Understanding the process of fibrosis in Duchenne muscular dystrophy

Yacine Kharraz, Joana Guerra, Patrizia Pessina, Antonio L Serrano, Pura Muñoz-Cánoves, Yacine Kharraz, Joana Guerra, Patrizia Pessina, Antonio L Serrano, Pura Muñoz-Cánoves

Abstract

Fibrosis is the aberrant deposition of extracellular matrix (ECM) components during tissue healing leading to loss of its architecture and function. Fibrotic diseases are often associated with chronic pathologies and occur in a large variety of vital organs and tissues, including skeletal muscle. In human muscle, fibrosis is most readily associated with the severe muscle wasting disorder Duchenne muscular dystrophy (DMD), caused by loss of dystrophin gene function. In DMD, skeletal muscle degenerates and is infiltrated by inflammatory cells and the functions of the muscle stem cells (satellite cells) become impeded and fibrogenic cells hyperproliferate and are overactivated, leading to the substitution of skeletal muscle with nonfunctional fibrotic tissue. Here, we review new developments in our understanding of the mechanisms leading to fibrosis in DMD and several recent advances towards reverting it, as potential treatments to attenuate disease progression.

Figures

Figure 1
Figure 1
Crosstalk between TGFβ signaling and the renin-angiotensin system in fibrosis. TGFβ can signal via its canonical pathway, involving Smad proteins, or through several alternative pathways such as the p38 MAPK signaling or the RAS/ERK MAPK signaling pathways. Both canonical and alternative pathways lead to expression of molecules implicated in fibrosis such as CTGF or PAI-1. Similarly, Ang II signals through AT1 or AT2 and can also activate Smad proteins and the p38 MAPK signaling pathway, leading to increased expression of profibrotic genes. Ang 1–7 has an opposite effect, inhibiting the canonical TGFβ pathway. Antifibrotic molecules inhibiting RAS or the TGFβ signaling are indicated in red.

