Induction and Myofibrillar Targeting of CARP, and Suppression of the Nkx2. 5 Pathway in the MDM Mouse with Impaired Titin-based Signaling

Christian C. Witt, Yasuko Ono, Eva Puschmann, Mark McNabb, Yiming Wu, Michael Gotthardt, Stephanie H. Witt, Markus Haak, Dietmar Labeit, Carol C. Gregorio, Hiroyuki Sorimachi, Henk Granzier, Siegfried Labeit

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80 Scopus citations


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 ∼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 12,488 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.

Original languageEnglish
Pages (from-to)145-154
Number of pages10
JournalJournal of Molecular Biology
Issue number1
StatePublished - 6 Feb 2004
Externally publishedYes


  • CARP
  • Calpain-3
  • MDM mouse muscular dystrophy
  • Muscle ankyrin repeat protein
  • Titin


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