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Skeletal muscle fibrosis: an overview

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Abstract

Extracellular matrix (ECM) is an essential component of skeletal muscle. It provides a framework structure that holds myofibers and blood capillaries and nerves supplying the muscle. In addition, it has a principal role in force transmission, maintenance and repair of muscle fibers. Excessive accumulation of ECM components, especially collagens, either due to excessive ECM production, alteration in ECM-degrading activities, or a combination of both is defined as fibrosis. Skeletal muscle fibrosis impairs muscle function, negatively affects muscle regeneration after injury and increases muscle susceptibility to re-injury, therefore, it is considered a major cause of muscle weakness. Fibrosis of skeletal muscle is a hallmark of muscular dystrophies, aging and severe muscle injuries. Thus, a better understanding of the mechanisms of muscle fibrosis will help to advance our knowledge of the events that occur in dystrophic muscle diseases and develop innovative anti-fibrotic therapies to reverse fibrosis in such pathologic conditions. This paper explores an overview of the process of muscle fibrosis, as well as different murine models for studying fibrosis in skeletal muscles. In addition, factors regulating fibrosis and strategies to inhibit muscle fibrosis are discussed.

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References

  • Akpulat U, Onbasilar I, Kocaefe YC (2016) Tenotomy immobilization as a model to investigate skeletal muscle fibrosis (with emphasis on secreted frizzled-related protein 2). Physiol Genomics 48:397–408

    Article  CAS  PubMed  Google Scholar 

  • Alameddine HS, Morgan JE (2016) Matrix metalloproteinases and tissue inhibitor of metalloproteinases in inflammation and fibrosis of skeletal muscles. J Neuromuscul Dis 3:455–473

    Article  PubMed  PubMed Central  Google Scholar 

  • Ameen V, Robson LG (2010) Experimental models of Duchenne muscular dystrophy: relationship with cardiovascular disease. Open Cardiovasc Med J 4:265–277

    Article  PubMed  PubMed Central  Google Scholar 

  • Amthor H, Hoogaars WM (2012) Interference with myostatin/ActRIIB signaling as a therapeutic strategy for Duchenne muscular dystrophy. Curr Gene Ther 12:245–259

    Article  CAS  PubMed  Google Scholar 

  • Arnold L, Henry A, Poron F, Baba-Amer Y, van Rooijen N, Plonquet A, Gherardi RK, Chazaud B (2007) Inflammatory monocytes recruited after skeletal muscle injury switch into antiinflammatory macrophages to support myogenesis. J Exp Med 204:1057–1069

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Arrighi N, Moratal C, Clément N, Giorgetti-Peraldi S, Peraldi P, Loubat A, Kurzenne JY, dani C, Chopard A, Dechesne CA (2015) Characterization of adipocytes derived from fibro/adipogenic progenitors resident in human skeletal muscle. Cell Death Dis 6:e1733

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Bedair HS, Karthikeyan T, Quintero A, Li Y, Huard J (2008) Angiotensin II receptor blockade administered after injury improves muscle regeneration and decreases fibrosis in normal skeletal muscle. Am J Sports Med 36

  • Bersini S, Gilardi M, Mora M, Krol S, Arrigoni C, Candrian C, Zanotti S, Moretti M (2018) Tackling muscle fibrosis: from molecular mechanisms to next generation engineered models to predict drug delivery. Adv Drug Deliv Rev 129:64–77

  • Biressi S, Miyabara EH, Gopinath SD, Carlig PMM, Rando TA (2014) A Wnt-TGFβ2 axis induces a fibrogenic program in muscle stem cells from dystrophic mice. Sci Transl Med 6(267):267ra176 

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Bodanovsky A, Guttman N, Barzilai-Tutsch H, Genin O, Levy O, Pines M, Halevy O (2014) Halofuginone improves muscle-cell survival in muscular dystrophies. Biochim Biophys Acta 1843:1339–1347

    Article  CAS  PubMed  Google Scholar 

  • Brack AS, Conboy MJ, Roy S, Lee M, Kuo CJ, Keller C, Rando TA (2007) Increased Wnt signaling during aging alters muscle stem cell fate and increases fibrosis. Science 317:807–810

    Article  CAS  PubMed  Google Scholar 

  • Braga TT, Agudelo JSH, Camara NOS (2015) Macrophages during the fibrotic process: M2 as friend and foe. Front Immunol 6:602

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Brandan E, Gutierrez J (2013) Role of proteoglycans in the regulation of the skeletal muscle fibrotic response. FEBS J 280:4109–4117

    Article  CAS  PubMed  Google Scholar 

  • Burks TN, Cohn RD (2011) Role of TGF-β signaling in inherited and acquired myopathies. Skelet Muscle 1:19

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Campbell KP, Stull JT (2003) Skeletal muscle basement membrane-sarcolemma-cytoskeleton interaction minireview series. J Biol Chem 278:12599–12600

    Article  CAS  PubMed  Google Scholar 

  • Chan YS, Li Y, Foster W, Horaguchi T, Somogyi G, Fu FH, Huard J (2003) Antifibrotic effects of suramin in injured skeletal muscle after laceration. J Appl Physiol (1985) 95:771–780

    Article  CAS  Google Scholar 

  • Chapman MA, Meza R, Lieber RL (2016) Skeletal muscle fibroblasts in health and disease. Differentiation 92:108–115

