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Loss of Calpain 3 Proteolytic Activity Leads to Muscular Dystrophy and to Apoptosis-associated IB/Nuclear Factor B Pathway Perturbation in Mice

Correspondence to: Jacques S. Beckmann, Department of Molecular Genetics, Weizman Institute of Science. PO Box 26, Rehovot, Israel. Fax:972-8-934-4108 E-mail: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 IB/nuclear factor 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, IB/NF-B pathway, knockout mice

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