Importância do camundongo mdx na fisiopatologia da distrofia muscular de Duchenne

Seixas, Sandra Lopes; Lagrota-Cândido, Jussara; Savino, Wilson; Quirico-Santos, Thereza

doi:10.1590/S0004-282X1997000400017

Resumos

O camundongo mdx desenvolve distrofia muscular recessiva ligada ao cromossoma X (locus Xp21.1) e não expressa distrofina. Embora não apresente intensa fibrose do tecido muscular e acúmulo de tecido adiposo, é considerado o modelo animal mais adequado da distrofia muscular de Duchenne. As alterações estruturais no tecido muscular associadas à mionecrose e presença do infiltrado inflamatório com predomínio de linfócitos e monócitos/macrófagos sugerem uma participação do sistema imunológico nesta miopatia. Além disso a modulação na expressão dos componentes da matriz extracelular no microambiente muscular nas várias fases da doença (início, mionecrose, regeneração) indicam um papel importante do conjuntivo no direcionamento das células inflamatórias para o foco da lesão muscular. O camundongo mdx coloca-se como um excelente modelo para o estudo dos mecanismos patogenéticos da mionecrose e regeneração na distrofia muscular de Duchenne, possibilitando inclusive o desenvolvimento de estratégias terapêuticas mais adequadas.

distrofia muscular; distrofina; mdx; modelo animal

The mdx mouse develop an X-linked recessive muscular dystrophy (locus Xp21.1) and lack dystrophin expression. Despite showing less intense myofibrosis and scarce deposition of fatty tissue, mdx mice are considered an adequate animal model for studies on the pathogenesis of Duchenne-type muscular dystrophy. Marked histological alterations in the muscular tissues associated to myonecrosis and inflammatory mononuclear cell infiltrate (lymphocytes, monocytes/macrophages) suggest a participation of the immune system in this myopathy. Modulation of the extracellular matrix (ECM) components in the muscular tissue during all phases (onset, myonecrosis and regeneration) of disease, indicate an important role for the ECM driving inflammatory cells to the foci of lesion. Therefore mdx mice should be regarded as an important tool for studies on pathogenetic mechanisms of Duchenne-type muscular dystrophy. Such experimental model would allow development of new therapeutic approaches for increasing survival and clinical amelioration.

Duchenne muscular dystrophy; dystrophin; mdx; animal model

Importância do camundongo mdx na fisiopatologia da distrofia muscular de Duchenne

The importance of mdx mouse in the pathophysiology of Duchenne's muscular distrophy

Sandra Lopes Seixas^I; Jussara Lagrota-Cândido^II; Wilson Savino^III; Thereza Quirico-Santos^IV

^ILaboratório de Patologia Celular & Molecular, Departamento de Biologia Celular & Molecular, Universidade Federal Fluminense (UFF): M.Sc., Professora Assistente do Departamento de Morfologia

^IIM.Sc., Professora Assistente do Departamento de Imunobiologia da UFF

^IIIPh.D., Pesquisador Titular do Departamento de Imunologia da FIOCRUZ/RJ

^IVPh.D., Professora Titular do Departamento de Biologia Celular & Molecular da UFF e Pesquisadora do Departamento de Imunologia da FIOCRUZ/RJ

RESUMO

O camundongo mdx desenvolve distrofia muscular recessiva ligada ao cromossoma X (locus Xp21.1) e não expressa distrofina. Embora não apresente intensa fibrose do tecido muscular e acúmulo de tecido adiposo, é considerado o modelo animal mais adequado da distrofia muscular de Duchenne. As alterações estruturais no tecido muscular associadas à mionecrose e presença do infiltrado inflamatório com predomínio de linfócitos e monócitos/macrófagos sugerem uma participação do sistema imunológico nesta miopatia. Além disso a modulação na expressão dos componentes da matriz extracelular no microambiente muscular nas várias fases da doença (início, mionecrose, regeneração) indicam um papel importante do conjuntivo no direcionamento das células inflamatórias para o foco da lesão muscular. O camundongo mdx coloca-se como um excelente modelo para o estudo dos mecanismos patogenéticos da mionecrose e regeneração na distrofia muscular de Duchenne, possibilitando inclusive o desenvolvimento de estratégias terapêuticas mais adequadas.

Palavras-chave: distrofia muscular, distrofina, mdx, modelo animal.

