Résumé
Limb-girdle muscular dystrophy type 2A (LGMD2A) is a recessive genetic disorder caused by mutations in the cysteine protease calpain 3 (CAPN3) that leads to selective muscle wasting. We previously showed that CAPN3 deficiency is associated with a profound perturbation of the NF-kappa B/I kappa B alpha survival pathway. In this study, the consequences of altered NF-kappa B/I kappa B alpha pathway were investigated using biological materials from LGMD2A patients. We first show that die antiapoptotic factor cellular-FUCE inhibitory protein (c-FLIP), which is dependent on the NF-kappa B pathway in normal muscle cells, is down-regulated in LGMD2A biopsies. In muscle cells isolated from LGMD2A patients, NF-kappa B is readily activated on cytokine induction as shown by an increase in its DNA binding activity. However, we observed discrepant transcriptional responses depending on the NF-kappa B target genes. I kappa B alpha is expressed following NF-kappa B activation independent of the CAPN3 status, whereas expression of c-FLIP is obtained only when CAPN3 is present. These data lead us to postulate that CAPN3 intervenes in the regulation of the expression of NF-kappa B-dependent survival genes to prevent apoptosis in skeletal muscle. Deregulations in the NF-kappa B pathway could be part of the mechanism responsible for the muscle wasting resulting from CAPN3 deficiency.