Inhibition of muscle fibrosis and improvement of muscle histopathology in dysferlin knock-out mice treated with halofuginone

Histology and Histopathology

Volumn 28, Issue 2, 2013, Pages 211-226

  Halevy, Orna ^a   Genin, Olga ^b   Barzilai Tutsch, Hila ^a   Pima, Yaniv ^b   Levi, Oshrat ^b   Moshe, Itai ^b   Pines, Mark ^b  

^a HEBREW UNIVERSITY OF JERUSALEM   (Israel)

^b VOLCANI CENTER   (Israel)

Author keywords

Dysferlinopathies; Fibrosis; Fusion; Halofuginone; Macrophage; Muscular dystrophies; Myofibroblast

Indexed keywords

COLLAGEN; DYSF PROTEIN, MOUSE; GELATINASE A; GELATINASE B; HALOFUGINONE; MEMBRANE PROTEIN; PIPERIDINE DERIVATIVE; PROTEIN SYNTHESIS INHIBITOR; QUINAZOLINONE DERIVATIVE; SMAD3 PROTEIN; SMAD3 PROTEIN, MOUSE;

ANIMAL; ARTICLE; C57BL MOUSE; DISEASE MODEL; DRUG ANTAGONISM; DRUG EFFECT; DYSFERLINOPATHY; FIBROSIS; GENETICS; LIMB GIRDLE MUSCULAR DYSTROPHY; MALE; METABOLISM; MOUSE; MOUSE MUTANT; PATHOLOGY; PHOSPHORYLATION; SKELETAL MUSCLE; TREATMENT OUTCOME;

ANIMALS; COLLAGEN; DISEASE MODELS, ANIMAL; FIBROSIS; MALE; MATRIX METALLOPROTEINASE 2; MATRIX METALLOPROTEINASE 9; MEMBRANE PROTEINS; MICE; MICE, INBRED C57BL; MICE, KNOCKOUT; MUSCLE, SKELETAL; MUSCULAR DYSTROPHIES, LIMB-GIRDLE; PHOSPHORYLATION; PIPERIDINES; PROTEIN SYNTHESIS INHIBITORS; QUINAZOLINONES; SMAD3 PROTEIN; TREATMENT OUTCOME;

EID: 84873831697     PISSN: 02133911     EISSN: None     Source Type: Journal    
DOI: None     Document Type: Article

References (76)