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Charge SB, Rudnicki MA (2004) Cellular and molecular regulation of muscle regeneration. Physiol Rev 84:209–238

    Article  CAS  PubMed  Google Scholar 

  • Chaudhary NI, Roth GJ, Hilberg F, Muller-Quernheim J, Prasse A, Zissel G, Schnapp A, Park JE (2007) Inhibition of PDGF, VEGF and FGF signalling attenuates fibrosis. Eur Respir J 29:976–985

    Article  CAS  PubMed  Google Scholar 

  • Chen S, Birk DE (2013) The regulatory roles of small leucine-rich proteoglycans in extracellular assembly. FEBS J 280:2120–2137

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Chen X, Li Y (2009) Role of matrix metalloproteinases in skeletal muscle: migration, differentiation, regeneration and fibrosis. Cell Adhes Migr 3:337–341

    Article  Google Scholar 

  • Chen JW, Chen SY, Li HY, Shang XL, Wu ZY (2008) Effect of exogenous interferon gamma on the healing of injured skeletal muscle following injury. Zhongguo Gu Shang 21:434–437

    CAS  PubMed  Google Scholar 

  • Cheng M, Nguyen MH, Fantuzzi G, Koh TJ (2008) Endogenous interferon-gamma is required for efficient skeletal muscle regeneration. Am J Physiol Cell Physiol 294:C1183–C1191

    Article  CAS  PubMed  Google Scholar 

  • Ciciliot S, Schiaffino S (2010) Regeneration of mammalian skeletal muscle. Basic mechanisms and clinical implications. Curr Pharm Des 16:906–914

    Article  CAS  PubMed  Google Scholar 

  • Cisternas P, Henriquez JP, Brandan E, Inestrosa NC (2014a) Wnt signaling in skeletal muscle dynamics: myogenesis, neuromuscular synapse and fibrosis. Mol Neurobiol 49:574–589

    Article  CAS  PubMed  Google Scholar 

  • Cisternas P, Vio CP, Inestrosa NC (2014b) Role of Wnt signaling in tissue fibrosis, lessons from skeletal muscle and kidney. Curr Mol Med 14:510–522

    Article  CAS  PubMed  Google Scholar 

  • Coley WD, Bogdanik L, Vila MC, Yu Q, Van Der Meulen JH, Rayavarapu S, Novak JS, Nearing M, Quinn JL, Saunders A, Dolan C, Andrews W, Lammert C, Austin A, Partridge TA, Cox GA, Lutz C, Nagaraju K (2016) Effect of genetic background on the dystrophic phenotype in mdx mice. Hum Mol Genet 25:130–145

    Article  CAS  PubMed  Google Scholar 

  • Czerwinska AM, Streminska W, Ciemerych MA, Grabowska I (2012) Mouse gastrocnemius muscle regeneration after mechanical or cardiotoxin injury. Folia Histochem Cytobiol 50:144–153

    Article  PubMed  Google Scholar 

  • Darby IA, Zakuan N, Billet F, Desmouliere A (2016) The myofibroblast, a key cell in normal and pathological tissue repair. Cell Mol Life Sci 73:1145–1157

    Article  CAS  PubMed  Google Scholar 

  • de Rezende Pinto W, de Souza P, Oliveira A (2015) Normal muscle structure, growth, development, and regeneration. Curr Rev Musculosklet Med 8:1–6

    Article  Google Scholar 

  • Delaney K, Kasprzycka P, Ciemerych MA, Zimowska M (2017) The role of TGF-β1 during skeletal muscle regeneration. Cell Biol Int 41:706–715

    Article  CAS  PubMed  Google Scholar 

  • Elbaz M, Yanay N, Aga-Mizrachi S, Brunschwig Z, Kassis I, Ettinger K, Barak V, Nevo Y (2012) Losartan, a therapeutic candidate in congenital muscular dystrophy: studies in the dy2J/dy2J mouse. Ann Neurol 71:699–708

    Article  CAS  PubMed  Google Scholar 

  • Fanbin M, Jianghai C, Juan L, Yang W, Yuxiong W, Yanhua C, Tao L, Zhenbing C (2011) Role of transforming growth factor-β1 in the process of fibrosis of denervated skeletal muscle. J Huazhong Univ Sci Technolog Med Sci 31:77–82

    Article  CAS  PubMed  Google Scholar 

  • Faturi FM, Franco RC, Gigo-Benato D, Turi AC, Silva-Couto MA, Messa SP, Russo TL (2016) Intermittent stretching induces fibrosis in denervated rat muscle. Muscle Nerve 53:118–126

    Article  PubMed  Google Scholar 

  • Filippin LI, Cuevas MJ, Lima E, Marroni NP, Gonzalez-Gallego J, Xavier RM (2011) Nitric oxide regulates the repair of injured skeletal muscle. Nitric Oxide 24:43–49

    Article  CAS  PubMed  Google Scholar 

  • Forcina L, Miano C, Musaro A (2018) The physiopathologic interplay between stem cells and tissue niche in muscle regeneration and the role of IL-6 on muscle homeostasis and diseases. Cytokine Growth Factor Rev 41:1–9

    Article  CAS  PubMed  Google Scholar 

  • Foster W, Li Y, Usas A, Somogyi G, Huard J (2003) Gamma interferon as an antifibrosis agent in skeletal muscle. J Orthop Res 21:798–804

