The fibrinolitys system in muscle regeneration and dystrophy

• Autores: Berta Vidal Iglesias
• Directores de la Tesis: Purificacion Muñoz Canoves (dir. tes.)
• Lectura: En la Universitat Pompeu Fabra ( España ) en 2008
• Idioma: español
• Tribunal Calificador de la Tesis: Pilar Navarro Medrano (presid.), Mónica Suelves Esteban (secret.), Antonio Zorzano Olarte (voc.), Francisco X Real (voc.), Yoshikuni Nagamine (voc.)
• Materias:
  • Ciencias de la vida
• Enlaces
  • Tesis en acceso abierto en:  TDX  e-Repositori UPF 
• Resumen

  • Duchenne muscular dystrophy (DMD) is a fatal degenerative disorder of locomotor and respiratory muscles, in which myofibers are progressively replaced by non-muscular fibrotic tissue. One of the findings of this Thesis is that uPA plays an important reparative role in muscular dystrophy. Indeed, uPA expression and activity increases during dystrophic disease and genetic loss of uPA exacerbates muscle dystrophinopathy and worsens muscle performance in the mdx mouse model of Duchenne's disease. Importantly, these defects in the absence of uPA are significantly rescued by transplantation of uPA-expressing BM, thus highlighting the importance of uPA-secreting BM-derived cells in muscular dystrophy. Notably, muscle dystrophinopathy is unaffected in the absence of uPAR, suggesting that uPA exerts its effect independently of its receptor. %&/ In this Thesis, we also show that fibrin/ogen accumulates in dystrophic muscles of DMD patients and of the mdx mouse model of DMD. Genetic loss or pharmacological depletion of fibrin/ogen in mdx mice attenuates muscular dystrophy progression and improves locomotor capacity. More importantly, fibrin/ogen depletion reduces fibrosis in mdx mouse diaphragm. Our data indicate that fibrin/ogen, through induction of IL-1 , drives the synthesis of TGF by mdx macrophages, which in turn, induces collagen production in mdx fibroblasts. Fibrin/ogen-produced TGF further amplifies collagen accumulation through recruitment and activation of pro-fibrotic alternatively activated macrophages. Fibrin/ogen also stimulates collagen synthesis directly in mdx fibroblasts, via v 3 integrin engagement. In addition, when analyzing a group of 39 DMD patients, fibrin/ogen accumulation in locomotor muscles was found associated with fibrosis and disease severity. These data unveil a novel role of fibrin/ogen in muscular dystrophy and, importantly, in the replacement of muscle by fibrotic tissue.