The fibrinolitys system in muscle regeneration and dystrophy

Vidal Iglesias, Berta

The fibrinolitys system in muscle regeneration and dystrophy

Document Type

Doctoral thesis
Published Version

Author

Vidal Iglesias, Berta

Director

Muñoz Cánoves, Pura

Publication Date

2008-09-17

Citation

Vidal Iglesias, B. The fibrinolitys system in muscle regeneration and dystrophy. Universitat Pompeu Fabra; 2008. handle: http://hdl.handle.net/10803/7143

This citation was generated automatically.

Doctoral program

Programa de doctorat en Biomedicina

Abstract

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. Here, we 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 attenuated muscular dystrophy progression and improved locomotor capacity. More importantly, fibrin/ogen depletion reduced fibrosis in mdx mouse diaphragm. Our data indicate that fibrin/ogen, through induction of IL-1 Ò, drives the synthesis of TGF Ò by mdx macrophages, which in turn, induces collagen production in mdx fibroblasts. Fibrin/ogen-produced TGF Ò further amplifies collagen accumulation through recruitment and activation of pro-fibrotic alternatively activated macrophages. Fibrin/ogen also stimulated collagen synthesis directly in mdx fibroblasts, via Ñv Ò3 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.