Human Molecular Genetics Advance Access published online on May 11, 2004
Human Molecular Genetics, doi:10.1093/hmg/ddh153
© 2004 by Oxford University Press
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1 Department of Pediatrics and Mattel Children's Hospital, David Geffen School of Medicine at UCLA, Los Angeles, CA, USA; Duchenne Muscular Dystrophy Research Center, UCLA
* To whom correspondence should be addressed. E-mail: mspencer{at}mednet.ucla.edu.
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 (LGMD2A). To test the hypothesis that C3 mediates remodeling during myofibrillogenesis, C3 knockout (C3KO) mice were generated. 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. Titin distribution was normal in longitudinal sections from C3KO mice; however, electron microscopy 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.
Article
Null mutation of calpain 3 (p94) in mice causes abnormal sarcomere formation in vivo and in vitro
2 Departments of Physiological Science and Pathology and Laboratory Medicine, UCLA; Duchenne Muscular Dystrophy Research Center, UCLA
3 Department of Pediatrics and Mattel Children's Hospital, David Geffen School of Medicine at UCLA, Los Angeles, CA, USA; Duchenne Muscular Dystrophy Research Center, University of California, Los Angeles, 621 Young Dr. South, Los Angeles, CA 90095-1606
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