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Angiotensin-(1-7) Attenuates Skeletal Muscle Fibrosis and Stiffening in a Mouse Model of Extremity Sarcoma Radiation Therapy.

Publication ,  Journal Article
Willey, JS; Bracey, DN; Gallagher, PE; Tallant, EA; Wiggins, WF; Callahan, MF; Smith, TL; Emory, CL
Published in: J Bone Joint Surg Am
January 6, 2016

BACKGROUND: Radiation-induced fibrosis (RIF) of musculoskeletal tissue is a common complication of radiation therapy for extremity soft-tissue sarcoma, with no standardized strategy for prevention and treatment. Angiotensin-(1-7) (Ang-[1-7]), a well-tolerated endogenous heptapeptide hormone with antitumor and antifibrotic properties, was tested as a radioprotectant for RIF and stiffening of irradiated muscles. METHODS: Male CD-1 mice were randomized to one of three treatment groups: control, simulated sarcoma radiation therapy to the gastrocnemius and soleus muscles, or radiation therapy along with continuous Ang-(1-7) delivery initiated three days before radiation therapy. The biologically equivalent dose of radiation (∼100.3 Gy) absorbed by normal musculature during the course of radiation therapy for extremity sarcoma was delivered by means of four dose fractions of 7.3 Gy over two weeks. Fibrosis (n = 5 per group) and mechanical properties (n = 4 to 6 per group) of the muscles were measured at six weeks and four months after radiation therapy, and the intramuscular concentration of the profibrotic cytokines transforming growth factor-beta (TGF-β) and connective tissue growth factor (CTGF) (n = 8 to 10 per group) were measured at six weeks. RESULTS: Interstitial (p < 0.01) and perivascular (p < 0.05) fibrosis increased significantly in the muscles treated with radiation therapy alone versus the nonirradiated controls at both six weeks (interstitial, +89%; perivascular, +112%) and four months (interstitial, +154%; perivascular, +88%). The muscles treated with radiation alone also exhibited increased tension (p < 0.01) versus nonirradiated controls at both six weeks (+779%) and four months (+1761%) when placed under 5% strain, and at four months (+1390%; p < 0.001) under 10% strain. At four months, muscle stiffness had increased in the mice treated with radiation therapy alone (+90%; p = 0.002) compared with nonirradiated controls. TGF-β production was also greater in this group at six weeks (+37%; p = 0.06) versus control. Ang-(1-7) administration prevented RIF and stiffening, with no differences observed for any other outcome between those receiving radiation therapy with Ang-(1-7) and the nonirradiated controls. Likewise, Ang-(1-7) mitigated the increase in TGF-β and CTGF concentration from radiation therapy. CONCLUSIONS: Ang-(1-7) attenuated RIF, stiffening, and production of profibrotic cytokines that were elevated in mouse skeletal muscles after simulated radiation therapy for extremity sarcoma. CLINICAL RELEVANCE: Ang-(1-7) may serve as a potential therapy for the prevention of RIF in patients who require radiation therapy as adjuvant treatment for soft-tissue sarcoma.

Duke Scholars

Published In

J Bone Joint Surg Am

DOI

EISSN

1535-1386

Publication Date

January 6, 2016

Volume

98

Issue

1

Start / End Page

48 / 55

Location

United States

Related Subject Headings

  • Spasm
  • Sensitivity and Specificity
  • Sarcoma, Experimental
  • Reference Values
  • Random Allocation
  • Peptide Fragments
  • Orthopedics
  • Muscle, Skeletal
  • Muscle Neoplasms
  • Mice, Inbred Strains
 

Citation

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MLA
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Willey, J. S., Bracey, D. N., Gallagher, P. E., Tallant, E. A., Wiggins, W. F., Callahan, M. F., … Emory, C. L. (2016). Angiotensin-(1-7) Attenuates Skeletal Muscle Fibrosis and Stiffening in a Mouse Model of Extremity Sarcoma Radiation Therapy. J Bone Joint Surg Am, 98(1), 48–55. https://doi.org/10.2106/JBJS.O.00545
Willey, Jeffrey S., Daniel N. Bracey, Patricia E. Gallagher, E Ann Tallant, Walter F. Wiggins, Michael F. Callahan, Thomas L. Smith, and Cynthia L. Emory. “Angiotensin-(1-7) Attenuates Skeletal Muscle Fibrosis and Stiffening in a Mouse Model of Extremity Sarcoma Radiation Therapy.J Bone Joint Surg Am 98, no. 1 (January 6, 2016): 48–55. https://doi.org/10.2106/JBJS.O.00545.
Willey JS, Bracey DN, Gallagher PE, Tallant EA, Wiggins WF, Callahan MF, et al. Angiotensin-(1-7) Attenuates Skeletal Muscle Fibrosis and Stiffening in a Mouse Model of Extremity Sarcoma Radiation Therapy. J Bone Joint Surg Am. 2016 Jan 6;98(1):48–55.
Willey, Jeffrey S., et al. “Angiotensin-(1-7) Attenuates Skeletal Muscle Fibrosis and Stiffening in a Mouse Model of Extremity Sarcoma Radiation Therapy.J Bone Joint Surg Am, vol. 98, no. 1, Jan. 2016, pp. 48–55. Pubmed, doi:10.2106/JBJS.O.00545.
Willey JS, Bracey DN, Gallagher PE, Tallant EA, Wiggins WF, Callahan MF, Smith TL, Emory CL. Angiotensin-(1-7) Attenuates Skeletal Muscle Fibrosis and Stiffening in a Mouse Model of Extremity Sarcoma Radiation Therapy. J Bone Joint Surg Am. 2016 Jan 6;98(1):48–55.

Published In

J Bone Joint Surg Am

DOI

EISSN

1535-1386

Publication Date

January 6, 2016

Volume

98

Issue

1

Start / End Page

48 / 55

Location

United States

Related Subject Headings

  • Spasm
  • Sensitivity and Specificity
  • Sarcoma, Experimental
  • Reference Values
  • Random Allocation
  • Peptide Fragments
  • Orthopedics
  • Muscle, Skeletal
  • Muscle Neoplasms
  • Mice, Inbred Strains