Non-proteolytic functions of calpain-3 in sarcoplasmic reticulum in skeletal muscles |
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Authors: | Ojima Koichi Ono Yasuko Ottenheijm Coen Hata Shoji Suzuki Hidenori Granzier Henk Sorimachi Hiroyuki |
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Institution: | 1 Calpain Project, The Tokyo Metropolitan Institute of Medical Science (Rinshoken), 2-1-6 Kamikitaza, Setagaya-ku, Tokyo 156-8506, Japan2 Meat Proteins Research Team, NILGS, Tsukuba 305-0901, Japan3 Department of Physiology, University of Arizona, Tucson, AZ 85724, USA4 Laboratory of Electron Micrography, The Tokyo Metropolitan Institute of Medical Science (Rinshoken), Tokyo 156-8506, Japan |
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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 Capn3CS/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, Capn3CS/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 Capn3CS/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, Capn3CS/CS mice showed that the nonenzymatic role of calpain-3 is required for proper Ca2+ efflux from the SR to cytosol during muscle contraction. These results indicate that calpain-3 functions as a nonenzymatic element for the Ca2+ 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. |
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Keywords: | limb-girdle muscular dystrophy type 2A calpainopathy ryanodine receptor protease proteolysis |
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