ESTUDO DA INFLUÊNCIA DO DIMORFISMO SEXUAL NA LESÃO MUSCULAR DE CAMUNDONGO mdx COM DISTROFIA MUSCULAR DE DUCHENNE
Autor(a) principal: | |
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Data de Publicação: | 2009 |
Tipo de documento: | Tese |
Idioma: | por |
Título da fonte: | Repositório Institucional da Universidade Federal Fluminense (RIUFF) |
Texto Completo: | https://app.uff.br/riuff/handle/1/18379 |
Resumo: | Mdx mouse, the animal model of Duchenne muscular dystrophy, lacks dystrophin and develops an X- linked recessive inflammatory myopathy characterized by degeneration of skeletal muscle fibers and replacement by connective tissue. The present work aimed to establish a possible relation of the sexual dimorphism with changes in the microenvironment of the skeletal muscle and lesion pattern at distinct phases of the myopathy. Male and female mdx and control nondystrophic C57 mice with 4 and 8 weeks of postnatal life. A group of mdx was submitted to the surgical castration: ovariectomy (OVX) and orchiectomy (OOX), and another group treated with tamoxifen, an agonist of estrogen receptor dissolved in ELVAX resin implanted locally in the right gastrocnemius muscle, with corresponding contralateral used as non-treated control muscle. Transversal sections of gastrocnemius muscle embedded in paraffin were processed for histochemistry and stained with syrius red, Giemsa, oil red, ATPase enzyme and also immunohistochemistry for identification of adhesion molecule NCAM, progenitor cells (SCA) and macrophages (Mac-1+ and F4-80). Frozen muscle fragments were processed for determination of metalloprotease MMP-2 and MMP-9 activities. Morphometric analysis showed higher percentage of mionecrose and lesser regeneration in non-operated and OOX mdx males than in both groups of females non-operated and OVX, which presented higher percentage of regenerated fibers. Mdx male and female mice did not show significant difference in the number of adipocytes in the gastrocnemius muscle, but mdx male presented less adipocytes than corresponding mdx females. Comparing to control (C57) nondystrophic mice, both male and female mdx mice, especially the castrated ones (OOX, OVX), presented higher MMP-2 and -9 activities. However, mdx intergroup analysis showed augmented MMP-9 activity in OOX males and of MMP-2 in females OVX. Comparing with the contralateral muscle, male and female mdx muscles treated with tamoxifen presented increased numbers of myofibers with membrane integrity and marked reduction of macrophages than the contralateral muscle of C57 and mdx mice. Altogether, the results indicate a beneficial effect of endogenous sexual female hormone and also the estrogen modulator receptor (tamoxifen) as therapeutic strategy capable of mitigating inflammation e myonecrosis (antiinflammatory effect), functioning as structural membrane stabilizer (sarcolemma integrity) and promoting muscle regeneration in mdx mice with Duchenne dystrophy. |
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ESTUDO DA INFLUÊNCIA DO DIMORFISMO SEXUAL NA LESÃO MUSCULAR DE CAMUNDONGO mdx COM DISTROFIA MUSCULAR DE DUCHENNEStudy of the influence of the sexual dimorphism mdx muscle damage in mice with Duchenne muscular dystrophyDistrofia muscularDimorfismo sexualDistrofia muscular de DuchenneCamundongoRatoMúsculo esqueléticoMuscular dystrophySexual Dimorphismof Duchenne muscular dystrophyMice, Mouse, Skeletal muscleCNPQ::CIENCIAS BIOLOGICAS::IMUNOLOGIAMdx mouse, the animal model of Duchenne muscular dystrophy, lacks dystrophin and develops an X- linked recessive inflammatory myopathy characterized by degeneration of skeletal muscle fibers and replacement by connective tissue. The present work aimed to establish a possible relation of the sexual dimorphism with changes in the microenvironment of the skeletal muscle and lesion pattern at distinct phases of the myopathy. Male and female mdx and control nondystrophic C57 mice with 4 and 8 weeks of postnatal life. A group of mdx was submitted to the surgical castration: ovariectomy (OVX) and orchiectomy (OOX), and another group treated with tamoxifen, an