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J. Biol. Chem., Vol. 282, Issue 19, 14493-14504, May 11, 2007

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Myogenic Stage, Sarcomere Length, and Protease Activity Modulate Localization of Muscle-specific Calpain^*

Koichi Ojima, Yasuko Ono, Naoko Doi, Katsuhide Yoshioka^¶, Yukiko Kawabata^¶, Siegfried Labeit^||, and Hiroyuki Sorimachi¹

From the Department of Enzymatic Regulation for Cell Functions, Tokyo Metropolitan Institute of Medical Science, Tokyo 113-8613, Japan, CREST, Japan Science and Technology Agency (JST), Kawaguchi 332-0012, Japan, ^¶Graduate School of Agricultural and Life Sciences, University of Tokyo, Tokyo 113-8657, Japan, and ^||Institut für Anästhesiologie und Operative Intensivmedizin, Universitätsklinikum Mannheim, 68167 Mannheim, Germany

p94/calpain 3 is a Ca²⁺-binding intracellular protease predominantly expressed in skeletal muscles. p94 binds to the N2A and M-line regions of connectin/titin and localizes in the Z-bands. Genetic evidence showing that compromised p94 proteolytic activity leads to muscular dystrophy (limb-girdle muscular dystrophy type 2A) indicates the importance of p94 function in myofibrils. Here we show that a series of p94 splice variants is expressed immediately after muscle differentiation and differentially change localization during myofibrillogenesis. We found that the endogenous N-terminal (but not C-terminal) domain of p94 was not only localized in the Z-bands but also directly bound to sarcomeric -actinin. These data suggest the incorporation of proteolytic N-terminal fragments of p94 into the Z-bands. In myofibrils localization of exogenously expressed p94 shifted from the M-line to N2A as the sarcomere lengthens beyond 2.6 and 2.8 µm for wild-type and proteaseinactive p94, respectively. These data demonstrate for the first time that p94 proteolytic activity is involved in responses to muscle conditions, which may explain why p94 inactivation causes limb-girdle muscular dystrophy.

Received for publication, November 22, 2006 , and in revised form, February 12, 2007.

^* This work was supported in part by MEXT.KAKENHI 16026209, 17028055, and 18076007 (to H. S.), JSPS.KAKENHI 18700392 (to K. O.), 18770124 (to Y. O.), and 18380085 (to H. S.), Research Grant (17A-10) for Nervous and Mental Disorders from the Ministry of Health, Labor and Welfare (to H. S.), Sasagawa Scientific Research Grant from The Japan Science Society (to K. O.), and by the Deutsche Forschungsgemeinschaft (La668/7-2) (to S. L.). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ To whom correspondence should be addressed: Dept. of Enzymatic Regulation for Cell Functions, Tokyo Metropolitan Institute of Medical Science, Tokyo 113-8613, Japan. Tel.: 81-3-3823-2181; Fax: 81-3-3823-2359; E-mail: sorimach{at}rinshoken.or.jp.

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