    Article  CAS  PubMed  Google Scholar 

  • Fukada S, Morikawa D, Yamamoto Y, Yoshida T, Sumie N, Yamaguchi M, Ito T, Miyagoe-Suzuki Y, Takeda S, Tsujikawa K, Yamamoto H (2010) Genetic background affects properties of satellite cells and mdx phenotypes. Am J Pathol 176:2414–2424

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Fukushima K, Badlani N, Usas A, Riano F, Fu F, Huard J (2001) The use of an antifibrosis agent to improve muscle recovery after laceration. Am J Sports Med 29:394–402

    Article  CAS  PubMed  Google Scholar 

  • Garg K, Corona BT, Walters TJ (2014) Losartan administration reduces fibrosis but hinders functional recovery after volumetric muscle loss injury. J Appl Physiol (1985) 117:1120–1131

    Article  CAS  Google Scholar 

  • Garg K, Corona BT, Walters TJ (2015) Therapeutic strategies for preventing skeletal muscle fibrosis after injury. Front Pharmacol 6:87

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Gillies AR, Lieber RL (2011) Structure and function of the skeletal muscle extracellular matrix. Muscle Nerve 44:318–331

    CAS  PubMed  PubMed Central  Google Scholar 

  • Gilson H, Schakman O, Kalista S, Lause P, Tsuchida K, Thissen JP (2009) Follistatin induces muscle hypertrophy through satellite cell proliferation and inhibition of both myostatin and activin. Am J Physiol Endocrinol Metab 297:E157–E164

    Article  CAS  PubMed  Google Scholar 

  • Gosselin LE, McCormick KM (2004) Targeting the immune system to improve ventilatory function in muscular dystrophy. Med Sci Sports Exerc 36:44–51

    Article  CAS  PubMed  Google Scholar 

  • Grounds MD (2008) Complexity of extracellular matrix and skeletal muscle regeneration. Skeletal muscle repair and regeneration. Springer Netherlands, Dordrecht, pp 269–302

    Book  Google Scholar 

  • Guo Y, Xiao L, Sun L, Liu F (2012) Wnt/β-catenin signaling: a promising new target for fibrosis diseases. Physiol Res 61:337–346

    CAS  PubMed  Google Scholar 

  • Gutpell KM, Hoffman LM (2015) VEGF induces stress fiber formation in fibroblasts isolated from dystrophic muscle. J Cell Commun Signal 9:353–360

    Article  PubMed  PubMed Central  Google Scholar 

  • Gutpell KM, Hrinivich WT, Hoffman LM (2015) Skeletal muscle fibrosis in the mdx/utrn+/- mouse validates its suitability as a murine model of Duchenne muscular dystrophy. PLoS One 10:e0117306

    Article  PubMed  PubMed Central  Google Scholar 

  • Hirunsai M, Srikuea R, Yimlamai T (2015) Heat stress promotes extracellular matrix remodelling via TGF-β1and MMP-2/TIMP-2 modulation in tenotomised soleus and plantaris muscles. Int J Hyperth 31:336–348

    Article  CAS  Google Scholar 

  • Huebner KD, Jassal DS, Halevy O, Pines M, Anderson JE (2008) Functional resolution of fibrosis in mdx mouse dystrophic heart and skeletal muscle by halofuginone. Am J Physiol Heart Circ Physiol 294:H1550–H1561

    Article  CAS  PubMed  Google Scholar 

  • Hwang JH, Ra Y-J, Lee KM, Lee JY, Ghil SH (2006) Therapeutic effect of passive mobilization exercise on improvement of muscle regeneration and prevention of fibrosis after laceration injury of rat. Arch Phys Med Rehabil 87:20–26

    Article  PubMed  Google Scholar 

  • Hwang OK, Park JK, Lee EJ, Lee EM, Kim AY, Jeong KS (2016) Therapeutic effect of losartan, an angiotensin II type 1 receptor antagonist, on CCl4-induced skeletal muscle injury. Int J Mol Sci 17:227

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Iwabu A, Smith K, Allen FD, Lauffenburger DA, Wells A (2004) Epidermal growth factor induces fibroblast contractility and motility via a protein kinase C delta-dependent pathway. J Biol Chem 279:14551–14560

    Article  CAS  PubMed  Google Scholar 

  • Jarvinen TA, Jozsa L, Kannus P, Jarvinen TL, Jarvinen M (2002) Organization and distribution of intramuscular connective tissue in normal and immobilized skeletal muscles. An immunohistochemical, polarization and scanning electron microscopic study. J Muscle Res Cell Motil 23:245–254

    Article  PubMed  Google Scholar 

  • Jarvinen TA, Jarvinen TL, Kaariainen M, Kalimo H, Jarvinen M (2005) Muscle injuries: biology and treatment. Am J Sports Med 33:745–764

    Article  PubMed  Google Scholar 

  • Juban G, Chazaud B (2017) Metabolic regulation of macrophages during tissue repair: insights from skeletal muscle regeneration. FEBS Lett 591:3007–3021

    Article  CAS  PubMed  Google Scholar 

  • Kang PB, Kunkel LM (2006) Muscular dystrophies. In: Runge M, Patterson C (eds) Principles of molecular medicine. Humana Press, New York, pp 693–699

    Chapter  Google Scholar 

  • Karalaki M, Fili S, Philippou A, Koutsilieris M (2009) Muscle regeneration: cellular and molecular events. In Vivo 23:779–796

