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Molecular and Cellular Biology, November 2006, p. 8437-8447, Vol. 26, No. 22
0270-7306/06/$08.00+0     doi:10.1128/MCB.01296-06
Copyright © 2006, American Society for Microbiology. All Rights Reserved.

Regulation of the M-Cadherin-ß-Catenin Complex by Calpain 3 during Terminal Stages of Myogenic Differentiation{triangledown}

Irina Kramerova,* Elena Kudryashova, Benjamin Wu, and Melissa J. Spencer

Department of Neurology, David Geffen School of Medicine at UCLA, and Duchenne Muscular Dystrophy Research Center, University of California at Los Angeles, Los Angeles, California 90095

Received 14 July 2006/ Returned for modification 10 August 2006/ Accepted 4 September 2006

The cysteine protease calpain 3 (CAPN3) is essential for normal muscle function, since mutations in CAPN3 cause limb girdle muscular dystrophy type 2A. Previously, we showed that myoblasts isolated from CAPN3 knockout (C3KO) mice were able to fuse to myotubes; however, sarcomere formation was disrupted. In this study we further characterized morphological and biochemical features of C3KO myotubes in order to elucidate a role for CAPN3 during myogenesis. We showed that cell cycle withdrawal occurred normally in C3KO cultures, but C3KO myotubes have an increased number of myonuclei per myotube. We found that CAPN3 acts during myogenesis to specifically control levels of membrane-associated but not cytoplasmic ß-catenin and M-cadherin. CAPN3 was able to cleave both proteins, and in the absence of CAPN3, M-cadherin and ß-catenin abnormally accumulated at the membranes of myotubes. Given the role of M-cadherin in myoblast fusion, this finding suggests that the excessive myonuclear index of C3KO myotubes was due to enhanced fusion. Postfusion events, such as ß1D integrin expression and myofibrillogenesis, were suppressed in C3KO myotubes. These data suggest that the persistence of fusion observed in C3KO cells inhibits subsequent steps of differentiation, such as integrin complex rearrangements and sarcomere assembly.

* Corresponding author. Mailing address: Department of Neurology, David Geffen School of Medicine, Neuroscience Research Building, Room 404, University of California at Los Angeles, 635 Charles Young Drive South, Los Angeles, CA 90095-7334. Phone: (310) 267-4582. Fax: (310) 206-1998. E-mail: ikramero{at}ucla.edu.

{triangledown} Published ahead of print on 18 September 2006.

Molecular and Cellular Biology, November 2006, p. 8437-8447, Vol. 26, No. 22
0270-7306/06/$08.00+0     doi:10.1128/MCB.01296-06
Copyright © 2006, American Society for Microbiology. All Rights Reserved.



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  • Kramerova, I., Kudryashova, E., Wu, B., Ottenheijm, C., Granzier, H., Spencer, M. J. (2008). Novel role of calpain-3 in the triad-associated protein complex regulating calcium release in skeletal muscle. Hum Mol Genet 17: 3271-3280 [Abstract] [Full Text]  


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