1. Alexakis C., Partridge T. and Bou-Gharios G. (2007). Implication of the satellite cell in dystrophic muscle fibrosis: a self-perpetuating mechanism of collagen overproduction. Am. J. Physiol. Cell. Physiol. 293, C661-669.
2. Andreetta F., Bernasconi P., Baggi F., Ferro P., Oliva L., Arnoldi E., Cornelio F., Mantegazza R. and Confalonieri P. (2006). Immunomodulation of TGF-b1 in mdx mouse inhibits connective tissue proliferation in diaphragm but increases inflammatory response: implications for antifibrotic therapy. J. Neuroimmunol. 175, 77-86.
3. Bansal D., Miyake K., Vogel S.S., Groh S., Chen C.C., Williamson R., McNeil P.L. and Campbell K.P. (2003). Defective membrane repair in dysferlin-deficient muscular dystrophy. Nature 423, 168-172.
4. Barthélémy F., Wein N., Krahn M., Lévy N. and Bartoli M. (2011). Translational research and therapeutic perspectives in dysferlinopathies. Mol. Med. 17, 875-882.
5. Bashir R., Britton S., Strachan T., Keers S., Vafiadaki E., Lako M., Richard I., Marchand S., Bourg N., Argov Z., Sadeh M., Mahjneh I., Marconi G., Passos-Bueno M.R., Moreira Ede S., Zatz M., Beckmann J.S. and Bushby K. (1998). A gene related to Caenorhabditis elegans spermatogenesis factor fer-1 is mutated in limb-girdle muscular dystrophy type 2B. Nat. Genet. 20, 37-42.
6. Ben-Dov N., Shefer G., Irintchev A., Wernig A., Oron U. and Halevy O. (1999). Low-energy laser irradiation affects satellite cell proliferation and differentiation in vitro. Biochim. Biophys. Acta 1448, 372-380.
7. Bernasconi P., Torchiana E., Confalonieri P., Brugnoni R., Barresi R., Mora M., Cornelio F., Morandi L. and Mantegazza R. (1995). Expression of transforming growth factor-beta 1 in dystrophic patient muscles correlates with fibrosis. Pathogenetic role of a fibrogenic cytokine. J. Clin. Invest. 96, 1137-1144.
8. Bittner R.E., Anderson L.V., Burkhardt E., Bashir R., Vafiadaki E., Ivanova S., Raffelsberger T., Maerk I., Höger H., Jung M., Karbasiyan M., Storch M., Lassmann H., Moss J.A., Davison K., Harrison R., Bushby K.M. and Reis A. (1999). Dysferlin deletion in SJL mice (SJL-Dysf) defines a natural model for limb girdle muscular dystrophy 2B. Nat. Genet. 23, 141-142.
9. Blaauw B., Mammucari C., Toniolo L., Agatea L., Abraham R., Sandri M., Reggiani C. and Schiaffino S. (2008). Akt activation prevents the force drop induced by eccentric contractions in dystrophin-deficient skeletal muscle. Hum. Mol. Genet. 17, 3686-3696.
10. Bruck R., Genina O., Aeed H., Alexiev R., Nagler A., Avni Y. and Pines M. (2001). Halofuginone to prevent and treat thioacetamide-induced liver fibrosis in rats. Hepatology 33, 379-386.
11. Brunn A., Schröder R. and Deckert M. (2006). The inflammatory reaction pattern distinguishes primary dysferlinopathies from idiopathic inflammatory myopathies: an important role for the membrane attack complex. Acta Neuropathol. 112, 325-332.
12. Bushby K.M. (2000). Dysferlin and muscular dystrophy. Acta Neurol. Belg. 100, 142-145.
13. Cacciottolo M., Numitone G., Aurino S., Caserta I.R. and Fanin M. (2011). Muscular dystrophy with marked Dysferlin deficiency is consistently caused by primary dysferlin gene mutations. Eur. J. Hum. Genet. 19, 974-980.
14. Chan Y.S., Li Y., Foster W., Horaguchi T., Somogyi G., Fu F.H. and Huard J. (2003). Antifibrotic effects of suramin in injured skeletal muscle after laceration. J. Appl. Physiol. 95, 771-780.
15. Chase T.H., Cox G.A., Burzenski L., Foreman O. and Shultz L.D. (2009). Dysferlin deficiency and the development of cardiomyopathy in a mouse model of limb-girdle muscular dystrophy 2B. Am. J. Pathol. 175, 2299-2308.