    CAS  PubMed  Google Scholar 

  • Karvinen H, Pasanen E, Rissanen TT, Korpisalo P, Vahakangas E, Jazwa A, Giacca M, Yla-Herttuala S (2011) Long-term VEGF-A expression promotes aberrant angiogenesis and fibrosis in skeletal muscle. Gene Ther 18:1166–1172

    Article  CAS  PubMed  Google Scholar 

  • Kawai H, Nishino H, Kusaka K, Naruo T, Tamaki Y, Iwasa M (1990) Experimental glycerol myopathy: a histological study. Acta Neuropathol 80:192–197

    Article  CAS  PubMed  Google Scholar 

  • Kendall RT, Feghali-Bostwick CA (2014) Fibroblasts in fibrosis: novel roles and mediators. Front Pharmacol 5:123

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Kim J, Lee J (2017) Role of transforming growth factor-β in muscle damage and regeneration: focused on eccentric muscle contraction. J Exerc Rehabil 13:621–626

    Article  PubMed  PubMed Central  Google Scholar 

  • Kim H, Baek CH, Lee RB, Chang JW, Yang WS, Lee SK (2017) Anti-fibrotic effect of losartan, an angiotensin II receptor blocker, is mediated through inhibition of ER stress via up-regulation of SIRT1, followed by induction of HO-1 and thioredoxin. Int J Mol Sci 18:305

    Article  CAS  PubMed Central  Google Scholar 

  • Kjaer M (2004) Role of extracellular matrix in adaptation of tendon and skeletal muscle to mechanical loading. Physiol Rev 84:649–698

    Article  CAS  PubMed  Google Scholar 

  • Kobayashi T, Uehara K, Ota S, Tobita K, Ambrosio F, Cummins JH, Terada S, Fu FH, Huard J (2013) The timing of administration of a clinically relevant dose of losartan influences the healing process after contusion induced muscle injury. J Appl Physiol (1985) 114:262–273

    Article  CAS  Google Scholar 

  • Kovanen V (2002) Intramuscular extracellular matrix: complex environment of muscle cells. Exerc Sport Sci Rev 30:20–25

    Article  PubMed  Google Scholar 

  • Laumonier T, Menetrey J (2016) Muscle injuries and strategies for improving their repair. J Exp Orthop 3:1–9

    Article  Google Scholar 

  • Lei H, Leong D, Smith LR, Barton ER (2013) Matrix metalloproteinase 13 is a new contributor to skeletal muscle regeneration and critical for myoblast migration. Am J Physiol Cell Physiol 305:C529–C538

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Lemos DR, Babaeijandaghi F, Low M, Chang CK, Lee ST, Fiore D, Zhang RH, Natarajan A, Nedospasov SA, Rossi FM (2015) Nilotinib reduces muscle fibrosis in chronic muscle injury by promoting TNF-mediated apoptosis of fibro/adipogenic progenitors. Nat Med 21:786–794

    Article  CAS  PubMed  Google Scholar 

  • Li Y, Foster W, Deasy BM, Chan Y, Prisk V, Tang Y, Cummins J, Huard J (2004) Transforming growth factor-β1 induces the differentiation of myogenic cells into fibrotic cells in injured skeletal muscle: a key event in muscle fibrogenesis. Am J Pathol 164:1007–1019

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Li Y, Li J, Zhu J, Sun B, Branca M, Tang Y, Foster W, Xiao X, Huard J (2007) Decorin gene transfer promotes muscle cell differentiation and muscle regeneration. Mol Ther 15:1616–1622

    Article  CAS  PubMed  Google Scholar 

  • Li ZB, Kollias HD, Wagner KR (2008) Myostatin directly regulates skeletal muscle fibrosis. J Biol Chem 283:19371–19378

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Li ZB, Zhang J, Wagner KR (2012) Inhibition of myostatin reverses muscle fibrosis through apoptosis. J Cell Sci 125:3957–3965

    Article  CAS  Google Scholar 

  • Lieber RL, Ward SR (2013) Cellular mechanisms of tissue fibrosis. 4. Structural and functional consequences of skeletal muscle fibrosis. Am J Physiol Cell Physiol 305:C241–C252

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Lieu C, Heymach J, Overman M, Tran H, Kopetz S (2011) Beyond VEGF: inhibition of the fibroblast growth factor pathway and antiangiogenesis. Clin Cancer Res 17:6130–6139

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Liu F, Tang W, Chen D, Li M, Gao Y, Zheng H, Chen S (2016) Expression of TGF-beta1 and CTGF is associated with fibrosis of denervated sternocleidomastoid muscles in mice. Tohoku J Exp Med 238:49–56

    Article  CAS  PubMed  Google Scholar 

  • Madaro L, Passafaro M, Sala D, Etxaniz U, Lugarini F, Proietti D, Alfonsi MV, Nicoletti C, Gatto S, De Bardi M, Rojas-Garcia R, Giordani L, Marinelli S, Pagliarini V, Sette C, Sacco A, Puri PL (2018) Denervation-activated STAT3-IL-6 signalling in fibro-adipogenic progenitors promotes myofibres atrophy and fibrosis. Nat Cell Biol 20:917–927

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Mahdy MA(2018) Glycerol-induced injury as a new model of muscle regeneration. Cell Tissue Res 374:233–241

