Loss of calpain 3 proteolytic activity leads to muscular dystrophy and to apoptosis-associated IkappaBalpha/nuclear factor kappaB pathway perturbation in mice.
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.
Richard
I
I
Généthon, CNRS URA 1922-1923, 91000 Evry, France.
Roudaut
C
C
Marchand
S
S
Baghdiguian
S
S
Herasse
M
M
Stockholm
D
D
Ono
Y
Y
Suel
L
L
Bourg
N
N
Sorimachi
H
H
Lefranc
G
G
Fardeau
M
M
Sébille
A
A
Beckmann
J S
JS
D000818:Animals; D017209:Apoptosis; D002154:Calpain / Q000737:chemistry / Q000172:deficiency* / Q000235:genetics / Q000378:metabolism; D003402:Creatine Kinase / Q000378:metabolism; D003433:Crosses, Genetic; D004268:DNA-Binding Proteins / Q000378:metabolism*; D005070:Evans Blue; D005260:Female; D005298:Fertility; D017353:Gene Deletion; D018390:Gene Targeting; D005838:Genotype; D020672:I-kappa B Proteins; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D018485:Muscle Fibers, Skeletal / Q000201:enzymology / Q000378:metabolism / Q000473:pathology; D018482:Muscle, Skeletal / Q000201:enzymology / Q000378:metabolism / Q000473:pathology; D009136:Muscular Dystrophies / Q000201:enzymology* / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D000072000:NF-KappaB Inhibitor alpha; D016328:NF-kappa B / Q000378:metabolism*; D010641:Phenotype; D012333:RNA, Messenger / Q000032:analysis / Q000235:genetics; D012508:Sarcolemma / Q000473:pathology; D015398:Signal Transduction
D004268:DNA-Binding Proteins; D020672:I-kappa B Proteins; D016328:NF-kappa B; C000606204:NFKBIA protein, human; C000606205:Nfkbia protein, mouse; D012333:RNA, Messenger; D000072000:NF-KappaB Inhibitor alpha; D005070:Evans Blue; D003402:Creatine Kinase; D002154:Calpain