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 S. Fry

doi:10.1177/0363546519832864

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 S. Fry

Research output: Contribution to journal › Article › peer-review

48 Scopus citations

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 language	English
Pages (from-to)	1385-1395
Number of pages	11
Journal	American Journal of Sports Medicine
Volume	47
Issue number	6
DOIs	https://doi.org/10.1177/0363546519832864
State	Published - May 1 2019

Bibliographical note

Publisher Copyright:
© 2019 The Author(s).

Funding

One or more of the authors has declared the following potential conflict of interest or source of funding: This work was supported by the National Institute of Arthritis and Musculoskeletal and Skin Diseases of the National Institutes of Health (NIH; grant K23 AR062069 to B.N. and grant R01 AR072061 to C.S.F.) and the John Sealy Memorial Endowment Fund to C.S.F. C.S.F. is a former KL2 scholar supported by the Claude D. Pepper Older Americans Independence Center, University of Texas Medical Branch (National Institute on Aging, NIH; grant P30 AG024832). Additional support came from a pilot grant from the Center for Muscle Biology, University of Kentucky. D.L.J. and M.L.I. have received hospitality payments from Smith & Nephew. The procollagen 1 (SP1.D8) antibody was developed by H. Furthmayr and obtained from the Developmental Studies Hybridoma Bank, created by the National Institute of Child Health and Human Development of the NIH and maintained at the Department of Biology, The University of Iowa. AOSSM checks author disclosures against the Open Payments Database (OPD). AOSSM has not conducted an independent investigation on the OPD and disclaims any liability or responsibility relating thereto.

Funders	Funder number
Center for Muscle Biology
John Sealy Memorial Endowment Fund
National Institutes of Health (NIH)	K23 AR062069, R01 AR072061
National Institutes of Health (NIH)
National Institute on Aging	P30AG024832
National Institute on Aging
National Institute of Arthritis and Musculoskeletal and Skin Diseases
University of Kentucky
University of Texas Medical Branch
Claude D. Pepper Older Americans Independence Center, University of California San Francisco

Keywords

collagen
extracellular matrix
fibroblast
quadriceps

ASJC Scopus subject areas

Physical Therapy, Sports Therapy and Rehabilitation
Orthopedics and Sports Medicine

Access to Document

10.1177/0363546519832864

Cite this

@article{f3f2f89aef944c23af17720ce2213347,

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

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.",

keywords = "collagen, extracellular matrix, fibroblast, quadriceps",

author = "Peck, \{Bailey D.\} and Brightwell, \{Camille R.\} and Johnson, \{Darren L.\} and Ireland, \{Mary Lloyd\} and Brian Noehren and Fry, \{Christopher S.\}",

note = "Publisher Copyright: {\textcopyright} 2019 The Author(s).",

year = "2019",

month = may,

day = "1",

doi = "10.1177/0363546519832864",

language = "English",

volume = "47",

pages = "1385--1395",

number = "6",

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T1 - Anterior Cruciate Ligament Tear Promotes Skeletal Muscle Myostatin Expression, Fibrogenic Cell Expansion, and a Decline in Muscle Quality

AU - Peck, Bailey D.

AU - Brightwell, Camille R.

AU - Johnson, Darren L.

AU - Ireland, Mary Lloyd

AU - Noehren, Brian

AU - Fry, Christopher S.

PY - 2019/5/1

Y1 - 2019/5/1

N2 - 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.

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.

KW - collagen

KW - extracellular matrix

KW - fibroblast

KW - quadriceps

UR - https://www.scopus.com/pages/publications/85064639685

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U2 - 10.1177/0363546519832864

DO - 10.1177/0363546519832864

M3 - Article

C2 - 30995070

AN - SCOPUS:85064639685

SN - 0363-5465

VL - 47

SP - 1385

EP - 1395

JO - American Journal of Sports Medicine

JF - American Journal of Sports Medicine

IS - 6

ER -

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

Abstract

Bibliographical note

Funding

Keywords

ASJC Scopus subject areas

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