References

    1. Emery AEH. The muscular dystrophies. The Lancet. 2002;359(9307):687–695.
    1. Leung DG, Wagner KR. Therapeutic advances in muscular dystrophy. Annals of Neurology. 2013;74:404–411.
    1. Ruegg UT. Pharmacological prospects in the treatment of Duchenne muscular dystrophy. Current Opinion in Neurology. 2013;26:577–584.
    1. Meregalli M, Farini A, Belicchi M, et al. Perspectives of stem cell therapy in Duchenne muscular dystrophy. FEBS Journal. 2013;280:4251–4262.
    1. Benedetti S, Hoshiya H, Tedesco FS. Repair or replace? Exploiting novel gene and cell therapy strategies for muscular dystrophies. FEBS Journal. 2013;280:4263–4280.
    1. Briggs D, Morgan JE. Recent progress in satellite cell/myoblast engraftment—relevance for therapy. FEBS Journal. 2013;280:4281–4293.
    1. Konieczny P, Swiderski K, Chamberlain JS. Gene and cell-mediated therapies for muscular dystrophy. Muscle & Nerve. 2013;47:649–663.
    1. Mann CJ, Perdiguero E, Kharraz Y, et al. Aberrant repair and fibrosis development in skeletal muscle. Skeletal Muscle. 2011;1, article 21
    1. Schessl J, Zou Y, Bönnemann CG. Congenital muscular dystrophies and the extracellular matrix. Seminars in Pediatric Neurology. 2006;13(2):80–89.
    1. MacDonald EM, Cohn RD. TGFbeta signaling: its role in fibrosis formation and myopathies. Current Opinion in Rheumatology. 2012;24:628–634.
    1. Lieber RL, Ward SR. Cellular mechanisms of tissue fibrosis—4. Structural and functional consequences of skeletal muscle fibrosis. American Journal of Physiology. Cell Physiology. 2013;305:C241–C252.
    1. Serrano AL, Muñoz-Cánoves P. Regulation and dysregulation of fibrosis in skeletal muscle. Experimental Cell Research. 2010;316(18):3050–3058.
    1. Bowen T, Jenkins RH, Fraser DJ. MicroRNAs, transforming growth factor beta-1, and tissue fibrosis. Journal of Pathology. 2013;229:274–285.
    1. Zhou L, Porter JD, Cheng G, et al. Temporal and spatial mRNA expression patterns of TGF-β1, 2, 3 and TβRI, II, III in skeletal muscles of mdx mice. Neuromuscular Disorders. 2006;16(1):32–38.
    1. Horiguchi M, Ota M, Rifkin DB. Matrix control of transforming growth factor-beta function. Journal of Biochemistry. 2013;152:321–329.
    1. Vidal B, Serrano AL, Tjwa M, et al. Fibrinogen drives dystrophic muscle fibrosis via a TGFβ/alternative macrophage activation pathway. Genes and Development. 2008;22(13):1747–1752.
    1. Ardite E, Perdiguero E, Vidal B, Gutarra S, Serrano AL, Muñoz-Cánoves P. PAI-1-regulated miR-21 defines a novel age-associated fibrogenic pathway in muscular dystrophy. Journal of Cell Biology. 2012;196(1):163–175.
    1. Wynn TA. Cellular and molecular mechanisms of fibrosis. Journal of Pathology. 2008;214(2):199–210.
    1. Samarakoon R, Dobberfuhl AD, Cooley C, et al. Induction of renal fibrotic genes by TGF-beta1 requires EGFR activation, p53 and reactive oxygen species. Cellular Signalling. 2013;25:2198–2209.
    1. Wynn TA. Common and unique mechanisms regulate fibrosis in various fibroproliferative diseases. Journal of Clinical Investigation. 2007;117(3):524–529.
    1. Shi Y, Massagué J. Mechanisms of TGF-β signaling from cell membrane to the nucleus. Cell. 2003;113(6):685–700.
    1. Shi-Wen X, Parapuram SK, Pala D, et al. Requirement of transforming growth factor β-activated kinase 1 for transforming growth factor β-induced α-smooth muscle actin expression and extracellular matrix contraction in fibroblasts. Arthritis and Rheumatism. 2009;60(1):234–241.
    1. Dong Y, Lakhia R, Thomas SS, Wang XH, Silva KA, Zhang L. Interactions between p-Akt and Smad3 in injured muscles initiate myogenesis or fibrogenesis. American Journal of Physiology. Endocrinology and Metabolism. 2013;305:E367–E375.
    1. Brandan E, Cabello-Verrugio C, Vial C. Novel regulatory mechanisms for the proteoglycans decorin and biglycan during muscle formation and muscular dystrophy. Matrix Biology. 2008;27(8):700–708.
