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

Hum Mol Genet. 2004 Jul 1;13(13):1373-88. doi: 10.1093/hmg/ddh153. Epub 2004 May 11.


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.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Animals
  • Calpain / genetics*
  • Calpain / metabolism*
  • Connectin
  • Mice
  • Mice, Knockout
  • Muscle Development / genetics*
  • Muscle Proteins / genetics*
  • Muscle Proteins / metabolism*
  • Muscular Dystrophies, Limb-Girdle / genetics
  • Muscular Dystrophies, Limb-Girdle / metabolism
  • Muscular Dystrophies, Limb-Girdle / pathology
  • Muscular Dystrophy, Animal / genetics*
  • Muscular Dystrophy, Animal / metabolism*
  • Muscular Dystrophy, Animal / pathology
  • Protein Kinases / metabolism
  • Sarcomeres / genetics
  • Sarcomeres / metabolism*
  • Sarcomeres / ultrastructure


  • Connectin
  • Muscle Proteins
  • TTN protein, human
  • Protein Kinases
  • Calpain
  • Capn3 protein, mouse