Projet ANR-08-GENO-0023 – IN-A-FIB : Mécanismes communs de l'atrophie musculaire dans les myopathies et la sarcopénie : interaction entre inflammation, fibrose et atrophie
Programme : Du gène à la physiopathologie, des maladies rares aux maladies communes (GENOPAT) 2008
Année de financement : 2008
Coordinateur du projet : UNIVERSITE PARIS VI [PIERRE ET MARIE CURIE] (UNIVERSITE PARIS VI [PIERRE ET MARIE CURIE])
Partenaires : Institut national de la santé et de la recherche médicale; Institut national de la santé et de la recherche médicale; Université Pierre et Marie Curie
Montant : 600000.0 euros
Date de début : 2009
Durée : 36 mois
Résumé : Muscular dystrophies are a heterogenous group of rare genetic disorders. These diseases, in common with age related sarcopenia are characterised by muscle atrophy, fibrosis and fatty infiltration. Inflammation plays a role in this process but the exact cellular and molecular mechanisms are poorly understood. Characterization of common disease mechanisms could lead to the identification of molecular pathways and the identification of novel therapeutic targets. 
Our aim is to identify the cellular and molecular components involved in the inflammation of diseased and its role in the development of fibrosis and lipid accumulation. We will identify the different signalling pathways involved in these physiopathological processes. Particular attention will be given to the transcription factor SRF, since preliminary results suggest that lack of SRF in skeletal muscle leads to premature ageing of the muscle involving atrophy, fibrosis and an accumulation of lipids.
 The aim of our project is to identify the cellular and molecular components involved in the inflammation of diseased or aged skeletal muscle and their putative role in the development of fibrosis or the accumulation of lipids. It is clear that there is a direct relation between elevated inflammatory signals and reduction in opposing growth factor signals and this interplay may have an important effect on the progression of fibrosis during muscle wasting and disease. Many muscular diseases are characterised by massive macrophage infiltration.The exact nature of this infiltration will be identified in terms of activation status of the inflammatory cells. We will use a global proteomics approach to characterise the secretome of the different cellular compartments : macrophages, myoblasts, myofibers and fibroblasts. We will determine i) to what extent does inflammation contribute to the physiopathology of neuromuscular disease. ii) does it induce the p16 stress pathway or iii) the secretion of specific biomarkers. We will identify the different signalling pathways involved in these physiopathological processes by testing biological effects on myogenic cells in vitro and ex vivo. Particular attention will be given to the transcription factor SRF (Serum Response Factor), since preliminary results from the group of team 2 suggest that the lack of SRF in skeletal muscle leads to premature ageing of the muscle involving atrophy, fibrosis and an accumulation of lipids. Other murine models of human diseases will be used, such as that of DM1 or laminopathy, or the mutant dy/dy (CMD) to study these common pathological features. Investigations will also be carried out on cell cultures derived either from patients suffering from these pathologies (e.g. DMD, DM1 and laminopathy) or from normal skeletal muscle from young or aged subjects. The molecular or cellular events identified will be eventually validated on human muscle biopsies already available within the network.  Identification of the cell type(s) responsible for synthesis of the extracellular matrix in fibrosis.
Identification of the molecular pathways involved in myogenesis, atrophy and fibrosis triggered by macrophages.
Identification of new biomarkers involved in atrophy, fibrosis and adipogenesis.
Characterisation of the interplay between inflammation, proliferative status of muscle progenitors and myogenic phenotype.
Identify the effect of inflammation and stress on p16 signalling and the influence this will have muscle progenitors.
Role of SRF in different neuromuscular disease as well as in sarcopenia.
Identification of mechanisms involved in muscle atrophy, lipid accumulation and fibrosis (putative role of SRF).
These results will enable us to determine common mechanisms which could lead to the identification of common molecular pathways and hence the identification of novel therapeutic targets to prevent or cure these pathological processes involved in both muscle disease and aging.