Capn3-KO Mouse

Capn3, also known as p94 or calpain-3, is a muscle-specific Ca2+-dependent cysteine protease. It has unique N-terminus and insertion sequence 1 and 2 domains, conferring characteristics like rapid autolysis, Ca2+-independent activation and Na+ activation. CAPN3 is involved in promoting calcium release from skeletal muscle fibers, calcium uptake of sarcoplasmic reticulum, muscle formation and remodeling [1,2]. It is also part of the nucleolus-localized Def-CAPN3 protein degradation pathway which is essential to ribosome production and cell-cycle progression [3].

Mutations in CAPN3 cause limb-girdle muscular dystrophy (MD) type 2A and other types of MD. Recessive mutations in CAPN3 are responsible for limb-girdle muscular dystrophy type 2A, and the c.1746-20C>G variant is hypomorphic for LGMD R1 calpain 3-related, presenting a mild/medium severity phenotype [1,4,5]. There are also reports of autosomal dominant calpainopathies associated with CAPN3 variants [6]. In titinopathy, CAPN3-mediated processing of C-terminal titin is disrupted due to CAPN3 deficiency [7].

In conclusion, CAPN3 is crucial for muscle-related physiological functions. Research on CAPN3, especially through studies of its mutations in disease models, has significantly enhanced our understanding of the pathogenesis of limb-girdle muscular dystrophies and other related muscle disorders, providing potential directions for future therapeutic strategies.