G.P.229

• Published in: Neuromuscular disorders : NMD 2014-10, Vol.24 (9), p.885-885
• Main Authors: Charton, K, Sarparanta, J, Vihola, A, Suel, L, Daniele, N, Hackman, P, Udd, B, Richard, I
• Format: Article
• Language: English
• Subjects: Neurology
• ISSN: 0960-8966
• DOI: 10.1016/j.nmd.2014.06.305

Several published studies strongly implied the existence of functional relationship between calpain 3 and titin proteins. Calpain 3, the cysteine protease mutated in Limb Girdle Muscular Dystrophy type 2A (LGMD2A), has at least 2 different binding sites on titin, which is also one of calpain 3 substrates. Moreover, Tibial Muscular Dystrophy (TMD) and LGMD2J, both caused by the mutations in the last exons of the titin gene, are characterised by secondary reduction of calpain 3 expression. We also showed that the last domains of titin are not present in the TMD/LGMD2J muscle. Here, we tested several calpain 3 properties in vivo and in vitro conditions to better clarify the relationship between calpain 3 and titin in the M-band of the sarcomere, as well as its possible implication in the pathogenesis of LGMD2A and LGMD2J. An in vitro analysis validated the C-terminal part of the titin protein as a proteolytic substrate for calpain 3. Moreover, we demonstrated that TMD/LGMD2J mutations induce disruption of these cleavages in vitro while calpain 3 is still able to interact with titin. Interestingly and unexpectedly, we showed that the disappearance of the M-band titin seen in vivo as a consequence of TMD/LGMD2J mutations is still observed in the absence of calpain 3, indicating that this event is not caused by a calpain 3 proteolytic cleavage.