    1. Li Y, Foster W, Deasy BM, et al. Transforming growth factor-beta1 induces the differentiation of myogenic cells into fibrotic cells in injured skeletal muscle: a key event in muscle fibrogenesis. American Journal of Pathology. 2004;164(3):1007–1019.
    1. Li Y, Li J, Zhu J, et al. Decorin gene transfer promotes muscle cell differentiation and muscle regeneration. Molecular Therapy. 2007;15(9):1616–1622.
    1. Narola J, Pandey SN, Glick A, Chen YW. Conditional expression of TGF-beta1 in skeletal muscles causes endomysial fibrosis and myofibers atrophy. PLoS ONE. 2013;8e79356
    1. Heydemann A, Ceco E, Lim JE, et al. Latent TGF-β-binding protein 4 modifies muscular dystrophy in mice. Journal of Clinical Investigation. 2009;119(12):3703–3712.
    1. Sun G, Haginoya K, Wu Y, et al. Connective tissue growth factor is overexpressed in muscles of human muscular dystrophy. Journal of the Neurological Sciences. 2008;267(1-2):48–56.
    1. Morales MG, Gutierrez J, Cabello-Verrugio C, et al. Reducing CTGF/CCN2 slows down mdx muscle dystrophy and improves cell therapy. Human Molecular Genetics. 2013;22:4938–4951.
    1. Frazier K, Williams S, Kothapalli D, Klapper H, Grotendorst GR. Stimulation of fibroblast cell growth, matrix production, and granulation tissue formation by connective tissue growth factor. Journal of Investigative Dermatology. 1996;107(3):404–411.
    1. Morales MG, Cabello-Verrugio C, Santander C, Cabrera D, Goldschmeding R, Brandan E. CTGF/CCN-2 over-expression can directly induce features of skeletal muscle dystrophy. Journal of Pathology. 2011;225(4):490–501.
    1. Vial C, Gutiérrez J, Santander C, Cabrera D, Brandan E. Decorin interacts with connective tissue growth factor (CTGF)/CCN2 by LRR12 inhibiting its biological activity. Journal of Biological Chemistry. 2011;286(27):24242–24252.
    1. Vial C, Zúñiga LM, Cabello-Verrugio C, Cañón P, Fadic R, Brandan E. Skeletal muscle cells express the profibrotic cytokine connective tissue growth factor (CTGF/CCN2), which induces their dedifferentiation. Journal of Cellular Physiology. 2008;215(2):410–421.
    1. Morales MG, Cabrera D, Cespedes C, et al. Inhibition of the angiotensin-converting enzyme decreases skeletal muscle fibrosis in dystrophic mice by a diminution in the expression and activity of connective tissue growth factor (CTGF/CCN-2) Cell and Tissue Research. 2013;353:173–187.
    1. Vío CP, Jeanneret VA. Local induction of angiotensin-converting enzyme in the kidney as a mechanism of progressive renal diseases. Kidney International. 2003;64(86):S57–S63.
    1. Sun G, Haginoya K, Dai H, et al. Intramuscular renin-angiotensin system is activated in human muscular dystrophy. Journal of the Neurological Sciences. 2009;280(1-2):40–48.
    1. Cabello-Verrugio C, Acuña MJ, Morales MG, Becerra A, Simon F, Brandan E. Fibrotic response induced by angiotensin-II requires NAD(P)H oxidase-induced reactive oxygen species (ROS) in skeletal muscle cells. Biochemical and Biophysical Research Communications. 2011;410(3):665–670.
    1. Painemal P, Acuna MJ, Riquelme C, Brandan E, Cabello-Verrugio C. Transforming growth factor type beta 1 increases the expression of angiotensin II receptor type 2 by a SMAD- and p38 MAPK-dependent mechanism in skeletal muscle. Biofactors. 2013;39:467–475.
    1. Acuna MJ, Pessina P, Olguin H, et al. Restoration of muscle strength in dystrophic muscle by angiotensin-1-7 through inhibition of TGF-beta signalling. Human Molecular Genetics. 2014;23:1237–1249.
    1. Chen X, Li Y. Role of matrix metalloproteinases in skeletal muscle: migration, differentiation, regeneration and fibrosis. Cell Adhesion & Migration. 2009;3(4):337–341.
    1. Nagamine Y, Medcalf RL, Muñoz-Cánoves P. Transcriptional and posttranscriptional regulation of the plasminogen activator system. Thrombosis and Haemostasis. 2005;93(4):661–675.
