Calpain 3 deficiency is associated with myonuclear apoptosis and profound perturbation of the IκBα/NF-κB pathway in limb-girdle muscular dystrophy type 2A

• Published in: Nature medicine Vol. 5; no. 5; pp. 503 - 511
• Main Authors: Lefranc, Gérard, Baghdiguian, Stephen, Martin, Marianne, Richard, Isabelle, Pons, Françoise, Astier, Catherine, Bourg, Nathalie, Hay, Ronald T, Chemaly, Raymond, Halaby, Georges, Loiselet, Jacques, Anderson, Louise V. B, Munain, Adolfo Lopez de, Fardeau, Michel, Mangeat, Paul, Beckmann, Jacques S
• Format: Journal Article
• Language: English
• Published: New York Nature Publishing Group US 01.05.1999
• Subjects: Biomedical and Life Sciences; Biomedicine; Cancer Research; Infectious Diseases; Metabolic Diseases; Molecular Medicine; Neurosciences
• ISSN: 1078-8956; 1546-170X
• DOI: 10.1038/8385

Using fluorescence microscopy techniques, we show here that muscle biopsies of LGMD2A patients present apoptotic features that are associated with subsarcolemmal localization of NF- Kappa B and selective nuclear accumulation of I Kappa B alpha . Furthermore, we reconstituted calpain 3-dependent degradation of I Kappa B alpha in an in vitro cell expression system, and I Kappa B alpha -dependent apoptosis in human myogenic satellite cells grown in primary culture. Thus, the apoptotic cell death event in LGMD2A is compatible with a sequence of events involving a failure in calpain 3-dependent I Kappa B alpha proteolysis resulting in I Kappa B alpha accumulation in both the cytoplasm and nucleus, and sequestration of NF- Kappa B in the cytoplasm and subsequent non-expression of survival genes.