title: Induction and myofibrillar targeting of CARP, and suppression of the Nkx2.5 pathway in the MDM mouse with impaired titin-based signaling.
abstract: 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.
authors.affiliation: Institut für Anästhesiologie und Operative Intensivmedizin, Universitätsklinikum Mannheim, Mannheim 68167, Germany.
authors.forename: Christian C
authors.initials: CC
authors.lastname: Witt
authors.forename: Yasuko
authors.initials: Y
authors.lastname: Ono
authors.forename: Eva
authors.initials: E
authors.lastname: Puschmann
authors.forename: Mark
authors.initials: M
authors.lastname: McNabb
authors.forename: Yiming
authors.initials: Y
authors.lastname: Wu
authors.forename: Michael
authors.initials: M
authors.lastname: Gotthardt
authors.forename: Stephanie H
authors.initials: SH
authors.lastname: Witt
authors.forename: Markus
authors.initials: M
authors.lastname: Haak
authors.forename: Dietmar
authors.initials: D
authors.lastname: Labeit
authors.forename: Carol C
authors.initials: CC
authors.lastname: Gregorio
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Sorimachi
authors.forename: Henk
authors.initials: H
authors.lastname: Granzier
authors.forename: Siegfried
authors.initials: S
authors.lastname: Labeit
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D064211:Connectin; D005786:Gene Expression Regulation; D018398:Homeodomain Proteins / Q000235:genetics / Q000378:metabolism*; D046911:Macromolecular Substances; D051379:Mice; D008810:Mice, Inbred C57BL; D008815:Mice, Inbred Strains; D008969:Molecular Sequence Data; D009124:Muscle Proteins / Q000235:genetics / Q000378:metabolism*; D018482:Muscle, Skeletal / Q000166:cytology / Q000473:pathology / Q000502:physiology; D009137:Muscular Dystrophy, Animal / Q000235:genetics / Q000378:metabolism; D009210:Myofibrils / Q000378:metabolism* / Q000473:pathology / Q000648:ultrastructure; D009220:Myositis / Q000235:genetics / Q000378:metabolism; D009687:Nuclear Proteins / Q000235:genetics* / Q000378:metabolism; D011494:Protein Kinases / Q000235:genetics / Q000378:metabolism*; D012097:Repressor Proteins / Q000235:genetics* / Q000378:metabolism; D015398:Signal Transduction / Q000502:physiology*; D000070584:Tripartite Motif Proteins; D044767:Ubiquitin-Protein Ligases / Q000235:genetics / Q000378:metabolism
chemical_list: C491304:ANKRD1 protein, human; C104844:Ankrd1 protein, mouse; C485877:Ankrd2 protein, mouse; D064211:Connectin; D018398:Homeodomain Proteins; D046911:Macromolecular Substances; D009124:Muscle Proteins; D009687:Nuclear Proteins; D012097:Repressor Proteins; C577285:TTN protein, human; D000070584:Tripartite Motif Proteins; C440908:TRIM63 protein, human; C499084:Trim63 protein, mouse; D044767:Ubiquitin-Protein Ligases; D011494:Protein Kinases