  • Mahdy MA, Lei HY, Wakamatsu J-I, Hosaka YZ, Nishimura T (2015) Comparative study of muscle regeneration following cardiotoxin and glycerol injury. Ann Anat 202:18–27

    Article  PubMed  Google Scholar 

  • Mahdy MA, Warita K, Hosaka YZ (2016) Early ultrastructural events of skeletal muscle damage following cardiotoxin-induced injury and glycerol-induced injury. Micron 91:29–40

    Article  CAS  PubMed  Google Scholar 

  • Mahdy MA, Warita K, Hosaka YZ (2017) Effects of transforming growth factor-β1 treatment on muscle regeneration and adipogenesis in glycerol-injured muscle. Anim Sci J 88:1811–1819

    Article  CAS  PubMed  Google Scholar 

  • Mahdy MA, Warita K, Hosaka YZ (2018) Glycerol induces early fibrosis in regenerating rat skeletal muscles. J Vet Med Sci. https://doi.org/10.1292/jvms.18-0328

  • Mann CJ, Perdiguero E, Kharraz Y, Aguilar S, Pessina P, Serrano AL, Munoz-Canoves P (2011) Aberrant repair and fibrosis development in skeletal muscle. Skelet Muscle 4:21

    Article  Google Scholar 

  • McCormick RJ, Phillips AL (1999) Muscle extracellular matrix. In: Xiong YL, Chi-Tang H, Shahidi F (eds) Quality attributes of muscle foods. Springer US, Boston, MA, pp 219–227

    Chapter  Google Scholar 

  • McCroskery S, Thomas M, Platt L, Hennebry A, Nishimura T, McLeay L, Sharma M, Kambadur R (2005) Improved muscle healing through enhanced regeneration and reduced fibrosis in myostatin-null mice. J Cell Sci 118:3531–3541

    Article  CAS  PubMed  Google Scholar 

  • McGreevy JW, Hakim CH, McIntosh MA, Duan D (2015) Animal models of Duchenne muscular dystrophy: from basic mechanisms to gene therapy. Dis Models Mech 8:195–213

    Article  CAS  Google Scholar 

  • Menetrey J, Kasemkijwattana C, Fu FH, Moreland MS, Huard J (1999) Suturing versus immobilization of a muscle laceration. A morphological and functional study in a mouse model. Am J Sports Med 27:222–229

    Article  CAS  PubMed  Google Scholar 

  • Mimura Y, Ihn H, Jinnin M, Asano Y, Yamane K, Tamaki K (2004) Epidermal growth factor induces fibronectin expression in human dermal fibroblasts via protein kinase C δ signaling pathway. J Invest Dermatol 122:1390–1398

    Article  CAS  PubMed  Google Scholar 

  • Morales MG, Cabello-Verrugio C, Santander C, Cabrera D, Goldschmeding R, Brandan E (2011) CTGF/CCN-2 over-expression can directly induce features of skeletal muscle dystrophy. J Pathol 225:490–501

    Article  CAS  PubMed  Google Scholar 

  • Morales MG, Gutierrez J, Cabello-Verrugio C, Cabrera D, Lipson KE, Goldschmeding R, Brandan E (2013) Reducing CTGF/CCN2 slows down mdx muscle dystrophy and improves cell therapy. Hum Mol Genet 22:4938–4951

    Article  CAS  PubMed  Google Scholar 

  • Morales MG, Acuna MJ, Cabrera D, Goldschmeding R, Brandan E (2018) The pro-fibrotic connective tissue growth factor (CTGF/CCN2) correlates with the number of necrotic-regenerative foci in dystrophic muscle. J Cell Commun Signal 12:413–421

    Article  PubMed  Google Scholar 

  • Morine KJ, Bish LT, Selsby JT, Gazzara JA, Pendrak K, Sleeper MM, Barton ER, Lee SJ, Sweeney HL (2010) Activin IIB receptor blockade attenuates dystrophic pathology in a mouse model of Duchenne muscular dystrophy. Muscle Nerve 42:722–730

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Munoz-Canoves P, Serrano AL (2015) Macrophages decide between regeneration and fibrosis in muscle. Trends Endocrinol Metab 26:449–450

    Article  CAS  PubMed  Google Scholar 

  • Murphy S, Ohlendieck K (2016) The extracellular matrix complexome from skeletal muscle In: Travascio F (ed) Composition and function of the extracellular matrix in the human body. pp 69–92

  • Murphy MM, Lawson JA, Mathew SJ, Hutcheson DA, Kardon G (2011) Satellite cells, connective tissue fibroblasts and their interactions are crucial for muscle regeneration. Development 138:3625–3637

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Murray IR, Gonzalez ZN, Baily J, Dobie R, Wallace RJ, Mackinnon AC, Smith JR, Greenhalgh SN, Thompson AI, Conroy KP, Griggs DW, Ruminski PG, Gray GA, Singh M, Campbell MA, Kendall TJ, Dai J, Li Y, Iredale JP, Simpson H, Huard J, Peault B, Henderson NC (2017) Alphav integrins on mesenchymal cells regulate skeletal and cardiac muscle fibrosis. Nat Commun 8:1118

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Nozaki M, Li Y, Zhu J, Ambrosio F, Uehara K, Fu FH, Huard J (2008) Improved muscle healing after contusion injury by the inhibitory effect of suramin on myostatin, a negative regulator of muscle growth. Am J Sports Med 36:2354–2362