ABSTRACT

The mdx mouse develop an X-linked recessive muscular dystrophy (locus Xp21.1) and lack dystrophin expression. Despite showing less intense myofibrosis and scarce deposition of fatty tissue, mdx mice are considered an adequate animal model for studies on the pathogenesis of Duchenne-type muscular dystrophy. Marked histological alterations in the muscular tissues associated to myonecrosis and inflammatory mononuclear cell infiltrate (lymphocytes, monocytes/macrophages) suggest a participation of the immune system in this myopathy. Modulation of the extracellular matrix (ECM) components in the muscular tissue during all phases (onset, myonecrosis and regeneration) of disease, indicate an important role for the ECM driving inflammatory cells to the foci of lesion. Therefore mdx mice should be regarded as an important tool for studies on pathogenetic mechanisms of Duchenne-type muscular dystrophy. Such experimental model would allow development of new therapeutic approaches for increasing survival and clinical amelioration.

Key-words: Duchenne muscular dystrophy, dystrophin, mdx, animal model.

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Aceite: 25-abril-1997.

Dra. Thereza Quirico-Santos - Laboratório de Patologia Celular & Molecular, Departamento de Biologia Celular & Molecular, Instituto de Biologia, UFF - 24030-120 Niterói RJ - Brasil. Fax 021 719 5934.

1. Beezhold DH, Personius C. Fibronectin fragments stimulate tumor necrosis factor secretion by monocytes. J Leuk Biol, 1992; 51:59-64.
2. Boland B, Himpens B, Denef JF, Gillis JM. Site-dependent pathological differences in smooth muscles and skeletal muscles of the adult mdx mouse. Muscle & Nerve, 1995;18:649-657.
3. Brown RH. Dystrophin-associated proteins and the muscular dystrophies: a glossary. Brain Pathol, 1996;6:19-24.
4. Bullfield G, Siller WG, Wight PAL, Moore KJ. X-chromosome-linked muscular dystrophy (mdx) in the mouse. Proc Natl Acad Sci USA 1984;81:1189-1192.
5. Campbell KP. Three muscular dystrophies: loss of the cytoskeleton extracellular matrix linkage. Cell, 1995, 80: 675-679
6. De Jong, L, Walterman S, Hillarius S, Bolhius PA. Collagen synthesis in cultured myoblasts and myotubes from patient with DMD. J Neurol Sci 1987;82:271-279.
7. Dupont-Versteegden EE, McCarter RJ, Katz MS. Voluntary exercise decreases progression of muscular dystrophy in diaphragm of mdx mice J Appl Physiol 1994;77:1736-1741.
8. Gasghen ER, Hoffman EP, Gorospe JR, Uhl EW, Senior DF, Cardinet GH, Pearse LK. Dystrophy deficiency causes lethal muscle hipertrophy in cats. J Neurol Sci 1992;110:149-153.
9. Hershkoviz R, Cahalon L, Gilatt D, Mirin S, Miller A, Lider D. Physically damaged extracellular matrix induces TNF alpha secretion by interaction resting CD4+ T cells and macrophages. Scand J Immunol 1993;37:111-118.
10. Hoffman EP. Clinical and histopathological features of abnormalities of dystrophin-based membrane cytoskeleton. Brain Pathol 1996;6:49-61.
11. Jones GE, Witkowski JA. Membrane abnormalities in Duchenne muscular dystrophy. J Neurol Sci 1983;58:159-163.
12. Lefaucheur JP, Pastoret C, Sebille A phenotype of dystrophinopathy in old mdx mice. Anat Rec 1995;242:70-76.
13. Lidov HG. Dystrophin in the nervous system. Brain Pathol 1996;6:63-77.
14. Matsumura K, Campbell KP. Dystrophin-glycoprotein complex: its role in the molecular pathogenesis of muscular dystrophies. Muscle & Nerve 1994;17:2-15.
15. Michelson AM, Russel ES, Harman PJ. Dystrophia muscularis: a hereditary primary myopathy in the house mouse. Proc Natl Acad Sci USA;1995,41:1079.
16. Partridge T. Pathophysiology of muscular dystrophy. Br J Hosp Med 1993;49:26-34.
17. Pasternack C, Woung S, Wilson EL. Mechanical function of dystrophin in muscle cells. J Cell Biol 1995;128:355-361.
18. Pastoret C, Sebille A. Age related differences in regeneration of dystrophic (mdx) and normal muscle in the mouse. Muscle & Nerve 1995;18:1147-1154.
19. Quirico-Santos TJ, Ribeiro MM, Savino W. Increased deposition of extracellular matrix components in the thymus gland of MDX mouse: correlation with muscular lesion. J Neuroimmunol 1995,59:9-18.
20. Roberds SL, Ervasti JM, Anderson RD, Ohlendieck K, Kahl SD, Zoloto D, Campbell KD. Disruption of the dystrophin-glycoprotein complex in the cardiomyopathic hamster. J Biol Chem 1993;268:11496-11499.
21. Rodemann HP, Bayreuther K. Abnormal collagen metabolism in cultured skin fibroblasts from patients with Duchenne muscular dystrophy. Proc Natl Acad Sci. USA 1984;81:5130-5133.
22. Saudolet-Puccio HM, Kunkel LM. Dystrophin and its isoforms. Brain Pathol 1996;6:25-35.
23. Schloesser M, Slomski R, Wagner M, Reiss J, Berg LP, Kakkar VV, Cooper DN. Characterization of pathological dystrophin transcripts from the lymphocytes of a muscular dystrophy carrier. Mol Biol Med 1990;79:519-523.
24. Scott OM, Hyde SA, Goddard C, Jones R., Dubowitz V. Effect of exercise in Duchenne muscular dystrophy: a controlled six-month feasibility sudy of the effects of two different regimes of exercises in children with Duchenne muscular dystrophy. Physiotherapy 1981;67:174-176.
25. Seixas SIL, Wajsenzon LI, Savino W, Quirico-Santos T. Altered deposition of extracellular matrix components in the skeletal muscle and lymph node of the mdx dystrophic mouse. Braz J Med Biol 1994;27:2229-2240.
26. Sicinski P, Geng Y, Ryder-Cook AS, Barnard EA, Darlinson MG, Barnard PJ. The molecular basis of muscular dystrophy in the mdx mouse: a point mutation. Science 1989;244:1578-1580.
27. Tidball JG, Albrech DE, Lokensgard BE, Spencer MJ. Apoptosis precedes necrosis of dystrophin-deficient muscle. J Cell Sci 1995;108:2197-2204.
28. Tome FMS, Evangelista T, Leclerc A, Sunada Y, Manole E, Estournet B, Barois A, Campbell KP, Fardeau M. Congenital muscular dystrophy with merosin deficiency. C R Acad Sci Paris 1994;3J 7:351-357.
29. Valentine BA, Cooper BJ, Cummings JF, De Lahynta A. Progressive muscular dystrophy in a golden retriever dog: light microscopic and ultrastructural features at 4 and 8 months. Acta Neuropathol (Berl) 1986;71:301-305.
30. Xu H, Christmas P, Wu XR, Wewer U, Engvall E. Defective muscle basement membrane and lack of M-laminin in the dystrophic dy/dy mouse. Proc Natl Acad Sci USA 1994;91:5572-5576.

