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Radiation Oncology
Published in: Radiation Oncology 1/2018

Open Access 01-12-2018 | Research

Radiation-induced muscle fibrosis rat model: establishment and valuation

Authors: Yue Zhou, Xiaowu Sheng, Feiyan Deng, Hui Wang, Liangfang Shen, Yong Zeng, Qianxi Ni, Shibin Zhan, Xiao Zhou

Published in: Radiation Oncology | Issue 1/2018

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Abstract

Background

Lack of animal model of radiation induced muscle fibrosis, this study aimed to establish such a model by using 90 Gy single dose irradiation to mimic clinical relevance and also to explore the potential post-irradiation regenerative mechanism.

Methods

SD rats were randomly divided into dose investigation groups and time gradient groups. Group1–6 were irradiated with a single dose of 65Gy, 70Gy, 75Gy, 80Gy, 85Gy and 90Gy respectively, and the degree of rectus femoris fibrosis in the irradiated area was detected at 4 weeks after irradiation. Group 7–9 were irradiated with a single dose of 90Gy, and the results were detected 1, 2, 4, and 8 weeks after irradiation. Then the general condition of rats was recorded. Masson staining was used to detect muscle fibrosis. The ultrastructure of muscles was observed by electron microscope, and the expression changes of satellite cell proliferation and differentiation related genes were detected by quantitative real-time-PCR.

Results

A single dose of 90Gy irradiation could cause muscle fibrosis in rats. As time goes on, the severity of muscle fibrosis and the expression of TGF- β1 increased. Significant swelling of mitochondria, myofilament disarrangement and dissolution, obvious endothelial cell swelling, increased vascular permeability, decrease of blood cell, deposition of fibrosis tissue around the vessel could be found compared with the control group. At around the 4th week, the expressions of Pax7, Myf5, MyoD, MyoG, Mrf4 increased.

