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

Calpain 3 is known as the skeletal muscle-specific member of the calpains, a family of intracellular nonlysosomal cysteine proteases, It was previousl y shown that defects in the human calpain 3 gene are responsible for limb g irdle muscular dystrophy type 2A (LGMD2A), an inherited disease affecting p redominantly the proximal limb muscles. To better understand the function o f calpain 3 and the pathophysiological mechanisms of LGMD2A and also to dev elop an adequate model for therapy research, we generated capn3-deficient m ice by gene targeting. capn3-deficient mice are fully fertile and viable. A llele transmission in intercross progeny demonstrated a statistically signi ficant departure from Mendel's law. capn3-deficient mice show a mild progre ssive muscular dystrophy that affects a specific group of muscles. The age of appearance of myopathic features varies with the genetic background, sug gesting the involvement of modifier genes. Affected muscles manifest a simi lar apoptosis-associated perturbation of the I kappaB alpha /nuclear factor kappaB pathway as seen in LGMD2A patients. In addition, Evans blue stainin g of muscle fibers reveals that the pathological process due to calpain 3 d eficiency is associated with membrane alterations.