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Human Molecular Genetics Advance Access originally published online on May 11, 2004
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Human Molecular Genetics, 2004, Vol. 13, No. 13 1373-1388
DOI: 10.1093/hmg/ddh153
Human Molecular Genetics, Vol. 13, No. 13 © Oxford University Press 2004; all rights reserved

Null mutation of calpain 3 (p94) in mice causes abnormal sarcomere formation in vivo and in vitro

I. Kramerova1,2,{dagger}, E. Kudryashova1,2,{dagger}, J.G. Tidball2,3 and Melissa J. Spencer1,2,*

1Department of Pediatrics and Mattel Children's Hospital, David Geffen School of Medicine at University of California, Los Angeles, CA 90095-1606, USA, 2Duchenne Muscular Dystrophy Research Center and 3Departments of Physiological Science and Pathology and Laboratory Medicine, University of California at Los Angeles, Los Angeles, CA 90095-1606, USA

Received March 13, 2004; Accepted April 30, 2004

The giant protein titin serves a primary role as a scaffold for sarcomere assembly; however, proteins that mediate this remodeling have not been identified. One potential mediator of this process is the protease calpain 3 (C3), the protein mutated in limb girdle muscular dystrophy type 2A. To test the hypothesis that C3 mediates remodeling during myofibrillogenesis, C3 knockout (C3KO) mice were generated. The C3KO mice were atrophic containing small foci of muscular necrosis. Myogenic cells fused normally in vitro, but lacked well-organized sarcomeres, as visualized by electron microscopy (EM). Titin distribution was normal in longitudinal sections from the C3KO mice; however, EM of muscle fibers showed misaligned A-bands. In vitro studies revealed that C3 can bind and cleave titin and that some mutations that are pathogenic in human muscular dystrophy result in reduced affinity of C3 for titin. These studies suggest a role for C3 in myofibrillogenesis and sarcomere remodeling.

* To whom correspondence should be addressed at: Duchenne Muscular Dystrophy Research Center, University of California at Los Angeles, 621 Young Drive South, Los Angeles, CA 90095-1606, USA. Tel: +1 3107945225; Fax: +1 3108258489; Email: mspencer{at}mednet.ucla.edu


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