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Published online 25 December 2000. doi:10.1083/jcb.151.7.1583
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© The Rockefeller University Press, 0021-9525/2000//1583 $5.00
The Journal of Cell Biology, Volume 151, Number 7, , 2000 1583-1590

Report

Loss of Calpain 3 Proteolytic Activity Leads to Muscular Dystrophy and to Apoptosis-Associated I{kappa}b{alpha}/Nuclear Factor {kappa}b Pathway Perturbation in Mice



Isabelle Richarda, Carinne Roudauta, Sylvie Marchanda, Stephen Baghdiguianb, Muriel Herassea, Daniel Stockholma, Yasuko Onod, Laurence Suela, Nathalie Bourga, Hiroyuki Sorimachid, Gérard Lefrancc, Michel Fardeaue, Alain Sébillef, and Jacques S. Beckmanna,g

a Généthon, CNRS URA 1922–1923, 91000 Évry, France
b Laboratoire de Dynamique Moléculaire des Interactions Membranaires, CNRS-UMR 5539
c Laboratoire d'ImmunoGénétique Moléculaire, Institut de Génétique Humaine, CNRS UPR 1142, Université Montpellier 2, 34095 Montpellier Cedex 5, France
d Graduate School of Agricultural and Life Sciences, University of Tokyo, Tokyo 113-8657, Japan
e Institut de Myologie, Hôpital Pitié-Salpétrière, 75013 Paris, France
f Atelier de Régénération Neuromusculaire, Faculté de Médecine Saint Antoine, 75012 Paris, France
g Centre National de Genotypage, 91057 Evry, France
Department of Molecular Genetics, Weizman Institute of Science. PO Box 26, Rehovot, Israel.972-8-934-4108

beckman{at}weizman.ac.il

Calpain 3 is known as the skeletal muscle–specific member of the calpains, a family of intracellular nonlysosomal cysteine proteases. It was previously shown that defects in the human calpain 3 gene are responsible for limb girdle muscular dystrophy type 2A (LGMD2A), an inherited disease affecting predominantly the proximal limb muscles. To better understand the function of calpain 3 and the pathophysiological mechanisms of LGMD2A and also to develop an adequate model for therapy research, we generated capn3-deficient mice by gene targeting. capn3-deficient mice are fully fertile and viable. Allele transmission in intercross progeny demonstrated a statistically significant departure from Mendel's law. capn3-deficient mice show a mild progressive muscular dystrophy that affects a specific group of muscles. The age of appearance of myopathic features varies with the genetic background, suggesting the involvement of modifier genes. Affected muscles manifest a similar apoptosis-associated perturbation of the I{kappa}B{alpha}/nuclear factor {kappa}B pathway as seen in LGMD2A patients. In addition, Evans blue staining of muscle fibers reveals that the pathological process due to calpain 3 deficiency is associated with membrane alterations.

Key Words: calpain • apoptosis • muscular dystrophies • I{kappa}B{alpha}/NF-{kappa}B pathway • knockout mice

© 2000 The Rockefeller University Press

Abbreviations used in this paper: CK, creatine kinase; ES, embryonic stem; EB, Evans blue; H&E, hematoxilin and eosin; LGMD2A, limb girdle muscular dystrophy type 2A; neoR, neomycin resistance; NF, nuclear factor; RT, reverse transcriptase; tk, thymidine kinase; TUNEL, terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling.


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