title: Non-proteolytic functions of calpain-3 in sarcoplasmic reticulum in skeletal muscles.
abstract: Mutations in CAPN3/Capn3, which codes for skeletal muscle-specific calpain-3/p94 protease, are responsible for limb-girdle muscular dystrophy type 2A. Using "knock-in" (referred to as Capn3(CS/CS)) mice, in which the endogenous calpain-3 is replaced with a mutant calpain-3:C129S, which is a proteolytically inactive but structurally intact calpain-3, we demonstrated in our previous studies that loss of calpain-3 protease activity causes muscular dystrophy [Ojima, K. et al. (2010) J. Clin. Invest. 120, 2672-2683]. However, compared to Capn3-null (Capn3(-/-)) mice, Capn3(CS/CS) mice showed less severe dystrophic symptoms. This suggests that calpain-3 also has a non-proteolytic function. This study aimed to elucidate the non-proteolytic functions of calpain-3 through comparison of Capn3(CS/CS) mice with Capn3(-/-) mice. We found that calpain-3 is a component of the sarcoplasmic reticulum (SR), and that calpain-3 interacts with, but does not proteolyze, typical SR components such as ryanodine receptor and calsequestrin. Furthermore, Capn3(CS/CS) mice showed that the nonenzymatic role of calpain-3 is required for proper Ca(2+) efflux from the SR to cytosol during muscle contraction. These results indicate that calpain-3 functions as a nonenzymatic element for the Ca(2+) efflux machinery in the SR, rather than as a protease. Thus, defects in the nonenzymatic function of calpain-3 must also be involved in the pathogenesis of limb-girdle muscular dystrophy type 2A.
authors.affiliation: Calpain Project, The Tokyo Metropolitan Institute of Medical Science (Rinshoken), 2-1-6 Kamikitaza, Setagaya-ku, Tokyo 156-8506, Japan.
authors.forename: Koichi
authors.initials: K
authors.lastname: Ojima
authors.forename: Yasuko
authors.initials: Y
authors.lastname: Ono
authors.forename: Coen
authors.initials: C
authors.lastname: Ottenheijm
authors.forename: Shoji
authors.initials: S
authors.lastname: Hata
authors.forename: Hidenori
authors.initials: H
authors.lastname: Suzuki
authors.forename: Henk
authors.initials: H
authors.lastname: Granzier
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Sorimachi
mesh_terms: D000818:Animals; D019556:COS Cells; D002154:Calpain / Q000235:genetics / Q000378:metabolism*; D002522:Chlorocebus aethiops; D006801:Humans; D051379:Mice; D008810:Mice, Inbred C57BL; D008815:Mice, Inbred Strains; D009124:Muscle Proteins / Q000235:genetics / Q000378:metabolism*; D018482:Muscle, Skeletal / Q000378:metabolism*; D012519:Sarcoplasmic Reticulum / Q000378:metabolism*
chemical_list: D009124:Muscle Proteins; C105884:CAPN3 protein, human; D002154:Calpain; C491373:Capn3 protein, mouse