CELL SIGNALING IN MUSCLE WASTING. IDENTIFICATION OF CRITICAL TARGETS IN FoxO, MYOSTATIN AND UBIQUITIN-PROTEASOME PATHWAYS TO DEVELOP NEW THERAPEUTIC STRATEGIES FOR MUSCULAR DYSTROPHY

Genetic Muscular Dystrophies are characterized by a progressive loss of skeletal muscle mass which leads to weakness and culminates with death. These diseases might be cured in the future by gene- or cell-therapy. However there are still serious problems with these approaches hindering their application in clinical practice. The possibility to block or retard muscle wasting in muscular dystrophies by promoting muscle growth is an attractive alternative approach. Muscle growth and loss are carefully regulated by intracellular signaling and an exact understanding of these processes will allow us to develop new drugs. Therefore it seems justify to explore intracellular signaling during muscle wasting. Recently, overexpression of growth promoting factors such as IGF1, as well as blocking negative regulators of muscle growth such as myostatin reduced muscle degeneration and improved muscle strength in mdx mouse, the animal model for Duchenne Muscular Dystrophy. It has been reported that blocking proteasome, a multicomponent system for the proteins degradation, with inhibitors ameliorates the dystrophic phenotype by restoring the expression and the membrane localization of truncated dystrophin. Thus these three signaling pathways are involved in beneficial effects on dystrophic phenotype however, a progression in this direction requires a better understanding. The proposed projects aims to define the role of FoxOs, the transcription factors inhibited by IGF1 and involved in muscle wasting, of myostatin and of ubiquitin-proteasome system. I will use multiple approaches to perturb these pathways in order to identify critical signaling proteins. These results will allow us either to develop new therapeutic strategies or to define a rationale for the clinical application of proteasome inhibitors in muscular dystrophies.