Datas de Publicação

Publicação nesta coleção
18 Out 2010
Data do Fascículo
Set 1997

This work is licensed under a Creative Commons Attribution-NonCommercial 4.0 International License.

[1] 1. Beezhold DH, Personius C. Fibronectin fragments stimulate tumor necrosis factor secretion by monocytes. J Leuk Biol, 1992; 51:59-64.

[2] 2. Boland B, Himpens B, Denef JF, Gillis JM. Site-dependent pathological differences in smooth muscles and skeletal muscles of the adult mdx mouse. Muscle & Nerve, 1995;18:649-657.

[3] 3. Brown RH. Dystrophin-associated proteins and the muscular dystrophies: a glossary. Brain Pathol, 1996;6:19-24.

[4] 4. Bullfield G, Siller WG, Wight PAL, Moore KJ. X-chromosome-linked muscular dystrophy (mdx) in the mouse. Proc Natl Acad Sci USA 1984;81:1189-1192.

[5] 5. Campbell KP. Three muscular dystrophies: loss of the cytoskeleton extracellular matrix linkage. Cell, 1995, 80: 675-679

[6] 6. De Jong, L, Walterman S, Hillarius S, Bolhius PA. Collagen synthesis in cultured myoblasts and myotubes from patient with DMD. J Neurol Sci 1987;82:271-279.

[7] 7. Dupont-Versteegden EE, McCarter RJ, Katz MS. Voluntary exercise decreases progression of muscular dystrophy in diaphragm of mdx mice J Appl Physiol 1994;77:1736-1741.

[8] 8. Gasghen ER, Hoffman EP, Gorospe JR, Uhl EW, Senior DF, Cardinet GH, Pearse LK. Dystrophy deficiency causes lethal muscle hipertrophy in cats. J Neurol Sci 1992;110:149-153.

[9] 9. Hershkoviz R, Cahalon L, Gilatt D, Mirin S, Miller A, Lider D. Physically damaged extracellular matrix induces TNF alpha secretion by interaction resting CD4+ T cells and macrophages. Scand J Immunol 1993;37:111-118.

