Résumé :
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Progressive muscle loss is a common feature of different genetic and acquired muscle diseases for which no pharmacological treatment is presently available. Promoting muscle growth or blocking catabolic pathways are possible therapeutic approaches to combat muscle wasting. However the unexpected failure of myostatin inhibitor in clinical trial strongly confirms that we need a precise picture of the signalling pathways that control muscle mass before moving to drugs development and their clinical application. Our work is an effort in this direction. The size of skeletal muscle is determined by a balance between protein synthesis and protein degradation. In mammalian cells half-life of proteins is controlled by two proteolytic systems the ubiquitin-proteasome and the autophagy-lysosome. Autophagy is an evolutionarily conserved mechanism that allows cell survival during starvation through the bulk degradation of proteins and organelles by lysosomal enzymes. We have recently discovered that autophagy has a major role in the maintenance of muscle mass. In fact when we specifically delete the critical autophagy gene Atg7 in muscles, we revealed that autophagy inhibition does not protect from muscle wasting but instead it induces muscle loss and weakness. Altered regulation of autophagy results in muscle degeneration, weakness and several features characteristic of different myopathies. In fact autophagy inhibition causes oxidative stress, appearance of inclusions and protein aggregates, problems in the control of protein folding, accumulation of abnormal mitochondria and distension of sarcoplasmic reticulum. The morphological alterations of autophagy knockout mice are reminiscent of features of some myopathies. Indeed we found that collagenVI myopathies, i.e. Ullirch dystrophy and Bethlem myopathy, are characterized by autophagy defect. Importanlty, reactivation of the autophagic flux by either nutritional approaches or by pharmacological and genetics tools removes dysfunctional organelles and greatly ameliorates muscle force and structure. These findings indicate that defective activation of the autophagic machinery plays a pathogenic role in congenital muscular dystrophies. Thus, dissecting the regulation of autophagy system in skeletal muscle and its role in muscle homeostasis is crucial for developing new therapeutic tools
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