    Article  PubMed  Google Scholar 

  • Ogle ME, Segar CE, Sridhar S, Botchwey EA (2016) Monocytes and macrophages in tissue repair: implications for immunoregenerative biomaterial design. Exp Biol Med 241:1084–1097

    Article  CAS  Google Scholar 

  • Osses N, Brandan E (2002) ECM is required for skeletal muscle differentiation independently of muscle regulatory factor expression. Am J Physiol Cell Physiol 282:C383–C394

    Article  CAS  PubMed  Google Scholar 

  • Parker MH (2015) The altered fate of aging satellite cells is determined by signaling and epigenetic changes. Front Genet 6:59

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Pedersen BK, Steensberg A, Schjerling P (2001) Muscle-derived interleukin-6: possible biological effects. J Physiol 536:329–337

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Perandini LA, Chimin P, Lutkemeyer DDS, Camara NOS (2018) Chronic inflammation in skeletal muscle impairs satellite cells function during regeneration: can physical exercise restore the satellite cell niche? FEBS J 285:1973–1984

    Article  CAS  PubMed  Google Scholar 

  • Pessina P, Cabrera D, Morales MG, Riquelme CA, Gutierrez J, Serrano AL, Brandan E, Munoz-Canoves P (2014) Novel and optimized strategies for inducing fibrosis in vivo: focus on Duchenne muscular dystrophy. Skelet Muscle 4:7

    Article  PubMed  PubMed Central  Google Scholar 

  • Pines M, Spector I (2015) Halofuginone—the multifaceted molecule. Molecules 20:573–594

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Piñol-Jurado P, Suárez-Calvet X, Fernández-Simón E, Gallardo E, de la Oliva N, Martínez-Muriana A, Gómez-Gálvez P, Escudero LM, Pérez-Peiró M, Wollin L, de Luna N, Navarro X, Illa I, Díaz-Manera J (2018) Nintedanib decreases muscle fibrosis and improves muscle function in a murine model of dystrophinopathy. Cell Death Dis 9:776

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Prazeres PHDM, Turquetti AOM, Azevedo PO, Barreto RSN, Miglino MA, Mintz A, Delbono O, Birbrair A (2018) Perivascular cell αv integrins as a target to treat skeletal muscle fibrosis. Int J Biochem Cell Biol 5:109–113

    Article  CAS  Google Scholar 

  • Purslow PP (2010) Muscle fascia and force transmission. J Bodyw Mov Ther 14:411–417

    Article  PubMed  Google Scholar 

  • Purslow PP (2014) New developments on the role of intramuscular connective tissue in meat toughness. Annu Rev Food Sci Technol 5:133–153

    Article  CAS  PubMed  Google Scholar 

  • Rajasekaran MR, Kanoo S, Fu J, Nguyen ML, Bhargava V, Mittal RK (2017) Age-related external anal sphincter muscle dysfunction and fibrosis: possible role of Wnt/beta-catenin signaling pathways. Am J Physiol Gastrointest Liver Physiol 313:G581–g588

    Article  CAS  PubMed  Google Scholar 

  • Riso E-M, Kaasik P, Seene T (2016) Remodelling of skeletal muscle extracellular matrix: effect of unloading and reloading. In: Travascio F (ed) Composition and function of the extracellular matrix in the human body. InTech, Rijeka, pp 45–68

    Google Scholar 

  • Rodino-Klapac LR, Haidet AM, Kota J, Handy C, Kaspar BK, Mendell JR (2009) Inhibition of myostatin with emphasis on follistatin as a therapy for muscle disease. Muscle Nerve 39:283–296

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Rodrigues M, Echigoya Y, Fukada SI, Yokota T (2016) Current translational research and murine models for Duchenne muscular dystrophy. J Neuromuscul Dis 3:29–48

    Article  PubMed  PubMed Central  Google Scholar 

  • Rosenbloom J, Mendoza FA, Jimenez SA (2013) Strategies for anti-fibrotic therapies. Biochim Biophys Acta 1832:1088–1103

    Article  CAS  PubMed  Google Scholar 

  • Ross MH, Pawlina W (2010) Histology: a text and atlas: with correlated cell and molecular biology. Lippincott Williams and Wilkins, Philadelphia

    Google Scholar 

  • Saclier M, Cuvellier S, Magnan M, Mounier R, Chazaud B (2013) Monocyte/macrophage interactions with myogenic precursor cells during skeletal muscle regeneration. FEBS J 280:4118–4130

    Article  CAS  PubMed  Google Scholar 

  • Sambasivan R, Tajbakhsh S (2015) Adult skeletal muscle stem cells. Results Probl Cell Differ 56:191–213

    Article  CAS  PubMed  Google Scholar 

  • Serrano AL, Muñoz-Cánoves P (2010) Regulation and dysregulation of fibrosis in skeletal muscle. Exp Cell Res 316:3050–3058

    Article  CAS  PubMed  Google Scholar 

  • Serrano AL, Muñoz-Cánoves P (2016) Fibrosis development in early-onset muscular dystrophies: mechanisms and translational implications. Sem Cell Dev Biol 64:181–190

    Article  CAS  Google Scholar 

  • Serrano AL, Mann CJ, Vidal B, Ardite E, Perdiguero E, Munoz-Canoves P (2011) Cellular and molecular mechanisms regulating fibrosis in skeletal muscle repair and disease. Curr Top Dev Biol 96:167–201