agonist of estrogen receptor dissolved in ELVAX resin implanted locally in the right gastrocnemius muscle, with corresponding contralateral used as non-treated control muscle. Transversal sections of gastrocnemius muscle embedded in paraffin were processed for histochemistry and stained with syrius red, Giemsa, oil red, ATPase enzyme and also immunohistochemistry for identification of adhesion molecule NCAM, progenitor cells (SCA) and macrophages (Mac-1+ and F4-80). Frozen muscle fragments were processed for determination of metalloprotease MMP-2 and MMP-9 activities. Morphometric analysis showed higher percentage of mionecrose and lesser regeneration in non-operated and OOX mdx males than in both groups of females non-operated and OVX, which presented higher percentage of regenerated fibers. Mdx male and female mice did not show significant difference in the number of adipocytes in the gastrocnemius muscle, but mdx male presented less adipocytes than corresponding mdx females. Comparing to control (C57) nondystrophic mice, both male and female mdx mice, especially the castrated ones (OOX, OVX), presented higher MMP-2 and -9 activities. However, mdx intergroup analysis showed augmented MMP-9 activity in OOX males and of MMP-2 in females OVX. Comparing with the contralateral muscle, male and female mdx muscles treated with tamoxifen presented increased numbers of myofibers with membrane integrity and marked reduction of macrophages than the contralateral muscle of C57 and mdx mice. Altogether, the results indicate a beneficial effect of endogenous sexual female hormone and also the estrogen modulator receptor (tamoxifen) as therapeutic strategy capable of mitigating inflammation e myonecrosis (antiinflammatory effect), functioning as structural membrane stabilizer (sarcolemma integrity) and promoting muscle regeneration in mdx mice with Duchenne dystrophy.Coordenação de Aperfeiçoamento de Pessoal de Nível SuperiorCamundongo mdx, o modelo animal da distrofia muscular de Duchenne, desenvolve uma miopatia inflamatória recessiva ligada ao cromossoma X, caracterizada por degeneração das miofibras esqueléticas e substituição por tecido conjuntivo. O objetivo deste trabalho foi estabelecer uma possível relação do dimorfismo sexual com o padrão da lesão e mudanças no microambiente do músculo esquelético durante diferentes fases da miopatia. Foram incluídos camundongos machos e fêmeas das linhagens mdx e controle C57 (não-distrófico) com 4 e 8 semanas de vida pós-natal. Um grupo de camundongos mdx foi submetido à castração cirúrgica: ovariectomia (OVX) e orquiectomia (OOX) e outro grupo foi tratado com tamoxifen, droga agonista do receptor de estrógeno dissolvida em resina ELVAX, implantada no músculo esquelético direito, tendo o contralateral como controle não tratado. Secções transversais de músculo gastrocnêmio incluído em parafina foram processadas para histoquímica e coradsa pelo picrosírius, Giemsa, oil red e imuno-histoquímica para identificação de molécula de adesão NCAM, células progenitoras (SCA-1) e macrófagos (Mac-1+ e F4-80). Fragmentos congelados de músculo foram processados para determinação da atividade das metaloproteases MMP-2 e MMP-9. A análise histomorfométrica mostrou nos camundongos mdx machos não operados e OOX, um percentual maior de mionecrose e menor regeneração do que nas fêmeas controle e OVX, que exibiram percentual maior de miofibras regenerando (64%, p<0.0001). Não houve diferença significativa no número de adipócitos no músculo gastrocnêmio dos camundongos mdx machos (p>0.05) e fêmeas (p>0.05), embora mdx machos apresentassem menor número de adipócitos que as fêmeas pareadas. Camundongos mdx machos e fêmeas, em especial os castrados (OOX e OVX), apresentaram maior atividade da MMP-2 e -9 do que o grupo controle C57 não-distrófico. Análise intergrupo mostrou atividade aumentada da MMP-9 no mdx macho OOX e da MMP-2 nas fêmeas mdx OVX. Músculo esquelético de camundongos mdx, machos e fêmeas, tratados com a droga tamoxifen apresentaram maior número de células musculares íntegras e redução acentuada de macrófagos do que o músculo