| Abstract | 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-kappaB/IkappaB alpha survival pathway. In this study, the consequences of altered NF-kappaB/IkappaB alpha pathway were investigated using biological materials from LGMD2A patients. We first show that the antiapoptotic factor cellular-FLICE inhibitory protein (c-FLIP), which is dependent on the NF-kappaB pathway in normal muscle cells, is down-regulated in LGMD2A biopsies. In muscle cells isolated from LGMD2A patients, NF-kappaB 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-kappaB target genes. IkappaB alpha is expressed following NF-kappaB 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-kappaB-dependent survival genes to prevent apoptosis in skeletal muscle. Deregulations in the NF-kappaB pathway could be part of the mechanism responsible for the muscle wasting resulting from CAPN3 deficiency. |
| Authors | Béatrice Benayoun, Stephen Baghdiguian, Alicia Lajmanovich, Marc Bartoli, Nathalie Daniele, Evelyne Gicquel, Nathalie Bourg, Fabrice Raynaud, Marie-Anne Pasquier, Laurence Suel, Hanns Lochmuller, Gérard Lefranc, Isabelle Richard
(Affiliation: Généthon CNRS FRE3018, 1, 91000 Evry, France.)
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| Journal | The FASEB journal : official publication of the Federation of American Societies for Experimental Biology
(FASEB J)
Vol. 22
Issue 5
Pg. 1521-9
(May 2008)
ISSN: 1530-6860 United States |
| PMID | 18073330
(Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
|
| Chemical References |
- CASP8 and FADD-Like Apoptosis Regulating Protein
- CFLAR protein, human
- I-kappa B Proteins
- Interleukin-1beta
- Muscle Proteins
- NF-kappa B
- Tumor Necrosis Factor-alpha
- bcl-2-Associated X Protein
- bcl-X Protein
- CAPN3 protein, human
- Calpain
|
| Topics |
- Apoptosis
(physiology)
- CASP8 and FADD-Like Apoptosis Regulating Protein
(biosynthesis)
- Calpain
(deficiency, physiology)
- Cells, Cultured
- Down-Regulation
- Humans
- I-kappa B Proteins
(biosynthesis)
- Interleukin-1beta
(physiology)
- Models, Biological
- Muscle Proteins
(deficiency, physiology)
- Muscle, Skeletal
(metabolism)
- Muscular Dystrophies, Limb-Girdle
(physiopathology)
- NF-kappa B
(physiology)
- Tumor Necrosis Factor-alpha
(physiology)
- bcl-2-Associated X Protein
(biosynthesis)
- bcl-X Protein
(biosynthesis)
|
