Loss of Calpain 3 Proteolytic Activity Leads to Muscular Dystrophy and to Apoptosis-Associated Iκbα/Nuclear Factor κb 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 IκBα/nuclear factor κB 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.

Resveratrol‐induced apoptosis in MCF‐7 human breast cancer cells involves a caspase‐independent mechanism with downregulation of Bcl‐2 and NF‐κB

“…Thus, inhibition of calpain activity results in increased levels of I-kB, which retains NF-kB in the cytosol and induces apoptosis. 26,27 Our results are in agreement with these data since concentrations of RES that decreased NF-kB activity and induced apoptosis also inhibited calpain activity in MCF-7 cells. Interestingly, the pattern of calpain activity closely followed that observed for the ERa-dependent PI3K and PKB/AKT, 14 which suggests that both pathways could be functionally related.…”

“…25 Decreased calpain activity, on the contrary, increases cytosolic I-kB and retains NF-kB outside the nucleus, thus contributing to apoptosis. 26,27 The antiapoptotic factor Bcl-2 is regulated by NF-kB-dependent transcription and is located at the external mitochondrial membrane. Through interaction with the related protein Bax or Bad, Bcl-2 regulates permeability to apoptotic molecules such as Cyt c. 28 Activation of PI3K results in the inactivation of Bad by PKB/ AKT-dependent phosphorylation, a process that makes Bcl-2 available for binding Bax and for inhibiting Cyt c release and apoptosis.…”

Normal growth and regenerating ability of myoblasts from unaffected muscles of facioscapulohumeral muscular dystrophy patients

“…The use of other dystrophic animal models would not have been relevant since most of these diseases are based on monogenic alterations and their pathophysiological mechanisms are unrelated to FSHD. [55][56][57][58] In the present study, human FSHD myoblasts were injected into immunodeficient Rag mice, a validated mouse model for the analysis of muscle regeneration in the context of xenogenic MT. The implantation results we obtained were close to that reported previously [47][48][49] and confirmed that myoblasts prepared from unaffected FSHD muscles, even used at the 6th and 7th passages, take part into in vivo muscle regeneration.…”

Mechanisms of exercise-induced muscle damage and fatigue: Intracellular calcium accumulation

“…It has been proposed that calpain-3 plays a role in muscle repair and maintenance 32) , myogenesis 60) and apoptosis 61,62) . Sudo and Kano 58) reported that, in myofiber longitudinal sections, myonuclear apoptosis occurs at the subsarcolemmal level, as opposed to the central cytoplasm, at 7 and 14 days after ECC contractions.…”