16. Chiu Y.H., Hornsey M.A., Klinge L., Jørgensen L.H., Laval S.H., Charlton R., Barresi R., Straub V., Lochmüller H. and Bushby K. (2009). Attenuated muscle regeneration is a key factor in dysferlindeficient muscular dystrophy. Hum. Mol. Genet. 18, 1976-1989.
17. Choi E.R., Park S.J., Choe Y.H., Ryu D.R., Chang S.A., Choi J.O., Lee S.C., Park S.W., Kim B.J., Kim D.K. and Oh J.K. (2010). Early detection of cardiac involvement in Miyoshi myopathy: 2D strain echocardiography and late gadolinium enhancement cardiovascular magnetic resonance. J. Cardiovasc. Magn. Reson. 12, 31.
18. Cohn R.D., van Erp C., Habashi J.P., Soleimani A.A., Klein E.C., Lisi M.T., Gamradt M., ap Rhys C.M., Holm T.M., Loeys B.L., Ramirez F., Judge D.P., Ward C.W. and Dietz H.C. (2007). Angiotensin II type 1 receptor blockade attenuates TGF-beta-induced failure of muscle regeneration in multiple myopathic states. Nat. Med. 13, 204-210.
19. Coirault C., Pignol B., Cooper R.N., Butler-Browne G., Chabrier P.E. and Lecarpentier Y. (2003). Severe muscle dysfunction precedes collagen tissue proliferation in mdx mouse diaphragm. J. Appl. Physiol. 94, 1744-1750.
20. Confalonieri P., Oliva L., Andreetta F., Lorenzoni R., Dassi P., Mariani E., Morandi L., Mora M., Cornelio F. and Mantegazza R. (2003). Muscle inflammation and MHC class I up-regulation in muscular dystrophy with lack of dysferlin: an immunopathological study. J. Neuroimmunol. 142, 130-136.
21. De Jonge M.J., Dumez H., Verweij J., Yarkoni S., Snyder D., Lacombe D., Marréaud S., Yamaguchi T., Punt C.J. and van Oosterom A.; EORTC New Drug Development Group (NDDG) (2006). Phase I and pharmacokinetic study of halofuginone, an oral quinazolinone derivative in patients with advanced solid tumours. Eur. J. Cancer 42, 1768-1774.
22. De Luna N., Gallardo E. and Illa I. (2004). In vivo and in vitro dysferlin expression in human muscle satellite cells. J. Neuropathol. Exp. Neurol. 63, 1104-1113.
23. De Luna N., Gallardo E., Soriano M., Dominguez-Perles R., de la Torre C., Rojas-García R., García-Verdugo J.M. and Illa I. (2006). Absence of dysferlin alters myogenin expression and delays human muscle differentiation 'in vitro'. J. Biol. Chem. 281, 17092-17098.
24. De Luna N., Gallardo E., Sonnet C., Chazaud B., Dominguez-Perles R., Suarez-Calvet X., Gherardi R.K. and Illa I. (2010). Role of thrombospondin 1 in macrophage inflammation in dysferlin myopathy. J. Neuropathol. Exp. Neurol. 69, 643-653.
25. Demonbreun A.R., Fahrenbach J.P., Deveaux K., Earley J.U., Pytel P. and McNally E.M. (2011). Impaired muscle growth and response to insulin-like growth factor 1 in dysferlin-mediated muscular dystrophy. Hum. Mol. Genet. 20, 779-789.
26. Desguerre I., Mayer M., Leturcq F., Barbet J.P., Gherardi R.K. and Christov C. (2009). Endomysial fibrosis in Duchenne muscular dystrophy: a marker of poor outcome associated with macrophage alternative activation. J. Neuropathol. Exp. Neurol. 68, 762-773.
27. Flanders K.C. (2004). Smad3 as a mediator of the fibrotic response. Int. J. Exp. Pathol. 85, 47-64.
28. Gallardo E., Rojas-García R., de Luna N., Pou A., Brown R.H. Jr. and Illa I. (2001). Inflammation in dysferlin myopathy: immunohistochemical characterization of 13 patients. Neurology 57, 2136-2138.
29. Gavish Z., Pinthus J.H., Barak V., Ramon J., Nagler A., Eshhar Z. and Pines M. (2002). Growth inhibition of prostate cancer xenografts by halofuginone. Prostate 51, 73-83.
30. Genin O., Rechavi G., Nagler A., Ben-Itzhak O., Nazemi K. and Pines M. (2008). Myofibroblasts in pulmonary and brain metastases of alveolar soft-part sarcoma: a novel target for treatment? Neoplasia 10, 940-948.
