DEFINING THE MOLECULAR SIGNATURE OF MUSCLE WASTING. IDENTIFICATION OF THERAPEUTIC TARGETS TO COUNTERAT MUSCLE DEGENERATION

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 which hinder 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. Our work is an effort in this direction. We have recently defined that FoxO and Smad transcription factors regulate expression of proteins that induce muscle loss while JunB transcription factor promotes proteins that regulate muscle growth. Moreover we have found that the correct functioning of the autophagic system is critical for preventing myofiber degeneration. Therefore the aims of this project are: i) to identify the genes that control muscle mass, ii) to dissect the autophagy-dependent mechanisms that, when perturbed, induce myofiber degeneration. 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 in muscular dystrophies.