    1. Suelves M, Vidal B, Ruiz V, et al. The plasminogen activation system in skeletal muscle regeneration: antagonistic roles of Urokinase-type Plasminogen Activator (UPA) and its inhibitor (PAI-1) Frontiers in Bioscience. 2005;10(3):2978–2985.
    1. Ohtake Y, Tojo H, Seiki M. Multifunctional roles of MT1-MMP in myofiber formation and morphostatic maintenance of skeletal muscle. Journal of Cell Science. 2006;119(18):3822–3832.
    1. Visse R, Nagase H. Matrix metalloproteinases and tissue inhibitors of metalloproteinases: structure, function, and biochemistry. Circulation Research. 2003;92(8):827–839.
    1. Suelves M, Vidal B, Serrano AL, et al. uPA deficiency exacerbates muscular dystrophy in MDX mice. Journal of Cell Biology. 2007;178(6):1039–1051.
    1. Zanotti S, Negri T, Cappelletti C, et al. Decorin and biglycan expression is differentially altered in several muscular dystrophies. Brain. 2005;128(11):2546–2555.
    1. Arnold L, Henry A, Poron F, et al. Inflammatory monocytes recruited after skeletal muscle injury switch into antiinflammatory macrophages to support myogenesis. Journal of Experimental Medicine. 2007;204(5):1057–1069.
    1. Kharraz Y, Guerra J, Mann CJ, Serrano AL, Munoz-Canoves P. Macrophage plasticity and the role of inflammation in skeletal muscle repair. Mediators of Inflammation. 2013;2013:9 pages.491497
    1. Wehling M, Spencer MJ, Tidball JG. A nitric oxide synthase transgene ameliorates muscular dystrophy in mdx mice. Journal of Cell Biology. 2001;155(1):123–131.
    1. Gordon S. Alternative activation of macrophages. Nature Reviews Immunology. 2003;3(1):23–35.
    1. Wynn TA. Fibrotic disease and the TH1/TH2 paradigm. Nature Reviews Immunology. 2004;4(8):583–594.
    1. Desguerre I, Christov C, Mayer M, et al. Clinical heterogeneity of Duchenne muscular dystrophy (DMD): definition of sub-phenotypes and predictive criteria by long-term follow-up. PLoS ONE. 2009;4(2)e4347
    1. Villalta SA, Nguyen HX, Deng B, Gotoh T, Tidbal JG. Shifts in macrophage phenotypes and macrophage competition for arginine metabolism affect the severity of muscle pathology in muscular dystrophy. Human Molecular Genetics. 2009;18(3):482–496.
    1. Wehling-Henricks M, Jordan MC, Gotoh T, Grody WW, Roos KP, Tidball JG. Arginine metabolism by macrophages promotes cardiac and muscle fibrosis in mdx muscular dystrophy. PloS ONE. 2010;5(5)e10763
    1. Ryu JK, Davalos D, Akassoglou K. Fibrinogen signal transduction in the nervous system. Journal of Thrombosis and Haemostasis. 2009;7(1):151–154.
    1. Vidal B, Ardite E, Suelves M, et al. Amelioration of Duchenne muscular dystrophy in mdx mice by elimination of matrix-associated fibrin-driven inflammation coupled to the αmβ2 leukocyte integrin receptor. Human Molecular Genetics. 2012;21(9):1989–2004.
    1. Farini A, Meregalli M, Belicchi M, et al. T and B lymphocyte depletion has a marked effect on the fibrosis of dystrophic skeletal muscles in the scid/mdx mouse. Journal of Pathology. 2007;213(2):229–238.
    1. Morrison J, Lu QL, Pastoret C, Partridge T, Bou-Gharios G. T-cell-dependent fibrosis in the mdx dystrophic mouse. Laboratory Investigation. 2000;80(6):881–891.
    1. Spencer MJ, Montecino-Rodriguez E, Dorshkind K, Tidball JG. Helper (CD4+) and cytotoxic (CD8+) T cells promote the pathology of dystrophin-deficient muscle. Clinical Immunology. 2001;98(2):235–243.
    1. Vetrone SA, Montecino-Rodriguez E, Kudryashova E, et al. Osteopontin promotes fibrosis in dystrophic mouse muscle by modulating immune cell subsets and intramuscular TGF-β . Journal of Clinical Investigation. 2009;119(6):1583–1594.
    1. Pagel CN, Wasgewatte Wijesinghe DK, Taghavi Esfandouni N, Mackie EJ. Osteopontin, inflammation and myogenesis: influencing regeneration, fibrosis and size of skeletal muscle. Journal of Cell Communication and Signaling. 2013
