RESUMO
Dysferlin mutations cause muscular dystrophy (dysferlinopathy) characterized by adult onset muscle weakness, high serum creatine kinase levels, attenuation of muscle regeneration and a prominent inflammatory infiltrate. In order to verify the role of lymphocytes and immune cells on this disease, we generated the Scid/A/J transgenic mice and compared these animals with the age-matched A/J mice. The absence of T and B lymphocytes in this animal model of dysferlinopathy resulted in an improvement of the muscle regeneration. Scid/A/J mice showed increased specific force in the myosin heavy chain 2A-expressing fibers of the diaphragm and abdominal muscles. Moreover, a partial reduction in complement deposition was observed together with a diminution in pro-inflammatory M1 macrophages. Consistent with this model, T and B lymphocytes seem to have a role in the muscle damaging immune response. The knowledge of the involvement of immune system in the development of dysferlinopathies could represent an important tool for their rescuing. By studying Scid/blAJ mice, we showed that it could be possible to modulate the pathological symptoms of these diseases by interfering with different components of the immune system.
Assuntos
Linfócitos B/patologia , Proteínas de Membrana/deficiência , Músculo Esquelético/fisiopatologia , Distrofia Muscular Animal/patologia , Linfócitos T/patologia , Animais , Complexo de Ataque à Membrana do Sistema Complemento/metabolismo , Modelos Animais de Doenças , Disferlina , Distrofina/metabolismo , Células Endoteliais/patologia , Feminino , Hibridização Genética , Técnicas In Vitro , Inflamação , Laminina/metabolismo , Macrófagos/patologia , Masculino , Proteínas de Membrana/genética , Proteínas de Membrana/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Camundongos SCID , Contração Muscular , Músculo Esquelético/irrigação sanguínea , Músculo Esquelético/metabolismo , Músculo Esquelético/patologia , Distrofia Muscular Animal/metabolismo , Regeneração , Sarcoglicanas/metabolismo , Sarcolema/genética , Sarcolema/metabolismo , Sarcolema/patologiaRESUMO
Recently published reports have described possible cellular therapy approaches to regenerate muscle tissues using arterial route delivery. However, the kinetic of distribution of these migratory stem cells within injected animal muscular dystrophy models is unknown. Using living X-ray computed microtomography, we established that intra-arterially injected stem cells traffic to multiple muscle tissues for several hours until their migration within dystrophic muscles. Injected stem cells express multiple traffic molecules, including VLA-4, LFA-1, CD44, and the chemokine receptor CXCR4, which are likely to direct these cells into dystrophic muscles. In fact, the majority of intra-arterially injected stem cells access the muscle tissues not immediately after the injection, but after several rounds of recirculation. We set up a new, living, 3D-imaging approach, which appears to be an important way to investigate the kinetic of distribution of systemically injected stem cells within dystrophic muscle tissues, thereby providing supportive data for future clinical applications.