Induction and myofibrillar targeting of CARP, and suppression of the Nkx2.5 pathway in the MDM mouse with impaired titin-based signaling

J Mol Biol. 2004 Feb 6;336(1):145-54. doi: 10.1016/j.jmb.2003.12.021.


Muscular dystrophy with myositis (mdm) is a recessive mouse mutation that is caused by a small deletion in the giant elastic muscle protein titin. Homozygous mdm/mdm mice develop a progressive muscular dystrophy, leading to death at approximately 2 months of age. We surveyed the transcriptomes of skeletal muscles from 24 day old homozygous mdm/mdm and +/+ wild-type mice, an age when MDM animals have normal passive and active tensions and sarcomeric structure. Of the 12488 genes surveyed (U74 affymetrix array), 75 genes were twofold to 30-fold differentially expressed, including CARP (cardiac ankyrin repeat protein), ankrd2/Arpp (a CARP-like protein) and MLP (muscle LIM protein), all of which associate with the titin filament system. The four genes most strongly affected (eightfold to 30-fold change) were all members of the CARP-regulated Nkx-2.5-dependent signal pathway, and CARP mRNA level was 30-fold elevated in MDM skeletal muscle tissues. The CARP protein overexpressed in MDM became associated with the I-band region of the sarcomere. The mdm mutation excises the C-terminal portion of titin's N2A region, abolishing its interaction with p94/calpain-3 protease. Thus, the composition of the titin N2A protein complex is altered in MDM by incorporation of CARP and loss of p94/calpain-3. These changes were absent from the following control tissues (1). cardiac muscles from homozygous mdm/mdm animals, (2). skeletal and cardiac muscle from heterozygous mdm/+ animals, and (3). dystrophic muscles from MDX mice. Thus, the altered composition of the titin N2A complex is specific for the titin-based skeletal muscular dystrophy in MDM.

Publication types

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

MeSH terms

  • Amino Acid Sequence
  • Animals
  • Connectin
  • Gene Expression Regulation*
  • Homeodomain Proteins / genetics
  • Homeodomain Proteins / metabolism*
  • Macromolecular Substances
  • Mice
  • Mice, Inbred C57BL
  • Mice, Inbred Strains
  • Molecular Sequence Data
  • Muscle Proteins / genetics
  • Muscle Proteins / metabolism*
  • Muscle, Skeletal / cytology
  • Muscle, Skeletal / pathology
  • Muscle, Skeletal / physiology
  • Muscular Dystrophy, Animal / genetics
  • Muscular Dystrophy, Animal / metabolism
  • Myofibrils / metabolism*
  • Myofibrils / pathology
  • Myofibrils / ultrastructure
  • Myositis / genetics
  • Myositis / metabolism
  • Nuclear Proteins / genetics*
  • Nuclear Proteins / metabolism
  • Protein Kinases / genetics
  • Protein Kinases / metabolism*
  • Repressor Proteins / genetics*
  • Repressor Proteins / metabolism
  • Signal Transduction / physiology*
  • Tripartite Motif Proteins
  • Ubiquitin-Protein Ligases / genetics
  • Ubiquitin-Protein Ligases / metabolism


  • ANKRD1 protein, human
  • Ankrd1 protein, mouse
  • Ankrd2 protein, mouse
  • Connectin
  • Homeodomain Proteins
  • Macromolecular Substances
  • Muscle Proteins
  • Nuclear Proteins
  • Repressor Proteins
  • TTN protein, human
  • Tripartite Motif Proteins
  • TRIM63 protein, human
  • Trim63 protein, mouse
  • Ubiquitin-Protein Ligases
  • Protein Kinases