Conclusion

Irradiation of 90Gy can successfully establish the rat model of radiation-induced muscle fibrosis. This model demonstrated that regenerative process was initiated by the irradiation only at an early stage, which can serve a suitable model for investigating regenerative therapy for post-radiation muscle fibrosis.
Literature
1.
2.
Straub JM, New J, Hamilton CD, Lominska C, Shnayder Y, Thomas SM. Radiation-induced fibrosis: mechanisms and implications for therapy. J Cancer Res Clin Oncol. 2015;141(11):1985–94.PubMedPubMedCentralCrossRef
3.
Jian LI, Wang RS, Gan LG. Radiation-induced neck fibrosis in patients with nasopharyngeal carcinoma. Chin J Radiat Mediation Prot. 2005;03:253–55.
4.
Yarnold J, Brotons MC. Pathogenetic mechanisms in radiation fibrosis. Radiother Oncol. 2010;97(1):149–61.PubMedCrossRef
5.
Cheresh P, Kim SJ, Tulasiram S, Kamp DW. Oxidative stress and pulmonary fibrosis. Biochim Biophys Acta. 2013;1832(7):1028–40.PubMedCrossRef
6.
7.
Koturbash I, Rugo RE, Hendricks CA, Loree J, Thibault B, Kutanzi K, Pogribny I, Yanch JC, Engelward BP, Kovalchuk O. Irradiation induces DNA damage and modulates epigenetic effectors in distant bystander tissue in vivo. Oncogene. 2006;25(31):4267–75.PubMedCrossRef
8.
Dickey JS, Baird BJ, Redon CE, Sokolov MV, Sedelnikova OA, Bonner WM. Intercellular communication of cellular stress monitored by gamma-H2AX induction. Carcinogenesis. 2009;30(10):1686–95.PubMedPubMedCentralCrossRef
9.
Coppes RP, van der Goot A, Lombaert IM. Stem cell therapy to reduce radiation-induced normal tissue damage. Semin Radiat Oncol. 2009;19(2):112–21.PubMedCrossRef
10.
11.
Kuhmann C, Weichenhan D, Rehli M, Plass C, Schmezer P, Popanda O. DNA methylation changes in cells regrowing after fractioned ionizing radiation. Radiother Oncol. 2011;101(1):116–21.PubMedCrossRef
12.
Gaugler MH, Vereycken-Holler V, Squiban C, Vandamme M, Vozenin-Brotons MC, Benderitter M. Pravastatin limits endothelial activation after irradiation and decreases the resulting inflammatory and thrombotic responses. Radiat Res. 2005;163(5):479–87.PubMedCrossRef
13.
Pohlers D, Brenmoehl J, Loffler I, Muller CK, Leipner C, Schultze-Mosgau S, Stallmach A, Kinne RW, Wolf G. TGF-beta and fibrosis in different organs - molecular pathway imprints. Biochim Biophys Acta. 2009;1792(8):746–56.PubMedCrossRef
14.
Kruse JJ, Floot BG, te Poele JA, Russell NS, Stewart FA. Radiation-induced activation of TGF-beta signaling pathways in relation to vascular damage in mouse kidneys. Radiat Res. 2009;171(2):188–97.PubMedCrossRef
15.
Ruiz-Ortega M, Rodriguez-Vita J, Sanchez-Lopez E, Carvajal G, Egido J. TGF-beta signaling in vascular fibrosis. Cardiovasc Res. 2007;74(2):196–206.PubMedCrossRef
16.
Fujii H, Kawada N. Inflammation and fibrogenesis in steatohepatitis. J Gastroenterol. 2012;47(3):215–25.PubMedCrossRef
17.
Westbury CB, Yarnold JR. Radiation fibrosis--current clinical and therapeutic perspectives. Clin Oncol (R Coll Radiol). 2012;24(10):657–72.CrossRef
18.
Li C, Wilson PB, Levine E, Barber J, Stewart AL, Kumar S. TGF-beta1 levels in pre-treatment plasma identify breast cancer patients at risk of developing post-radiotherapy fibrosis. Int J Cancer. 1999;84(2):155–9.PubMedCrossRef
19.
Haydont V, Riser BL, Aigueperse J, Vozenin-Brotons MC. Specific signals involved in the long-term maintenance of radiation-induced fibrogenic differentiation: a role for CCN2 and low concentration of TGF-beta1. Am J Phys Cell Physiol. 2008;294(6):C1332–41.CrossRef
20.
Hu S, Chen Y, Li L, Chen J, Wu B, Zhou X, Zhi G, Li Q, Wang R, Duan H, et al. Effects of adenovirus-mediated delivery of the human hepatocyte growth factor gene in experimental radiation-induced heart disease. Int J Radiat Oncol Biol Phys. 2009;75(5):1537–44.PubMedCrossRef
21.
Gottlober P, Steinert M, Bahren W, Weber L, Gerngross H, Peter RU. Interferon-gamma in 5 patients with cutaneous radiation syndrome after radiation therapy. Int J Radiat Oncol Biol Phys. 2001;50(1):159–66.PubMedCrossRef
22.
23.
Russell B, Dix DJ, Haller DL, Jacobs-El J. Repair of injured skeletal muscle: a molecular approach. Med Sci Sports Exerc. 1992;24(2):189–96.PubMedCrossRef
24.
Pownall ME, Gustafsson MK, Emerson CP Jr. Myogenic regulatory factors and the specification of muscle progenitors in vertebrate embryos. Annu Rev Cell Dev Biol. 2002;18:747–83.PubMedCrossRef