    Article  CAS  PubMed  Google Scholar 

  • Smith LR, Barton ER (2018) Regulation of fibrosis in muscular dystrophy. Matrix Biol 68-69:602–615

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Soehnlein O, Lindbom L, Weber C (2009) Mechanisms underlying neutrophil-mediated monocyte recruitment. Blood 114:4613–4623

    Article  CAS  PubMed  Google Scholar 

  • Speck K, Schneider BS, Deashinta N (2013) A rodent model to advance the field treatment of crush muscle injury during earthquakes and other natural disasters. Biol Res Nurs 15:17–25

    Article  PubMed  Google Scholar 

  • Stearns-Reider KM, D'Amore A, Beezhold K, Rothrauff B, Cavalli L, Wagner WR, Vorp DA, Tsamis A, Shinde S, Zhang C, Barchowsky A, Rando TA, Tuan RS, Ambrosio F (2017) Aging of the skeletal muscle extracellular matrix drives a stem cell fibrogenic conversion. Aging Cell 16:518–528

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Sun G, Haginoya K, Wu Y, Chiba Y, Nakanishi T, Onuma A, Sato Y, Takigawa M, Iinuma K, Tsuchiya S (2008) Connective tissue growth factor is overexpressed in muscles of human muscular dystrophy. J Neurol Sci 267:48–56

    Article  CAS  PubMed  Google Scholar 

  • Takagi R, Fujita N, Arakawa T, Kawada S, Ishii N, Miki A (2011) Influence of icing on muscle regeneration after crush injury to skeletal muscles in rats. J Appl Physiol (1985) 110:382–388

    Article  Google Scholar 

  • Thorley M, Malatras A, Duddy W, Le Gall L, Mouly V, Butler Browne G, Duguez S (2015) Changes in communication between muscle stem cells and their environment with aging. J Neuromuscul Dis 2:205–217

    Article  PubMed  PubMed Central  Google Scholar 

  • Tidball JG (2005) Inflammatory processes in muscle injury and repair. Am J Physiol Regul Integr Comp Physiol 288:R345–R353

    Article  CAS  PubMed  Google Scholar 

  • Tidball JG, Villalta SA (2010) Regulatory interactions between muscle and the immune system during muscle regeneration. Am J Physiol Regul Integr Comp Physiol 298:R1173–R1187

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Tidball JG, Welc SS (2015) Macrophage-derived IGF-1 is a potent coordinator of myogenesis and inflammation in regenerating muscle. Mol Ther 23:1134–1135

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Trensz F, Haroun S, Cloutier A, Richter MV, Grenier G (2010) A muscle resident cell population promotes fibrosis in hindlimb skeletal muscles of mdx mice through the Wnt canonical pathway. Am J Physiol Cell Physiol 299:C939–C947

    Article  CAS  PubMed  Google Scholar 

  • Turgeman T, Hagai Y, Huebner K, Jassal DS, Anderson JE, Genin O, Nagler A, Halevy O, Pines M (2008) Prevention of muscle fibrosis and improvement in muscle performance in the mdx mouse by halofuginone. Neuromuscul Disord 18:857–868

    Article  PubMed  Google Scholar 

  • Turrina A, Martinez-Gonzalez MA, Stecco C (2013) The muscular force transmission system: role of the intramuscular connective tissue. J Bodyw Mov Ther 17:95–102

    Article  PubMed  Google Scholar 

  • Uezumi A, Fukada S, Yamamoto N, Takeda S, Tsuchida K (2010) Mesenchymal progenitors distinct from satellite cells contribute to ectopic fat cell formation in skeletal muscle. Nat Cell Biol 12:143–152

    Article  CAS  PubMed  Google Scholar 

  • Uezumi A, Ito T, Morikawa D, Shimizu N, Yoneda T, Segawa M, Yamaguchi M, Ogawa R, Matev MM, Miyagoe-Suzuki Y, Takeda S, Tsujikawa K, Tsuchida K, Yamamoto H, Fukada S (2011) Fibrosis and adipogenesis originate from a common mesenchymal progenitor in skeletal muscle. J Cell Sci 124:3654–3664

    Article  CAS  PubMed  Google Scholar 

  • Uezumi A, Ikemoto-Uezumi M, Tsuchida K (2014) Roles of nonmyogenic mesenchymal progenitors in pathogenesis and regeneration of skeletal muscle. Front Physiol 5:68

    Article  PubMed  PubMed Central  Google Scholar 

  • Urciuolo A, Quarta M, Morbidoni V, Gattazzo F, Molon S, Grumati P, Montemurro F, Tedesco FS, Blaauw B, Cossu G, Vozzi G, Rando TA, Bonaldo P (2013) Collagen VI regulates satellite cell self-renewal and muscle regeneration. Nat Commun 4:1964

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Valencia AP, Iyer SR, Spangenburg EE, Gilotra MN, Lovering RM (2017) Impaired contractile function of the supraspinatus in the acute period following a rotator cuff tear. BMC Musculoskelet Disord 18:436

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Velleman SG, Shin J, Li X, Song Y (2012) Review: the skeletal muscle extracellular matrix: possible roles in the regulation of muscle development and growth. Can J Anim Sci 92:1–10

    Article  CAS  Google Scholar 

  • Vial C, Zuniga LM, Cabello-Verrugio C, Canon P, Fadic R, Brandan E (2008) Skeletal muscle cells express the profibrotic cytokine connective tissue growth factor (CTGF/CCN2), which induces their dedifferentiation. J Cell Physiol 215:410–421

