NF-kappaB-dependent expression of the antiapoptotic factor c-FLIP is regulated by calpain 3, the protein involved in limb-girdle muscular dystrophy type 2A

FASEB J. 2008 May;22(5):1521-9. doi: 10.1096/fj.07-8701com. Epub 2007 Dec 11.

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Apoptosis / physiology
  • CASP8 and FADD-Like Apoptosis Regulating Protein / biosynthesis*
  • Calpain / deficiency
  • Calpain / physiology*
  • Cells, Cultured
  • Down-Regulation
  • Humans
  • I-kappa B Proteins / biosynthesis
  • Interleukin-1beta / physiology
  • Models, Biological
  • Muscle Proteins / deficiency
  • Muscle Proteins / 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

Substances

  • 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