Loss of calpain 3 proteolytic activity leads to muscular dystrophy and to apoptosis-associated IkappaBalpha/nuclear factor kappaB pathway perturbation in mice.

Abstract

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 IkappaBalpha/nuclear factor kappaB 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.

• Authors: I Richard, C Roudaut, S Marchand, S Baghdiguian, M Herasse, D Stockholm, Y Ono, L Suel, N Bourg, H Sorimachi, G Lefranc, M Fardeau, A Sébille, J S Beckmann
• Journal: The Journal of cell biology (J Cell Biol) Vol. 151 Issue 7 Pg. 1583-90 (Dec 25 2000) ISSN: 0021-9525 [Print] United States
• PMID: 11134085 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• DNA-Binding Proteins
• I-kappa B Proteins
• NF-kappa B
• NFKBIA protein, human
• Nfkbia protein, mouse
• RNA, Messenger
• NF-KappaB Inhibitor alpha
• Evans Blue
• Creatine Kinase
• Calpain

Topics

• Animals
• Apoptosis
• Calpain (chemistry, deficiency, genetics, metabolism)
• Creatine Kinase (metabolism)
• Crosses, Genetic
• DNA-Binding Proteins (metabolism)
• Evans Blue
• Female
• Fertility
• Gene Deletion
• Gene Targeting
• Genotype
• I-kappa B Proteins
• Male
• Mice
• Mice, Knockout
• Muscle Fibers, Skeletal (enzymology, metabolism, pathology)
• Muscle, Skeletal (enzymology, metabolism, pathology)
• Muscular Dystrophies (enzymology, genetics, metabolism, pathology)
• NF-KappaB Inhibitor alpha
• NF-kappa B (metabolism)
• Phenotype
• RNA, Messenger (analysis, genetics)
• Sarcolemma (pathology)
• Signal Transduction