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

Richard I, Roudaut C, Marchand S, Baghdiguian S, Herasse M, Stockholm D, Ono Y, Suel L, Bourg N, Sorimachi H, Lefranc G, Fardeau M, Sébille A, Beckmann JS - J. Cell Biol. (2000)

Bottom Line: Calpain 3 is known as the skeletal muscle-specific member of the calpains, a family of intracellular nonlysosomal cysteine proteases.The age of appearance of myopathic features varies with the genetic background, suggesting the involvement of modifier genes.In addition, Evans blue staining of muscle fibers reveals that the pathological process due to calpain 3 deficiency is associated with membrane alterations.

View Article: PubMed Central - PubMed

Affiliation: Généthon, CNRS URA 1922-1923, 91000 Evry, France.

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.

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Histologic analysis of capn3-deficient mice. H&E-stained transverse muscle cryosections (7 μm) from mice of 129Sv genetic background. (a–d) 2-mo-old mice; (e–l) 6-mo-old mice. Dystrophic changes are evident in psoas (a and e), soleus (b and f), deltoid (c and g), and tibialis anterior (d and h), whereas quadriceps (i), gastrocnemius (j), and triceps (k) present a normal aspect. Diaphragm in l presents very slight abnormalities. The main features encountered are fibers with internal nuclei (b–f, and h) or area of infiltration of mononuclear cells (a and g). A cluster of small regenerating fibers can be seen in e. Bars, 50 μm.
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Figure 3: Histologic analysis of capn3-deficient mice. H&E-stained transverse muscle cryosections (7 μm) from mice of 129Sv genetic background. (a–d) 2-mo-old mice; (e–l) 6-mo-old mice. Dystrophic changes are evident in psoas (a and e), soleus (b and f), deltoid (c and g), and tibialis anterior (d and h), whereas quadriceps (i), gastrocnemius (j), and triceps (k) present a normal aspect. Diaphragm in l presents very slight abnormalities. The main features encountered are fibers with internal nuclei (b–f, and h) or area of infiltration of mononuclear cells (a and g). A cluster of small regenerating fibers can be seen in e. Bars, 50 μm.

Mentions: The pathological aspect of H&E-stained frozen cross sections of various muscles was evaluated in calpain 3–deficient mice from the ages of 8 wk to 19 mo and compared with those of age-matched normal mice. Pathological changes characteristic of muscular dystrophy such as centronucleation, area of necrosis/regeneration, splitting of fibers, and foci of mononuclear cell infiltrates can be seen in both genetic backgrounds (Fig. 3). It should be noted that, in most cases, fibers with internal nuclei are clustered. Alterations increase with age, and the level of abnormality is variable depending on the muscle examined. Considering the combined effect of all alterations, psoas, soleus, and deltoid are the most affected muscles; tibialis anterior and biceps are affected but to a lower extent, whereas the quadriceps, gastrocnemius, and triceps brachii do not seem to be substantially affected.


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

Richard I, Roudaut C, Marchand S, Baghdiguian S, Herasse M, Stockholm D, Ono Y, Suel L, Bourg N, Sorimachi H, Lefranc G, Fardeau M, Sébille A, Beckmann JS - J. Cell Biol. (2000)

Histologic analysis of capn3-deficient mice. H&E-stained transverse muscle cryosections (7 μm) from mice of 129Sv genetic background. (a–d) 2-mo-old mice; (e–l) 6-mo-old mice. Dystrophic changes are evident in psoas (a and e), soleus (b and f), deltoid (c and g), and tibialis anterior (d and h), whereas quadriceps (i), gastrocnemius (j), and triceps (k) present a normal aspect. Diaphragm in l presents very slight abnormalities. The main features encountered are fibers with internal nuclei (b–f, and h) or area of infiltration of mononuclear cells (a and g). A cluster of small regenerating fibers can be seen in e. Bars, 50 μm.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC2150676&req=5

Figure 3: Histologic analysis of capn3-deficient mice. H&E-stained transverse muscle cryosections (7 μm) from mice of 129Sv genetic background. (a–d) 2-mo-old mice; (e–l) 6-mo-old mice. Dystrophic changes are evident in psoas (a and e), soleus (b and f), deltoid (c and g), and tibialis anterior (d and h), whereas quadriceps (i), gastrocnemius (j), and triceps (k) present a normal aspect. Diaphragm in l presents very slight abnormalities. The main features encountered are fibers with internal nuclei (b–f, and h) or area of infiltration of mononuclear cells (a and g). A cluster of small regenerating fibers can be seen in e. Bars, 50 μm.
Mentions: The pathological aspect of H&E-stained frozen cross sections of various muscles was evaluated in calpain 3–deficient mice from the ages of 8 wk to 19 mo and compared with those of age-matched normal mice. Pathological changes characteristic of muscular dystrophy such as centronucleation, area of necrosis/regeneration, splitting of fibers, and foci of mononuclear cell infiltrates can be seen in both genetic backgrounds (Fig. 3). It should be noted that, in most cases, fibers with internal nuclei are clustered. Alterations increase with age, and the level of abnormality is variable depending on the muscle examined. Considering the combined effect of all alterations, psoas, soleus, and deltoid are the most affected muscles; tibialis anterior and biceps are affected but to a lower extent, whereas the quadriceps, gastrocnemius, and triceps brachii do not seem to be substantially affected.

Bottom Line: Calpain 3 is known as the skeletal muscle-specific member of the calpains, a family of intracellular nonlysosomal cysteine proteases.The age of appearance of myopathic features varies with the genetic background, suggesting the involvement of modifier genes.In addition, Evans blue staining of muscle fibers reveals that the pathological process due to calpain 3 deficiency is associated with membrane alterations.

View Article: PubMed Central - PubMed

Affiliation: Généthon, CNRS URA 1922-1923, 91000 Evry, France.

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.

Show MeSH
Related in: MedlinePlus