contralateral. Em conjunto, os resultados indicam os efeitos benéficos dos hormônios sexuais femininos endógenos e do modulador do receptor de estrógeno, tamoxifen, como estratégia de tratamento capaz de minimizar inflamação e mionecrose (efeito antinflamatório), de funcionar como mantenedores da integridade estrutural das miofibras esqueléticas (integridade do sarcolema) e de promover regeneração muscular no camundongo mdx com distrofia de Duchenne.Programa de Pós-graduação em NeuroimunologiaNeuroimunologiaSantos, Thereza Fonseca Quírico dosCPF:79186432622http://lattes.cnpq.br/0382591463869002Silva, Andréa Alice daCPF:07958271422http://buscatextual.cnpq.br/buscatextual/visualizacv.do?id=K4707853D9Coelho, ValériaCPF:23443223422Pinho, Maria de FátimaCPF:75843876522El-cheik, Márcia CuryCPF:66647484722Verícimo, Maurício AfonsoCPF:45283869768http://buscatextual.cnpq.br/buscatextual/visualizacv.do?id=K4701891P4Silva, Maria Cristina Salimena da2021-03-10T20:44:24Z2009-06-022021-03-10T20:44:24Zinfo:eu-repo/semantics/publishedVersioninfo:eu-repo/semantics/doctoralThesisapplication/pdfhttps://app.uff.br/riuff/handle/1/18379porCC-BY-SAinfo:eu-repo/semantics/openAccessreponame:Repositório Institucional da Universidade Federal Fluminense (RIUFF)instname:Universidade Federal Fluminense (UFF)instacron:UFF2021-03-10T20:44:24Zoai:app.uff.br:1/18379Repositório InstitucionalPUBhttps://app.uff.br/oai/requestriuff@id.uff.bropendoar:21202021-03-10T20:44:24Repositório Institucional da Universidade Federal Fluminense (RIUFF) - Universidade Federal Fluminense (UFF)false |
dc.title.none.fl_str_mv |
ESTUDO DA INFLUÊNCIA DO DIMORFISMO SEXUAL NA LESÃO MUSCULAR DE CAMUNDONGO mdx COM DISTROFIA MUSCULAR DE DUCHENNE Study of the influence of the sexual dimorphism mdx muscle damage in mice with Duchenne muscular dystrophy |
title |
ESTUDO DA INFLUÊNCIA DO DIMORFISMO SEXUAL NA LESÃO MUSCULAR DE CAMUNDONGO mdx COM DISTROFIA MUSCULAR DE DUCHENNE |
spellingShingle |
ESTUDO DA INFLUÊNCIA DO DIMORFISMO SEXUAL NA LESÃO MUSCULAR DE CAMUNDONGO mdx COM DISTROFIA MUSCULAR DE DUCHENNE Silva, Maria Cristina Salimena da Distrofia muscular Dimorfismo sexual Distrofia muscular de Duchenne Camundongo Rato Músculo esquelético Muscular dystrophy Sexual Dimorphism of Duchenne muscular dystrophy Mice, Mouse, Skeletal muscle CNPQ::CIENCIAS BIOLOGICAS::IMUNOLOGIA |
title_short |
ESTUDO DA INFLUÊNCIA DO DIMORFISMO SEXUAL NA LESÃO MUSCULAR DE CAMUNDONGO mdx COM DISTROFIA MUSCULAR DE DUCHENNE |
title_full |
ESTUDO DA INFLUÊNCIA DO DIMORFISMO SEXUAL NA LESÃO MUSCULAR DE CAMUNDONGO mdx COM DISTROFIA MUSCULAR DE DUCHENNE |
title_fullStr |
ESTUDO DA INFLUÊNCIA DO DIMORFISMO SEXUAL NA LESÃO MUSCULAR DE CAMUNDONGO mdx COM DISTROFIA MUSCULAR DE DUCHENNE |
title_full_unstemmed |
ESTUDO DA INFLUÊNCIA DO DIMORFISMO SEXUAL NA LESÃO MUSCULAR DE CAMUNDONGO mdx COM DISTROFIA MUSCULAR DE DUCHENNE |
title_sort |
ESTUDO DA INFLUÊNCIA DO DIMORFISMO SEXUAL NA LESÃO MUSCULAR DE CAMUNDONGO mdx COM DISTROFIA MUSCULAR DE DUCHENNE |
author |
Silva, Maria Cristina Salimena da |
author_facet |
Silva, Maria Cristina Salimena da |
author_role |
author |
dc.contributor.none.fl_str_mv |
Santos, Thereza Fonseca Quírico dos CPF:79186432622 http://lattes.cnpq.br/0382591463869002 Silva, Andréa Alice da CPF:07958271422 http://buscatextual.cnpq.br/buscatextual/visualizacv.do?id=K4707853D9 Coelho, Valéria CPF:23443223422 Pinho, Maria de Fátima CPF:75843876522 El-cheik, Márcia Cury CPF:66647484722 Verícimo, Maurício Afonso CPF:45283869768 http://buscatextual.cnpq.br/buscatextual/visualizacv.do?id=K4701891P4 |
dc.contributor.author.fl_str_mv |
Silva, Maria Cristina Salimena da |
dc.subject.por.fl_str_mv |
Distrofia muscular Dimorfismo sexual Distrofia muscular de Duchenne Camundongo Rato Músculo esquelético Muscular dystrophy Sexual Dimorphism of Duchenne muscular dystrophy Mice, Mouse, Skeletal muscle CNPQ::CIENCIAS BIOLOGICAS::IMUNOLOGIA |
topic |
Distrofia muscular Dimorfismo sexual Distrofia muscular de Duchenne Camundongo Rato Músculo esquelético Muscular dystrophy Sexual Dimorphism of Duchenne muscular dystrophy Mice, Mouse, Skeletal muscle CNPQ::CIENCIAS BIOLOGICAS::IMUNOLOGIA |