31. Guglieri M., Magri F. and Comi G.P. (2005). Molecular etiopathogenesis of limb girdle muscular and congenital muscular dystrophies: boundaries and contiguities. Clin. Chim. Acta 361, 54-79.
32. Han R., Bansal D., Miyake K., Muniz V.P., Weiss R.M., McNeil P.L. and Campbell K.P. (2007). Dysferlin-mediated membrane repair protects the heart from stress-induced left ventricular injury. J. Clin. Invest. 117, 1805-1813.
33. Han R., Frett E.M., Levy J.R., Rader E.P., Lueck J.D., Bansal D., Moore S.A., Ng R., Beltrán-Valero de Bernabé D., Faulkner J.A. and Campbell K.P. (2010). Genetic ablation of complement C3 attenuates muscle pathology in dysferlin-deficient mice. J. Clin. Invest. 120, 4366-4374.
34. Hino M., Hamada N., Tajika Y., Funayama T., Morimura Y., Sakashita T., Yokota Y., Fukamoto K., Kobayashi Y. and Yorifuji H. (2009). Insufficient membrane fusion in dysferlin-deficient muscle fibers after heavy-ion irradiation. Cell Struct. Funct. 34, 11-15.
35. Ho M., Post C.M., Donahue L.R., Lidov H.G., Bronson R.T., Goolsby H., Watkins S.C., Cox G.A. and Brown R.H. Jr. (2004). Disruption of muscle membrane and phenotype divergence in two novel mouse models of dysferlin deficiency. Hum. Mol. Genet. 13, 1999-2010.
36. Horsley V., Friday B.B., Matesson S., Kegley M., Gephart J. and Pavlath G.K. (2001). Regulation of the growth of multinucleated muscle cells by an NFATC2-dependent pathway. J. Cell Biol. 153, 329-338.
37. Huebner K.D., Jassal D.S., Halevy O., Pines M. and Anderson J.E. (2008). Functional resolution of fibrosis in mdx mouse dystrophic heart and skeletal muscle by halofuginone. Am. J. Physiol. Heart Circ. Physiol. 294, H1550-1561.
38. Ishitobi M., Haginoya K., Zhao Y., Ohnuma A., Minato J., Yanagisawa T., Tanabu M., Kikuchi M. and Iinuma K. (2000). Elevated plasma levels of transforming growth factor beta1 in patients with muscular dystrophy. NeuroReport 11, 4033-4035.
39. Kawabe K., Goto K., Nishino I., Angelini C. and Hayashi Y.K. (2004). Dysferlin mutation analysis in a group of Italian patients with limbgirdle muscular dystrophy and Miyoshi myopathy. Eur. J. Neurol. 11, 657-661.
40. Kim M.H., Kay D.I., Rudra R.T., Chen B.M., Hsu N., Izumiya Y., Martinez L., Spencer M.J., Walsh K., Grinnell A.D. and Crosbie R.H. (2011). Myogenic Akt signaling attenuates muscular degeneration, promotes myofiber regeneration and improves muscle function in dystrophin-deficient mdx mice. Hum. Mol. Genet. 20, 1324-1338.
41. Klinge L., Aboumousa A., Eagle M., Hudson J., Sarkozy A., Vita G., Charlton R., Roberts M., Straub V., Barresi R., Lochmüller H. and Bushby K. (2010). New aspects on patients affected by dysferlin deficient muscular dystrophy. J. Neurol. Neurosurg. Psychiatry 81, 946-953.
42. Lennon N.J., Kho A., Bacskai B.J., Perlmutter S.L., Hyman B.T. and Brown R.H. Jr (2003). Dysferlin interacts with annexins A1 and A2 and mediates sarcolemmal wound-healing. J. Biol. Chem. 278, 50466-50473.
43. Levi-Schaffer F., Nagler A., Slavin S., Knopov V. and Pines M. (1996). Inhibition of collagen synthesis and changes in skin morphology in murine graft-versus-host disease and tight skin mice: effect of halofuginone. J. Invest. Dermatol. 106, 4-8.
44. Liu J., Aoki M., Illa I., Wu C., Fardeau M., Angelini C., Serrano C., Urtizberea J.A., Hentati F., Hamida M.B., Bohlega S., Culper E.J., Amato A.A., Bossie K., Oeltjen J., Bejaoui K., McKenna-Yasek D., Hosler B.A., Schurr E., Arahata K., de Jong P.J. and Brown RH Jr (1998). Dysferlin, a novel skeletal muscle gene, is mutated in Miyoshi myopathy and limb girdle muscular dystrophy. Nat. Genet. 20, 31-36.
