cell Expansion, and a Decline in Muscle Quality

Bailey D. Peck, Camille R. Brightwell, Darren L. Johnson, Mary Lloyd Ireland, Brian Noehren, Christopher Fry

Research output: Contribution to journalArticle

Abstract

Background: Anterior cruciate ligament (ACL) tears result in significant quadriceps muscle atrophy that is resistant to recovery despite extensive rehabilitation. Recent work suggests an elevated fibrotic burden in the quadriceps muscle after the injury, which may limit recovery. Elucidating the mechanisms and cell types involved in the progression of fibrosis is critical for developing new treatment strategies. Purpose: To identify factors contributing to the elevated fibrotic burden found after the injury. Study Design: Descriptive laboratory study. Methods: After an ACL injury, muscle biopsy specimens were obtained from the injured and noninjured vastus lateralis of young adults (n = 14, mean ± SD: 23 ± 4 years). The expression of myostatin, transforming growth factor β, and other regulatory factors was measured, and immunohistochemical analyses were performed to assess turnover of extracellular matrix components. Results: Injured limb skeletal muscle demonstrated elevated myostatin gene (P <.005) and protein (P <.0005) expression, which correlated (R 2 = 0.38, P <.05) with fibroblast cell abundance. Immunohistochemical analysis showed that human fibroblasts express the activin type IIB receptor and that isolated primary human muscle-derived fibroblasts increased proliferation after myostatin treatment in vitro (P <.05). Collagen 1 and fibronectin, primary components of the muscle extracellular matrix, were significantly higher in the injured limb (P <.05). The abundance of procollagen 1–expressing cells as well as a novel index of collagen remodeling was also elevated in the injured limb (P <.05). Conclusion: These findings support a role for myostatin in promoting fibrogenic alterations within skeletal muscle after an ACL injury. Clinical Relevance: The current work shows that the cause of muscle quality decline after ACL injury likely involves elevated myostatin expression, and future studies should explore therapeutic inhibition of myostatin to facilitate improvements in muscle recovery and return to sport.

Original languageEnglish (US)
JournalAmerican Journal of Sports Medicine
DOIs
StatePublished - Jan 1 2019

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Myostatin
Skeletal Muscle
Muscles
Quadriceps Muscle
Extremities
Fibroblasts
Extracellular Matrix
Collagen
Procollagen
Muscular Atrophy
Wounds and Injuries
Transforming Growth Factors
Fibronectins
Anterior Cruciate Ligament Injuries
Young Adult
Fibrosis
Therapeutics
Rehabilitation
Biopsy
Genes

Keywords

  • collagen
  • extracellular matrix
  • fibroblast
  • quadriceps

ASJC Scopus subject areas

  • Orthopedics and Sports Medicine
  • Physical Therapy, Sports Therapy and Rehabilitation

Cite this

Anterior Cruciate Ligament Tear Promotes Skeletal Muscle Myostatin Expression, Fibrogenic Cell Expansion, and a Decline in Muscle Quality. / Peck, Bailey D.; Brightwell, Camille R.; Johnson, Darren L.; Ireland, Mary Lloyd; Noehren, Brian; Fry, Christopher.

In: American Journal of Sports Medicine, 01.01.2019.

Research output: Contribution to journalArticle

Peck, Bailey D. ; Brightwell, Camille R. ; Johnson, Darren L. ; Ireland, Mary Lloyd ; Noehren, Brian ; Fry, Christopher. / Anterior Cruciate Ligament Tear Promotes Skeletal Muscle Myostatin Expression, Fibrogenic Cell Expansion, and a Decline in Muscle Quality. In: American Journal of Sports Medicine. 2019.
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abstract = "Background: Anterior cruciate ligament (ACL) tears result in significant quadriceps muscle atrophy that is resistant to recovery despite extensive rehabilitation. Recent work suggests an elevated fibrotic burden in the quadriceps muscle after the injury, which may limit recovery. Elucidating the mechanisms and cell types involved in the progression of fibrosis is critical for developing new treatment strategies. Purpose: To identify factors contributing to the elevated fibrotic burden found after the injury. Study Design: Descriptive laboratory study. Methods: After an ACL injury, muscle biopsy specimens were obtained from the injured and noninjured vastus lateralis of young adults (n = 14, mean ± SD: 23 ± 4 years). The expression of myostatin, transforming growth factor β, and other regulatory factors was measured, and immunohistochemical analyses were performed to assess turnover of extracellular matrix components. Results: Injured limb skeletal muscle demonstrated elevated myostatin gene (P <.005) and protein (P <.0005) expression, which correlated (R 2 = 0.38, P <.05) with fibroblast cell abundance. Immunohistochemical analysis showed that human fibroblasts express the activin type IIB receptor and that isolated primary human muscle-derived fibroblasts increased proliferation after myostatin treatment in vitro (P <.05). Collagen 1 and fibronectin, primary components of the muscle extracellular matrix, were significantly higher in the injured limb (P <.05). The abundance of procollagen 1–expressing cells as well as a novel index of collagen remodeling was also elevated in the injured limb (P <.05). Conclusion: These findings support a role for myostatin in promoting fibrogenic alterations within skeletal muscle after an ACL injury. Clinical Relevance: The current work shows that the cause of muscle quality decline after ACL injury likely involves elevated myostatin expression, and future studies should explore therapeutic inhibition of myostatin to facilitate improvements in muscle recovery and return to sport.",
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AB - Background: Anterior cruciate ligament (ACL) tears result in significant quadriceps muscle atrophy that is resistant to recovery despite extensive rehabilitation. Recent work suggests an elevated fibrotic burden in the quadriceps muscle after the injury, which may limit recovery. Elucidating the mechanisms and cell types involved in the progression of fibrosis is critical for developing new treatment strategies. Purpose: To identify factors contributing to the elevated fibrotic burden found after the injury. Study Design: Descriptive laboratory study. Methods: After an ACL injury, muscle biopsy specimens were obtained from the injured and noninjured vastus lateralis of young adults (n = 14, mean ± SD: 23 ± 4 years). The expression of myostatin, transforming growth factor β, and other regulatory factors was measured, and immunohistochemical analyses were performed to assess turnover of extracellular matrix components. Results: Injured limb skeletal muscle demonstrated elevated myostatin gene (P <.005) and protein (P <.0005) expression, which correlated (R 2 = 0.38, P <.05) with fibroblast cell abundance. Immunohistochemical analysis showed that human fibroblasts express the activin type IIB receptor and that isolated primary human muscle-derived fibroblasts increased proliferation after myostatin treatment in vitro (P <.05). Collagen 1 and fibronectin, primary components of the muscle extracellular matrix, were significantly higher in the injured limb (P <.05). The abundance of procollagen 1–expressing cells as well as a novel index of collagen remodeling was also elevated in the injured limb (P <.05). Conclusion: These findings support a role for myostatin in promoting fibrogenic alterations within skeletal muscle after an ACL injury. Clinical Relevance: The current work shows that the cause of muscle quality decline after ACL injury likely involves elevated myostatin expression, and future studies should explore therapeutic inhibition of myostatin to facilitate improvements in muscle recovery and return to sport.

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