title: Novel and optimized strategies for inducing fibrosis in vivo: focus on Duchenne Muscular Dystrophy.
abstract: BACKGROUND
  Fibrosis, an excessive collagen accumulation, results in scar formation, impairing function of vital organs and tissues. Fibrosis is a hallmark of muscular dystrophies, including the lethal Duchenne muscular dystrophy (DMD), which remains incurable. Substitution of muscle by fibrotic tissue also complicates gene/cell therapies for DMD. Yet, no optimal models to study muscle fibrosis are available. In the widely used mdx mouse model for DMD, extensive fibrosis develops in the diaphragm only at advanced adulthood, and at about two years of age in the 'easy-to-access' limb muscles, thus precluding fibrosis research and the testing of novel therapies.
  
  
  METHODS
  We developed distinct experimental strategies, ranging from chronic exercise to increasing muscle damage on limb muscles of young mdx mice, by myotoxin injection, surgically induced trauma (laceration or denervation) or intramuscular delivery of profibrotic growth factors (such as TGFβ). We also extended these approaches to muscle of normal non-dystrophic mice.
  
  
  RESULTS
  These strategies resulted in advanced and enhanced muscle fibrosis in young mdx mice, which persisted over time, and correlated with reduced muscle force, thus mimicking the severe DMD phenotype. Furthermore, increased fibrosis was also obtained by combining these procedures in muscles of normal mice, mirroring aberrant repair after severe trauma.
  
  
  CONCLUSIONS
  We have developed new and improved experimental strategies to accelerate and enhance muscle fibrosis in vivo. These strategies will allow rapidly assessing fibrosis in the easily accessible limb muscles of young mdx mice, without necessarily having to use old animals. The extension of these fibrogenic regimes to the muscle of non-dystrophic wild-type mice will allow fibrosis assessment in a wide array of pre-existing transgenic mouse lines, which in turn will facilitate understanding the mechanisms of fibrogenesis. These strategies should improve our ability to combat fibrosis-driven dystrophy progression and aberrant regeneration.
authors.affiliation: Cell Biology Group, Department of Experimental and Health Sciences, CIBER on Neurodegenerative Diseases (CIBERNED), Pompeu Fabra University (UPF), Dr. Aiguader, 88, 08003 Barcelona, Spain.
authors.forename: Patrizia
authors.initials: P
authors.lastname: Pessina
authors.affiliation: Department of Cell and Molecular Biology, Catholic University of Chile, Avenida Libertador Bernardo O'Higgins, 340, Santiago, Chile.
authors.forename: Daniel
authors.initials: D
authors.lastname: Cabrera
authors.affiliation: Department of Cell and Molecular Biology, Catholic University of Chile, Avenida Libertador Bernardo O'Higgins, 340, Santiago, Chile.
authors.forename: María Gabriela
authors.initials: MG
authors.lastname: Morales
authors.affiliation: Department of Cell and Molecular Biology, Catholic University of Chile, Avenida Libertador Bernardo O'Higgins, 340, Santiago, Chile.
authors.forename: Cecilia A
authors.initials: CA
authors.lastname: Riquelme
authors.affiliation: Department of Cell and Molecular Biology, Catholic University of Chile, Avenida Libertador Bernardo O'Higgins, 340, Santiago, Chile.
authors.forename: Jaime
authors.initials: J
authors.lastname: Gutiérrez
authors.affiliation: Cell Biology Group, Department of Experimental and Health Sciences, CIBER on Neurodegenerative Diseases (CIBERNED), Pompeu Fabra University (UPF), Dr. Aiguader, 88, 08003 Barcelona, Spain.
authors.forename: Antonio L
authors.initials: AL
authors.lastname: Serrano
authors.affiliation: Department of Cell and Molecular Biology, Catholic University of Chile, Avenida Libertador Bernardo O'Higgins, 340, Santiago, Chile.
authors.forename: Enrique
authors.initials: E
authors.lastname: Brandan
authors.affiliation: Cell Biology Group, Department of Experimental and Health Sciences, CIBER on Neurodegenerative Diseases (CIBERNED), Pompeu Fabra University (UPF), Dr. Aiguader, 88, 08003 Barcelona, Spain ; Institució Catalana de Recerca i Estudis Avançats (ICREA), Dr. Aiguader, 88, 08003 Barcelona, Spain.
authors.forename: Pura
authors.initials: P
authors.lastname: Muñoz-Cánoves