    1. Barron L, Wynn TA. Fibrosis is regulated by Th2 and Th17 responses and by dynamic interactions between fibroblasts and macrophages. American Journal of Physiology. Gastrointestinal and Liver Physiology. 2011;300(5):G723–G728.
    1. Lo Re S, Lison D, Huaux F. CD4+ T lymphocytes in lung fibrosis: diverse subsets, diverse functions. Journal of Leukocyte Biology. 2013;93:499–510.
    1. Joe AWB, Yi L, Natarajan A, et al. Muscle injury activates resident fibro/adipogenic progenitors that facilitate myogenesis. Nature Cell Biology. 2010;12(2):153–163.
    1. Uezumi A, Fukada S-I, Yamamoto N, Takeda S, Tsuchida K. Mesenchymal progenitors distinct from satellite cells contribute to ectopic fat cell formation in skeletal muscle. Nature Cell Biology. 2010;12(2):143–152.
    1. Murphy MM, Lawson JA, Mathew SJ, Hutcheson DA, Kardon G. Satellite cells, connective tissue fibroblasts and their interactions are crucial for muscle regeneration. Development. 2011;138(17):3625–3637.
    1. Mathew SJ, Hansen JM, Merrell AJ, et al. Connective tissue fibroblasts and Tcf4 regulate myogenesis. Development. 2011;138(2):371–384.
    1. Judson RN, Zhang RH, Rossi FM. Tissue-resident mesenchymal stem/progenitor cells in skeletal muscle: collaborators or saboteurs? FEBS Journal. 2013;280:4100–4108.
    1. Uezumi A, Ito T, Morikawa D, et al. Fibrosis and adipogenesis originate from a common mesenchymal progenitor in skeletal muscle. Journal of Cell Science. 2011;124(21):3654–3664.
    1. Dulauroy S, di Carlo SE, Langa F, Eberl G, Peduto L. Lineage tracing and genetic ablation of ADAM12(+) perivascular cells identify a major source of profibrotic cells during acute tissue injury. Nature Medicine. 2012;18:1262–1270.
    1. Jørgensen LH, Jensen CH, Wewer UM, Schrøder HD. Transgenic overexpression of ADAM12 suppresses muscle regeneration and aggravates dystrophy in aged mdx mice. American Journal of Pathology. 2007;171(5):1599–1607.
    1. LeBleu VS, Taduri G, O'Connell J, et al. Origin and function of myofibroblasts in kidney fibrosis. Nature Medicine. 2013;19:1047–1053.
    1. Wu SM, Chien KR, Mummery C. Origins and fates of cardiovascular progenitor cells. Cell. 2008;132(4):537–543.
    1. Brack AS, Conboy MJ, Roy S, et al. Increased Wnt signaling during aging alters muscle stem cell fate and increases fibrosis. Science. 2007;317(5839):807–810.
    1. Zordan P, Rigamonti E, Freudenberg K, et al. Macrophages commit postnatal endothelium-derived progenitors to angiogenesis and restrict endothelial to mesenchymal transition during muscle regeneration. Cell Death & Disease. 2014;5e1031
    1. Carnwath JW, Shotton DM. Muscular dystrophy in the mdx mouse: histopathology of the soleus and extensor digitorum longus muscles. Journal of the Neurological Sciences. 1987;80(1):39–54.
    1. Banks GB, Chamberlain JS. The value of mammalian models for duchenne muscular dystrophy in developing therapeutic strategies. Current Topics in Developmental Biology. 2008;84:431–453.
    1. Zhou L, Rafael-Fortney JA, Huang P, et al. Haploinsufficiency of utrophin gene worsens skeletal muscle inflammation and fibrosis in mdx mice. Journal of the Neurological Sciences. 2008;264(1-2):106–111.
    1. Sacco A, Mourkioti F, Tran R, et al. Short telomeres and stem cell exhaustion model duchenne muscular dystrophy in mdx/mTR mice. Cell. 2010;143(7):1059–1071.
    1. Mourkioti F, Kustan J, Kraft P, et al. Role of telomere dysfunction in cardiac failure in Duchenne muscular dystrophy. Nature Cell Biology. 2013;15:895–904.
    1. Chandrasekharan K, Yoon JH, Xu Y, et al. A human-specific deletion in mouse Cmah increases disease severity in the mdx model of duchenne muscular dystrophy. Science Translational Medicine. 2010;2(42)42ra54