25.
Wang YX, Rudnicki MA. Satellite cells, the engines of muscle repair. Nat Rev Mol Cell Biol. 2011;13(2):127–33.PubMedCrossRef
26.
27.
Hinz B, Phan SH, Thannickal VJ, Galli A, Bochaton-Piallat ML, Gabbiani G. The myofibroblast: one function, multiple origins. Am J Pathol. 2007;170(6):1807–16.PubMedPubMedCentralCrossRef
28.
Huard J, Li Y, Fu FH. Muscle injuries and repair: current trends in research. J Bone Joint Surg Am. 2002;84-a(5):822–32.PubMedCrossRef
29.
30.
Bracey D, Willey JS, Tallant EA, Gallagher PD, Smith TL, Callahan MF, Emory CL. The endogenous peptide angiotensin-(1-7) prevents radiation-induced muscle fibrosis: an in vivo murine model. Int J Radiat Oncol Biol Phys. 2013;87(2):S167.CrossRef
31.
Care NRCCftUotGft, Animals UoL. Guide for the care and use of laboratory animals. Astronomy Astrophysics. 2011;327(3):963–5.
32.
Endo T. Molecular mechanisms of skeletal muscle development, regeneration, and osteogenic conversion. Bone. 2015;80:2–13.PubMedCrossRef
33.
Yuan-Yuan Chen MD, Chong ZM, Jin WM, Hong-Lian Ma MD, Shu-Zheng Lai MD, Yuan LM, Fei HM, Li-Xia Lu MD, Yong BM, Ming CM. Intensity-modulated radiation therapy reduces radiation-induced trismus in patients with nasopharyngeal carcinoma. Cancer. 2011;117(13):2910–6.PubMedCrossRef
34.
Johansen S, Fosså K, Nesvold IL, Malinen E, Fosså SD. Arm and shoulder morbidity following surgery and radiotherapy for breast cancer. Acta Oncol. 2014;53(4):521.PubMedCrossRef
35.
Gallet P, Phulpin B, Merlin JL, Leroux A, Bravetti P, Mecellem H, Tran N, Dolivet G. Long-term alterations of cytokines and growth factors expression in irradiated tissues and relation with histological severity scoring. PLoS One. 2011;6(12):e29399.PubMedPubMedCentralCrossRef
36.
Ni X, Sun W, Sun S, Yu J, Wang J, Nie B, Sun Z, Ni X, Cai L, Cao X. Therapeutic potential of adipose stem cells in tissue repair of irradiated skeletal muscle in a rabbit model. Cell Reprogram. 2014;16(2):140–50.PubMedPubMedCentralCrossRef
37.
Hsu HY, Chai CY, Lee MS. Radiation-induced muscle damage in rats after fractionated high-dose irradiation. Radiat Res. 1998;149(5):482–6.PubMedCrossRef
38.
39.
Dörr W, Hendry JH. Consequential late effects in normal tissues. Radiother Oncol. 2001;61(3):223–31.PubMedCrossRef
40.
Sun W, Ni X, Sun S, Cai L, Yu J, Wang J, Nie B, Sun Z, Ni X, Cao X. Adipose-derived stem cells alleviate radiation-induced muscular fibrosis by suppressing the expression of TGF-beta1. Stem Cells Int. 2016;2016:5638204.PubMed
41.
Vallee A, Lecarpentier Y, Guillevin R, Vallee JN. Interactions between TGF-beta1, canonical WNT/beta-catenin pathway and PPAR gamma in radiation-induced fibrosis. Oncotarget. 2017;8(52):90579–604.PubMedPubMedCentralCrossRef
42.
Wei J, Bhattacharyya S, Jain M, Varga J. Regulation of matrix remodeling by peroxisome proliferator-activated receptor-gamma: a novel link between metabolism and Fibrogenesis. Open Rheumatol J. 2012;6:103–15.PubMedPubMedCentralCrossRef
43.
Gabbiani G, Hirschel BJ, Ryan GB, Statkov PR, Majno G. Granulation tissue as a contractile organ. A study of structure and function. J Exp Med. 1972;135(4):719–34.PubMedPubMedCentralCrossRef
44.
Hasan HF, Abdel-Rafei MK, Galal SM. Diosmin attenuates radiation-induced hepatic fibrosis by boosting PPAR-gamma expression and hampering miR-17-5p-activated canonical Wnt-beta-catenin signaling. Biochem Cell Biol. 2017;95(3):400–14.PubMedCrossRef
45.
Zampieri F, Coen M, Gabbiani G. The prehistory of the cytoskeleton concept. Cytoskeleton (Hoboken, NJ). 2014;71(8):464–71.CrossRef
46.
Li Y, Foster W, Deasy BM, Chan Y, Prisk V, Tang Y, Cummins J, Huard J. Transforming growth factor-beta1 induces the differentiation of myogenic cells into fibrotic cells in injured skeletal muscle: a key event in muscle fibrogenesis. Am J Pathol. 2004;164(3):1007–19.PubMedPubMedCentralCrossRef
47.
Imaeda M, Ishikawa H, Yoshida Y, Takahashi T, Ohkubo Y, Musha A, Komachi M, Nakazato Y, Nakano T. Long-term pathological and immunohistochemical features in the liver after intraoperative whole-liver irradiation in rats. J Radiat Res. 2014;55(4):665–73.PubMedPubMedCentralCrossRef
48.
Martin M, Lefaix J, Delanian S. TGF-beta1 and radiation fibrosis: a master switch and a specific therapeutic target? Int J Radiat Oncol Biol Phys. 2000;47(2):277–90.PubMedCrossRef