[10] 10. Hoffman EP. Clinical and histopathological features of abnormalities of dystrophin-based membrane cytoskeleton. Brain Pathol 1996;6:49-61.

[11] 11. Jones GE, Witkowski JA. Membrane abnormalities in Duchenne muscular dystrophy. J Neurol Sci 1983;58:159-163.

[12] 12. Lefaucheur JP, Pastoret C, Sebille A phenotype of dystrophinopathy in old mdx mice. Anat Rec 1995;242:70-76.

[13] 13. Lidov HG. Dystrophin in the nervous system. Brain Pathol 1996;6:63-77.

[14] 14. Matsumura K, Campbell KP. Dystrophin-glycoprotein complex: its role in the molecular pathogenesis of muscular dystrophies. Muscle & Nerve 1994;17:2-15.

[15] 15. Michelson AM, Russel ES, Harman PJ. Dystrophia muscularis: a hereditary primary myopathy in the house mouse. Proc Natl Acad Sci USA;1995,41:1079.

[16] 16. Partridge T. Pathophysiology of muscular dystrophy. Br J Hosp Med 1993;49:26-34.

[17] 17. Pasternack C, Woung S, Wilson EL. Mechanical function of dystrophin in muscle cells. J Cell Biol 1995;128:355-361.

[18] 18. Pastoret C, Sebille A. Age related differences in regeneration of dystrophic (mdx) and normal muscle in the mouse. Muscle & Nerve 1995;18:1147-1154.

[19] 19. Quirico-Santos TJ, Ribeiro MM, Savino W. Increased deposition of extracellular matrix components in the thymus gland of MDX mouse: correlation with muscular lesion. J Neuroimmunol 1995,59:9-18.

[20] 20. Roberds SL, Ervasti JM, Anderson RD, Ohlendieck K, Kahl SD, Zoloto D, Campbell KD. Disruption of the dystrophin-glycoprotein complex in the cardiomyopathic hamster. J Biol Chem 1993;268:11496-11499.

[21] 21. Rodemann HP, Bayreuther K. Abnormal collagen metabolism in cultured skin fibroblasts from patients with Duchenne muscular dystrophy. Proc Natl Acad Sci. USA 1984;81:5130-5133.

[22] 22. Saudolet-Puccio HM, Kunkel LM. Dystrophin and its isoforms. Brain Pathol 1996;6:25-35.

[23] 23. Schloesser M, Slomski R, Wagner M, Reiss J, Berg LP, Kakkar VV, Cooper DN. Characterization of pathological dystrophin transcripts from the lymphocytes of a muscular dystrophy carrier. Mol Biol Med 1990;79:519-523.

[24] 24. Scott OM, Hyde SA, Goddard C, Jones R., Dubowitz V. Effect of exercise in Duchenne muscular dystrophy: a controlled six-month feasibility sudy of the effects of two different regimes of exercises in children with Duchenne muscular dystrophy. Physiotherapy 1981;67:174-176.

[25] 25. Seixas SIL, Wajsenzon LI, Savino W, Quirico-Santos T. Altered deposition of extracellular matrix components in the skeletal muscle and lymph node of the mdx dystrophic mouse. Braz J Med Biol 1994;27:2229-2240.

[26] 26. Sicinski P, Geng Y, Ryder-Cook AS, Barnard EA, Darlinson MG, Barnard PJ. The molecular basis of muscular dystrophy in the mdx mouse: a point mutation. Science 1989;244:1578-1580.

[27] 27. Tidball JG, Albrech DE, Lokensgard BE, Spencer MJ. Apoptosis precedes necrosis of dystrophin-deficient muscle. J Cell Sci 1995;108:2197-2204.

[28] 28. Tome FMS, Evangelista T, Leclerc A, Sunada Y, Manole E, Estournet B, Barois A, Campbell KP, Fardeau M. Congenital muscular dystrophy with merosin deficiency. C R Acad Sci Paris 1994;3J 7:351-357.

[29] 29. Valentine BA, Cooper BJ, Cummings JF, De Lahynta A. Progressive muscular dystrophy in a golden retriever dog: light microscopic and ultrastructural features at 4 and 8 months. Acta Neuropathol (Berl) 1986;71:301-305.

[30] 30. Xu H, Christmas P, Wu XR, Wewer U, Engvall E. Defective muscle basement membrane and lack of M-laminin in the dystrophic dy/dy mouse. Proc Natl Acad Sci USA 1994;91:5572-5576.