    Article  CAS  PubMed  Google Scholar 

  • von Maltzahn J, Chang NC, Bentzinger CF, Rudnicki MA (2012) Wnt signaling in myogenesis. Trends Cell Biol 22:602–609

    Article  CAS  Google Scholar 

  • Walton KL, Johnson KE, Harrison CA (2017) Targeting TGF-β mediated SMAD signaling for the prevention of fibrosis. Front Pharmacol 8:461

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Wang Z, Tang Z (2016) Composition and function of extracellular matrix in development of skeletal muscle. In: Travascio F (ed) Composition and function of the extracellular matrix in the human body. InTech, Rijeka, pp 25–43

    Google Scholar 

  • Wang X, Zhao W, Ransohoff RM, Zhou L (2016) Identification and function of fibrocytes in skeletal muscle injury repair and muscular dystrophy. J Immunol 197:4750–4761

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Wollin L, Maillet I, Quesniaux V, Holweg A, Ryffel B (2014) Antifibrotic and anti-inflammatory activity of the tyrosine kinase inhibitor nintedanib in experimental models of lung fibrosis. J Pharmacol Exp Ther 349:209–220

    Article  CAS  PubMed  Google Scholar 

  • Yaden BC, Croy JE, Wang Y, Wilson JM, Datta-Mannan A, Shetler P, Milner A, Bryant HU, Andrews J, Dai G, Krishnan V (2014) Follistatin: a novel therapeutic for the improvement of muscle regeneration. J Pharmacol Exp Ther 349:355–371

    Article  CAS  PubMed  Google Scholar 

  • Yin H, Price F, Rudnicki MA (2013) Satellite cells and the muscle stem cell niche. Physiol Rev 93:23–67

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • You DH, Nam MJ (2013) Effects of human epidermal growth factor gene-transfected mesenchymal stem cells on fibroblast migration and proliferation. Cell Prolif 46:408–415

    Article  CAS  PubMed  Google Scholar 

  • Yu A, Matsuda Y, Takeda A, Uchinuma E, Kuroyanagi Y (2012) Effect of EGF and bFGF on fibroblast proliferation and angiogenic cytokine production from cultured dermal substitutes. J Biomater Sci Polym Ed 23:1315–1324

    Article  CAS  PubMed  Google Scholar 

  • Yucel N, Chang AC, Day JW, Rosenthal N, Blau HM (2018) Humanizing the mdx mouse model of DMD: the long and the short of it. npj Regenerative Medicine 3:4

    Article  PubMed  PubMed Central  Google Scholar 

  • Zanotti S, Gibertini S, Di Blasi C, Cappelletti C, Bernasconi P, Mantegazza R, Morandi L, Mora M (2011) Osteopontin is highly expressed in severely dystrophic muscle and seems to play a role in muscle regeneration and fibrosis. Histopathology 59:1215–1228

    Article  PubMed  Google Scholar 

  • Wang X, Zhao W, Ransohoff RM, Zhou L (2018) Infiltrating macrophages are broadly activated at the early stage to support acute skeletal muscle injury repair. J Neuroimmunol 317:55–66

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Zhou Y, Lovell D, Bethea M, Yoseph B, Poteracki J, Soker S, Criswell T (2017) The impact of age on skeletal muscle progenitor cell survival and fate after injury. Tissue Eng Part C Methods 23:1012–1021

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Zhu J, Li Y, Shen W, Qiao C, Ambrosio F, Lavasani M, Nozaki M, Branca MF, Huard J (2007) Relationships between transforming growth factor-β1, myostatin, and decorin: implications for skeletal muscle fibrosis. J Biol Chem 282:25852–25863

    Article  CAS  PubMed  Google Scholar 

  • Zhu J, Li Y, Lu A, Gharaibeh B, Ma J, Kobayashi T, Quintero AJ, Huard J (2011) Follistatin improves skeletal muscle healing after injury and disease through an interaction with muscle regeneration, angiogenesis, and fibrosis. Am J Pathol 179:915–930

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Zimowska M, Duchesnay A, Dragun P, Oberbek A, Moraczewski J, Martelly I (2009) Immunoneutralization of TGF-β1 improves skeletal muscle regeneration: effects on myoblast differentiation and glycosaminoglycan content. J Cell Biol 2009:659372

    CAS  Google Scholar 

  • Živković SA, Clemens PR (2015) Muscular dystrophy. In: Zigmond MJ, Coyle JT, Rowland L (eds) Neurobiology of brain disorders. Academic Press, San Diego, pp 151–166

    Google Scholar 

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Acknowledgements

The author is supported by a Postdoctoral Fellowship from the University of Pretoria, South Africa. The author thanks Hamza I. Isa, Ahmadu Bello University, Zaria, for editing the draft of this manuscript.

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  1. Department of Anatomy and Physiology, Faculty of Veterinary Science, University of Pretoria, Onderstepoort, 0110, South Africa

    Mohamed A. A. Mahdy

  2. Department of Anatomy and Embryology, Faculty of Veterinary Medicine, South Valley University, Qena, 83525, Egypt

    Mohamed A. A. Mahdy

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Mahdy, M.A.A. Skeletal muscle fibrosis: an overview. Cell Tissue Res 375, 575–588 (2019). https://doi.org/10.1007/s00441-018-2955-2

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