49.
Citrin DE, Prasanna PGS, Walker AJ, Freeman ML, Eke I, Barcellos-Hoff MH, Arankalayil MJ, Cohen EP, Wilkins RC, Ahmed MM, et al. Radiation-induced fibrosis: mechanisms and opportunities to mitigate. Report of an NCI workshop, September 19, 2016. Radiat Res. 2017;188(1):1–20.PubMedPubMedCentralCrossRef
50.
Soboll S, Conrad A, Eistert A, Herick K, Kramer R. Uptake of creatine phosphate into heart mitochondria: a leak in the creatine shuttle. Biochim Biophys Acta. 1997;1320(1):27–33.PubMedCrossRef
51.
Alexander KC, Aiyar AS, Sreenivasan A. Site of impairment of oxidative phosphorylation in irradiated rats. Biochim Biophys Acta. 1972;283(2):206–16.PubMedCrossRef
52.
Barjaktarovic Z, Schmaltz D, Shyla A, Azimzadeh O, Schulz S, Haagen J, Dorr W, Sarioglu H, Schafer A, Atkinson MJ, et al. Radiation-induced signaling results in mitochondrial impairment in mouse heart at 4 weeks after exposure to X-rays. PLoS One. 2011;6(12):e27811.PubMedPubMedCentralCrossRef
53.
Barjaktarovic Z, Shyla A, Azimzadeh O, Schulz S, Haagen J, Dorr W, Sarioglu H, Atkinson MJ, Zischka H, Tapio S. Ionising radiation induces persistent alterations in the cardiac mitochondrial function of C57BL/6 mice 40 weeks after local heart exposure. Radiother Oncol. 2013;106(3):404–10.PubMedCrossRef
54.
Milliat F, Francois A, Isoir M, Deutsch E, Tamarat R, Tarlet G, Atfi A, Validire P, Bourhis J, Sabourin JC, et al. Influence of endothelial cells on vascular smooth muscle cells phenotype after irradiation: implication in radiation-induced vascular damages. Am J Pathol. 2006;169(4):1484–95.PubMedPubMedCentralCrossRef
55.
Dorresteijn LD, Kappelle AC, Boogerd W, Klokman WJ, Balm AJ, Keus RB, van Leeuwen FE, Bartelink H. Increased risk of ischemic stroke after radiotherapy on the neck in patients younger than 60 years. J Clin Oncol. 2002;20(1):282–8.PubMedCrossRef
56.
Heckmann M, Douwes K, Peter R, Degitz K. Vascular activation of adhesion molecule mRNA and cell surface expression by ionizing radiation. Exp Cell Res. 1998;238(1):148–54.PubMedCrossRef
57.
Langley RE, Bump EA, Quartuccio SG, Medeiros D, Braunhut SJ. Radiation-induced apoptosis in microvascular endothelial cells. Br J Cancer. 1997;75(5):666–72.PubMedPubMedCentralCrossRef
58.
Paris F, Fuks Z, Kang A, Capodieci P, Juan G, Ehleiter D, Haimovitz-Friedman A, Cordon-Cardo C, Kolesnick R. Endothelial apoptosis as the primary lesion initiating intestinal radiation damage in mice. Science (New York, NY). 2001;293(5528):293–7.CrossRef
59.
Hubenak JR, Zhang Q, Branch CD, Kronowitz SJ. Mechanisms of injury to normal tissue after radiotherapy: a review. Plast Reconstr Surg. 2014;133(1):49e–56e.PubMedPubMedCentralCrossRef
60.
Seale P, Sabourin LA, Girgis-Gabardo A, Mansouri A, Gruss P, Rudnicki MA. Pax7 is required for the specification of myogenic satellite cells. Cell. 2000;102(6):777–86.PubMedCrossRef
61.
Collins CA, Gnocchi VF, White RB, Boldrin L, Perez-Ruiz A, Relaix F, Morgan JE, Zammit PS. Integrated functions of Pax3 and Pax7 in the regulation of proliferation, cell size and myogenic differentiation. PLoS One. 2009;4(2):e4475.PubMedPubMedCentralCrossRef
62.
Lee EJ, Malik A, Pokharel S, Ahmad S, Mir BA, Cho KH, Kim J, Kong JC, Lee DM, Chung KY, et al. Identification of genes differentially expressed in myogenin knock-down bovine muscle satellite cells during differentiation through RNA sequencing analysis. PLoS One. 2014;9(3):e92447.PubMedPubMedCentralCrossRef
63.
Kuang S, Rudnicki MA. The emerging biology of satellite cells and their therapeutic potential. Trends Mol Med. 2008;14(2):82–91.PubMedCrossRef
64.
Yin H, Zhang S, Gilbert ER, Siegel PB, Zhu Q, Wong EA. Expression profiles of muscle genes in postnatal skeletal muscle in lines of chickens divergently selected for high and low body weight. Poult Sci. 2014;93(1):147–54.PubMedCrossRef
Metadata
Title
Radiation-induced muscle fibrosis rat model: establishment and valuation
Authors
Yue Zhou
Xiaowu Sheng
Feiyan Deng
Hui Wang
Liangfang Shen
Yong Zeng
Qianxi Ni
Shibin Zhan
Xiao Zhou
Publication date
01-12-2018
Publisher
BioMed Central
Published in
Radiation Oncology / Issue 1/2018
Electronic ISSN: 1748-717X
DOI
https://doi.org/10.1186/s13014-018-1104-0

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