45. McGaha T.L., Phelps R.G., Spiera H. and Bona C. (2002). Halofuginone, an inhibitor of type-I collagen synthesis and skin sclerosis, blocks transforming-growth-factor-beta-mediated Smad3 activation in fibroblasts. J. Invest. Dermatol. 118, 461-470.
46. Melone M.A., Peluso G., Petillo O., Galderisi U. and Cotrufo R. (1999). Defective growth in vitro of Duchenne muscular dystrophy myoblasts: the molecular and biochemical basis. J. Cell. Biochem. 76, 118-132.
47. Millay D.P., Maillet M., Roche J.A., Sargent M.A., McNally E.M., Bloch R.J. and Molkentin J.D. (2009). Genetic manipulation of dysferlin expression in skeletal muscle: novel insights into muscular dystrophy. Am. J. Pathol. 175, 1817-1823.
48. Nagaraju K., Rawat R., Veszelovszky E., Thapliyal R., Kesari A., Sparks S., Raben N., Plotz P. and Hoffman E.P. (2008). Dysferlin deficiency enhances monocyte phagocytosis: a model for the inflammatory onset of limbgirdle muscular dystrophy 2B. Am. J. Pathol. 172, 774-785.
49. Nagler A. and Pines M. (1999). Topical treatment of cutaneous chronic graft versus host disease (cGvHD) with halofuginone: a novel inhibitor of collagen type I synthesis. Transplantation 68, 1806-1809.
50. Nemoto H., Konno S., Nakazora H., Miura H. and Kurihara T. (2007). Histological and immunohistological changes of the skeletal muscles in older SJL/J mice. Eur. Neurol. 57, 19-25.
51. Nevo Y., Halevy O., Genin O., Moshe I., Turgeman T., Harel M., Biton E., Reif S. and Pines M. (2010). Fibrosis inhibition and muscle histopathology improvement in Laminin-·2-defient mice. Muscle Nerve 42, 218-229.
52. Pines M. (2008). Targeting TGFß signaling to inhibit fibroblasts activation as a therapy for fibrosis and cancer. Exp. Opin. Drug Dis. 3, 11-20.
53. Pines M., Vlodavsky I. and Nagler A. (2000). Halofuginone: from veterinary use to human therapy. Drug Dev. Res. 50, 371-378.
54. Pines M., Domb A., Ohana M., Inbar J., Genina O., Alexiev R. and Nagler A. (2001). Reduction in dermal fibrosis in the tight-skin (Tsk) mouse after local application of halofuginone. Biochem. Pharmacol. 62, 1221-1227.
55. Pinthus J.H., Sheffer Y., Nagler A., Fridman E., Mor Y., Genina O. and Pines M. (2005). Inhibition of Wilms tumor xenografts progression by halofuginone is accompanied by activation of WT-1 gene expression. J. Urol. 174, 1527-1531.
56. Popov Y., Patsenker E., Bauer M., Niedobitek E., Schulze-Krebs A. and Schuppan D. (2006). Halofuginone induces matrix metalloproteinases in rat hepatic stellate cells via activation of p38 and NFkappaB. J. Biol. Chem. 281, 15090-15098.
57. Prelle A., Sciacco M., Tancredi L., Fagiolari G., Comi G.P., Ciscato P., Serafini M., Fortunato F., Zecca C., Gallanti A., Chiveri L., Bresolin N., Scarlato G. and Moggio M. (2003). Clinical, morphological and immunological evaluation of six patients with dysferlin deficiency. Acta Neuropathol. (Berl) 105, 537-542.
58. Rawat R., Cohen T.V., Ampong B., Francia D., Henriques-Pons A., Hoffman E.P. and Nagaraju K. (2010). Inflammasome up-regulation and activation in dysferlin-deficient skeletal muscle. Am. J. Pathol. 176, 2891-2900.
59. Rayavarapu S., Van der Meulen J.H., Gordish-Dressman H., Hoffman E.P., Nagaraju K. and Knoblach S.M. (2010). Characterization of dysferlin deficient SJL/J mice to assess preclinical drug efficacy: fasudil exacerbates muscle disease phenotype. PLoS One 5, e12981.
60. Roche J.A., Lovering R.M. and Bloch R.J. (2008). Impaired recovery of dysferlin-null skeletal muscle after contraction-induced injury in vivo. Neuroreport 19, 1579-1584.