    1. Martin PT, Camboni M, Xu R, et al. N-Glycolylneuraminic acid deficiency worsens cardiac and skeletal muscle pathophysiology in alpha-sarcoglycan-deficient mice. Glycobiology. 2013;23:833–843.
    1. Fukada S-I, Morikawa D, Yamamoto Y, et al. Genetic background affects properties of satellite cells and mdx phenotypes. American Journal of Pathology. 2010;176(5):2414–2424.
    1. Desguerre I, Arnold L, Vignaud A, et al. A new model of experimental fibrosis in hindlimb skeletal muscle of adult mdx mouse mimicking muscular dystrophy. Muscle Nerve. 2012;45:803–814.
    1. de Luca A, Pierno S, Liantonio A, et al. Enhanced dystrophic progression in mdx mice by exercise and beneficial effects of taurine and insulin-like growth factor-1. Journal of Pharmacology and Experimental Therapeutics. 2003;304(1):453–463.
    1. Menetrey J, Kasemkijwattana C, Fu FH, Moreland MS, Huard J. Suturing versus immobilization of a muscle laceration. A morphological and functional study in a mouse model. American Journal of Sports Medicine. 1999;27(2):222–229.
    1. Carlson BM, Billington L, Faulkner J. Studies on the regenerative recovery of long-term denervated muscle in rats. Restorative Neurology and Neuroscience. 1996;10(2):77–84.
    1. Abdel-Hamid H, Clemens PR. Pharmacological therapies for muscular dystrophies. Current Opinion in Neurology. 2012;25:604–608.
    1. Elbaz M, Yanay N, Aga-Mizrachi S, et al. Losartan, a therapeutic candidate in congenital muscular dystrophy: studies in the dy2J/dy2J mouse. Annals of Neurology. 2012;71(5):699–708.
    1. Burks TN, Andres-Mateos E, Marx R, et al. Losartan restores skeletal muscle remodeling and protects against disuse atrophy in sarcopenia. Science Translational Medicine. 2011;3(82)82ra37
    1. Park JK, Ki MR, Lee EM, et al. Losartan improves adipose tissue-derived stem cell niche by inhibiting transforming growth factor-beta and fibrosis in skeletal muscle injury. Cell Transplantation. 2012;21:2407–2424.
    1. Bish LT, Yarchoan M, Sleeper MM, et al. Chronic losartan administration reduces mortality and preserves cardiac but not skeletal muscle function in dystrophic mice. PLoS ONE. 2011;6(6)e20856
    1. Rafael-Fortney JA, Chimanji NS, Schill KE, et al. Early treatment with lisinopril and spironolactone preserves cardiac and skeletal muscle in duchenne muscular dystrophy mice. Circulation. 2011;124(5):582–588.
    1. Allen HD, Flanigan KM, Thrush PT. A randomized, double-blind trial of lisinopril and losartan for the treatment of cardiomyopathy in duchenne muscular dystrophy. PLoS Currents. 2013
    1. Andreetta F, Bernasconi P, Baggi F, et al. Immunomodulation of TGF-beta1 in mdx mouse inhibits connective tissue proliferation in diaphragm but increases inflammatory response: implications for antifibrotic therapy. Journal of Neuroimmunology. 2006;175(1-2):77–86.
    1. Bizario JCDS, Cerri DG, Rodrigues LC, et al. Imatinib mesylate ameliorates the dystrophic phenotype in exercised mdx mice. Journal of Neuroimmunology. 2009;212(1-2):93–101.
    1. Ito T, Ogawa R, Uezumi A, et al. Imatinib attenuates severe mouse dystrophy and inhibits proliferation and fibrosis-marker expression in muscle mesenchymal progenitors. Neuromuscular Disorders. 2013;23:349–356.
    1. Pines M, Halevy O. Halofuginone and muscular dystrophy. Histology and Histopathology. 2011;26(1):135–146.
    1. Huebner KD, Jassal DS, Halevy O, Pines M, Anderson JE. Functional resolution of fibrosis in mdx mouse dystrophic heart and skeletal muscle by halofuginone. American Journal of Physiology. Heart and Circulatory Physiology. 2008;294(4):H1550–H1561.
    1. Sundrud MS, Koralov SB, Feuerer M, et al. Halofuginone inhibits th17 cell differentiation by activating the amino acid starvation response. Science. 2009;324(5932):1334–1338.

Source: PubMed

Sponsorit ja yhteistyökumppanit

Sairaudet

Huumeiden interventiot

3
Tilaa