Résumé :
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Communication n° 464 Limb-girdle muscular dystrophy type 2A (LGMD2A) is a skeletal muscle recessive atrophying disorder due to defects in the cysteine protease, calpain 3. This protein is mostly present in an inactive state in muscle and needs a signal to be activated. Although several of its substrates have been identified, its physiological role remains unknown. However, the demonstration that calpain 3 co-localizes with titin, a key player of mechanically regulated signalling pathways, suggests that calpain 3 could participate in the regulation of signals initiated from titin. Especially, it is known that calpain 3 is located in the titin's elastic N2A region near a binding site for a muscle transcriptional regulator complex that includes the Cardiac Ankyrin Repeat Protein (CARP). This protein exhibits an important role in the heart whereas its function is not fully understood in the skeletal muscle. Herein, we demonstrated that CARP is a calpain 3 substrate. To address its role in skeletal muscle and to determine the consequences of this cleavage, we investigated the in cellulo and in vivo localization of the full-length and cleaved forms of CARP and their effects on the activity of several transcription factors. We are pursuing this study to determine whether CARP signalling pathway dysregulation is associated with the emergence of LGMD2A. If so, this study could eventually lead to development of new therapeutic solutions for this dystrophy.
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