description |
Mdx mouse, the animal model of Duchenne muscular dystrophy, lacks dystrophin and develops an X- linked recessive inflammatory myopathy characterized by degeneration of skeletal muscle fibers and replacement by connective tissue. The present work aimed to establish a possible relation of the sexual dimorphism with changes in the microenvironment of the skeletal muscle and lesion pattern at distinct phases of the myopathy. Male and female mdx and control nondystrophic C57 mice with 4 and 8 weeks of postnatal life. A group of mdx was submitted to the surgical castration: ovariectomy (OVX) and orchiectomy (OOX), and another group treated with tamoxifen, an agonist of estrogen receptor dissolved in ELVAX resin implanted locally in the right gastrocnemius muscle, with corresponding contralateral used as non-treated control muscle. Transversal sections of gastrocnemius muscle embedded in paraffin were processed for histochemistry and stained with syrius red, Giemsa, oil red, ATPase enzyme and also immunohistochemistry for identification of adhesion molecule NCAM, progenitor cells (SCA) and macrophages (Mac-1+ and F4-80). Frozen muscle fragments were processed for determination of metalloprotease MMP-2 and MMP-9 activities. Morphometric analysis showed higher percentage of mionecrose and lesser regeneration in non-operated and OOX mdx males than in both groups of females non-operated and OVX, which presented higher percentage of regenerated fibers. Mdx male and female mice did not show significant difference in the number of adipocytes in the gastrocnemius muscle, but mdx male presented less adipocytes than corresponding mdx females. Comparing to control (C57) nondystrophic mice, both male and female mdx mice, especially the castrated ones (OOX, OVX), presented higher MMP-2 and -9 activities. However, mdx intergroup analysis showed augmented MMP-9 activity in OOX males and of MMP-2 in females OVX. Comparing with the contralateral muscle, male and female mdx muscles treated with tamoxifen presented increased numbers of myofibers with membrane integrity and marked reduction of macrophages than the contralateral muscle of C57 and mdx mice. Altogether, the results indicate a beneficial effect of endogenous sexual female hormone and also the estrogen modulator receptor (tamoxifen) as therapeutic strategy capable of mitigating inflammation e myonecrosis (antiinflammatory effect), functioning as structural membrane stabilizer (sarcolemma integrity) and promoting muscle regeneration in mdx mice with Duchenne dystrophy. |
publishDate |
2009 |
dc.date.none.fl_str_mv |
2009-06-02 2021-03-10T20:44:24Z 2021-03-10T20:44:24Z |
dc.type.status.fl_str_mv |
info:eu-repo/semantics/publishedVersion |
dc.type.driver.fl_str_mv |
info:eu-repo/semantics/doctoralThesis |
format |
doctoralThesis |
status_str |
publishedVersion |
dc.identifier.uri.fl_str_mv |
https://app.uff.br/riuff/handle/1/18379 |
url |
https://app.uff.br/riuff/handle/1/18379 |
dc.language.iso.fl_str_mv |
por |
language |
por |
dc.rights.driver.fl_str_mv |
CC-BY-SA info:eu-repo/semantics/openAccess |
rights_invalid_str_mv |
CC-BY-SA |
eu_rights_str_mv |
openAccess |
dc.format.none.fl_str_mv |
application/pdf |
dc.publisher.none.fl_str_mv |
Programa de Pós-graduação em Neuroimunologia Neuroimunologia |
publisher.none.fl_str_mv |
Programa de Pós-graduação em Neuroimunologia Neuroimunologia |
dc.source.none.fl_str_mv |
reponame:Repositório Institucional da Universidade Federal Fluminense (RIUFF) instname:Universidade Federal Fluminense (UFF) instacron:UFF |
instname_str |
Universidade Federal Fluminense (UFF) |
instacron_str |
UFF |
institution |
UFF |
reponame_str |
Repositório Institucional da Universidade Federal Fluminense (RIUFF) |
collection |
Repositório Institucional da Universidade Federal Fluminense (RIUFF) |
repository.name.fl_str_mv |
Repositório Institucional da Universidade Federal Fluminense (RIUFF) - Universidade Federal Fluminense (UFF) |
repository.mail.fl_str_mv |
riuff@id.uff.br |
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1825433635232153600 |