61. Roffe S., Hagai Y., Pines M. and Halevy O. (2010). Halofuginone inhibits Smad3 phosphorylation via the PI3K/Akt and MAPK/ERK pathways in muscle cells: effect on myotube fusion. Exp. Cell Res. 316, 1061-1069.
62. Segawa M., Fukada S., Yamamoto Y., Yahagi H., Kanematsu M., Sato M., Ito T., Uezumi A., Hayashi S., Miyagoe-Suzuki Y., Takeda S., Tsujikawa K. and Yamamoto H. (2008). Suppression of macrophage functions impairs skeletal muscle regeneration with severe fibrosis. Exp. Cell Res. 314, 3232-3244.
63. Selcen D., Stilling G. and Engel A.G. (2001). The earliest pathologic alterations in dysferlinopathy. Neurology 56, 1472-1481.
64. Serrano A.L., Mann C.J., Vidal B., Ardite E., Perdiguero E. and Muñoz-Cánoves P. (2011). Cellular and molecular mechanisms regulating fibrosis in skeletal muscle repair and disease. Curr. Top. Dev. Biol. 96, 167-201.
65. Shaw C.A., Larochelle N., Dudley R.W., Lochmuller H., Danialou G., Petrof B.J., Karpati G., Holland P.C. and Nalbantoglu J. (2006). Simultaneous dystrophin and dysferlin deficiencies associated with high-level expression of the coxsackie and adenovirus receptor in transgenic mice. Am. J. Pathol. 169, 2148-2160.
66. Sheffer Y., Leon O., Pinthus J.H., Nagler A., Mor Y., Genin O., Iluz M., Kawada N., Yoshizato K. and Pines M. (2007). Inhibition of fibroblast to myofibroblast transition by halofuginone contribute to the chemotherapy-mediated anti-tumoral effect. Mol. Cancer Ther. 6, 570-577.
67. Spector I., Honig H., Kawada N., Nagler A., Genin O. and Pines M. (2010). Inhibition of pancreatic stellate cell activation by halofuginone prevents pancreatic xenograft tumor development. Pancreas 39, 1008-1015.
68. Turgeman T., Hagai Y., Huebner K., Jassal D.S., Anderson J.E., Genin O., Nagler A., Halevy O. and Pines M. (2008). Inhibition of Smad3 phosphorylation by halofuginone prevents muscle fibrosis and improves muscle performance in the mdx mouse model of Duchenne muscular dystrophy. Neromuscular Disorders 18, 857-868.
69. Urtizberea J.A., Bassez G., Leturcq F., Nguyen K., Krahn M. and Levy N. (2008). Dysferlinopathies. Neurol. India 56, 289-297.
70. Vinit J., Samson M. Jr, Gaultier J.B., Laquerriere A., Ollagnon E., Petiot P., Marie I., Levesque H. and Rousset H. (2010). Dysferlin deficiency treated like refractory polymyositis. Clin. Rheumatol. 29, 103-106.
71. Weller A.H., Magliato S.A., Bell K.P. and Rosenberg N.L. (1997). Spontaneous myopathy in the SJL/J mouse: pathology and strength loss. Muscle Nerve 20, 72-82.
72. Wenzel K., Zabojszcza J., Carl M., Taubert S., Lass A., Harris C.L., Ho M., Schulz H., Hummel O., Hubner N., Osterziel K.J. and Spuler S. (2005). Increased susceptibility to complement attack due to downregulation of decay-accelerating factor/CD55 in dysferlin-deficient muscular dystrophy. J. Immunol. 175, 6219-6225.
73. Wenzel K., Geier C., Qadri F., Hubner N., Schulz H., Erdmann B., Gross V., Bauer D., Dechend R., Dietz R., Osterziel K.J., Spuler S. and Ozcelik C. (2007). Dysfunction of dysferlin-deficient hearts. J. Mol. Med. (Berl.) 85, 1203-1214.
74. Yee K.O., Connolly C.M., Pines M. and Lawler J. (2006). Halofuginone inhibits tumor growth in the polyoma middle T antigen mouse via a thrombospondin-1 independent mechanism. Cancer Biol. Ther. 5, 218-224.
75. Zanotti S., Gibertini S. and Mora M. (2010) Altered production of extracellular matrix components by muscle-derived Duchenne muscular dystrophy fibroblasts before and after TGF-beta1 treatment. Cell Tissue Res. 339, 397-410.
76. Zion O., Genin O., Kawada N., Yoshizato K., Roffe S., Nagler A., Iovanna J.L., Halevy O. and Pines M. (2009). Inhibition of TGFß signaling by halofuginone as a modality for pancreas fibrosis prevention. Pancreas 38, 427-435.