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

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.

[1]  Leena Peltonen,et al.  Tibial muscular dystrophy is a titinopathy caused by mutations in TTN, the gene encoding the giant skeletal-muscle protein titin. , 2002, American journal of human genetics.

[2]  John Atherton,et al.  Mutations of TTN, encoding the giant muscle filament titin, cause familial dilated cardiomyopathy , 2002, Nature Genetics.

[3]  Dietmar Labeit,et al.  The Complete Gene Sequence of Titin, Expression of an Unusual ≈700-kDa Titin Isoform, and Its Interaction With Obscurin Identify a Novel Z-Line to I-Band Linking System , 2001 .

[4]  T. Hayashi,et al.  Molecular etiology of idiopathic cardiomyopathy in Asian populations. , 2001, Journal of cardiology.

[5]  I. Nishino,et al.  Localization of calpain 3 in human skeletal muscle and its alteration in limb-girdle muscular dystrophy 2A muscle. , 2003, Journal of biochemistry.

[6]  T. Kemp,et al.  Identification of Ankrd2, a novel skeletal muscle gene coding for a stretch-responsive ankyrin-repeat protein. , 2000, Genomics.

[7]  M. Bang,et al.  Myopalladin, a Novel 145-Kilodalton Sarcomeric Protein with Multiple Roles in Z-Disc and I-Band Protein Assemblies , 2001, The Journal of cell biology.

[8]  K. Pelin,et al.  Identification of muscle specific ring finger proteins as potential regulators of the titin kinase domain. , 2001, Journal of molecular biology.

[9]  D J Glass,et al.  Identification of Ubiquitin Ligases Required for Skeletal Muscle Atrophy , 2001, Science.

[10]  John Trinick,et al.  Titin: properties and family relationships , 2003, Nature Reviews Molecular Cell Biology.

[11]  R. Schwartz,et al.  Combinatorial Expression of GATA4, Nkx2-5, and Serum Response Factor Directs Early Cardiac Gene Activity* , 2002, The Journal of Biological Chemistry.

[12]  Yiming Wu,et al.  Changes in Titin Isoform Expression in Pacing-Induced Cardiac Failure Give Rise to Increased Passive Muscle Stiffness , 2002, Circulation.

[13]  Roger J Hajjar,et al.  Titin Isoform Switch in Ischemic Human Heart Disease , 2002, Circulation.

[14]  Siegfried Labeit,et al.  Cardiac titin: an adjustable multi‐functional spring , 2002, The Journal of physiology.

[15]  A. Pastore,et al.  The elastic I-band region of titin is assembled in a "modular" fashion by weakly interacting Ig-like domains. , 1996, Journal of molecular biology.

[16]  I. Nonaka,et al.  Cardiac-Restricted Ankyrin-Repeated Protein Is Differentially Induced in Duchenne and Congenital Muscular Dystrophy , 2003, Laboratory Investigation.

[17]  J. Squire,et al.  Architecture and function in the muscle sarcomere. , 1997, Current opinion in structural biology.

[18]  L. Kedes,et al.  A Novel Cardiac-Restricted Target for Doxorubicin , 1997, The Journal of Biological Chemistry.

[19]  Pico Caroni,et al.  Accumulation of Muscle Ankyrin Repeat Protein Transcript Reveals Local Activation of Primary Myotube Endcompartments during Muscle Morphogenesis , 1997, The Journal of cell biology.

[20]  Masahiko Hoshijima,et al.  The Cardiac Mechanical Stretch Sensor Machinery Involves a Z Disc Complex that Is Defective in a Subset of Human Dilated Cardiomyopathy , 2002, Cell.

[21]  Y. Hiroi,et al.  Csx/Nkx2-5 Is Required for Homeostasis and Survival of Cardiac Myocytes in the Adult Heart* , 2002, The Journal of Biological Chemistry.

[22]  Wayne N Frankel,et al.  The muscular dystrophy with myositis (mdm) mouse mutation disrupts a skeletal muscle-specific domain of titin. , 2002, Genomics.

[23]  P. Caroni,et al.  Muscle LIM protein, a novel essential regulator of myogenesis, promotes myogenic differentiation , 1994, Cell.

[24]  Eric P Hoffman,et al.  A web-accessible complete transcriptome of normal human and DMD muscle , 2002, Neuromuscular Disorders.

[25]  W. Linke,et al.  A spring tale: new facts on titin elasticity. , 1998, Biophysical journal.

[26]  Y. Zou,et al.  CARP, a cardiac ankyrin repeat protein, is downstream in the Nkx2-5 homeobox gene pathway. , 1997, Development.

[27]  P. Caroni,et al.  Alterations at the Intercalated Disk Associated with the Absence of Muscle Lim Protein , 2001, The Journal of cell biology.

[28]  Minoru Hongo,et al.  MLP-Deficient Mice Exhibit a Disruption of Cardiac Cytoarchitectural Organization, Dilated Cardiomyopathy, and Heart Failure , 1997, Cell.

[29]  C. Gregorio,et al.  Muscle-specific RING finger-1 interacts with titin to regulate sarcomeric M-line and thick filament structure and may have nuclear functions via its interaction with glucocorticoid modulatory element binding protein-1 , 2002, The Journal of cell biology.

[30]  Francisco H Andrade,et al.  Constitutive properties, not molecular adaptations, mediate extraocular muscle sparing in dystrophic mdx mice , 2003, FASEB journal : official publication of the Federation of American Societies for Experimental Biology.

[31]  M. Matsuo,et al.  Molecular Identification and Characterization of a Novel Nuclear Protein Whose Expression Is Up-regulated in Insulin-resistant Animals* , 2003, The Journal of Biological Chemistry.

[32]  J. D. Porter,et al.  A chronic inflammatory response dominates the skeletal muscle molecular signature in dystrophin-deficient mdx mice. , 2002, Human molecular genetics.

[33]  J. Beckmann,et al.  Loss of Calpain 3 Proteolytic Activity Leads to Muscular Dystrophy and to Apoptosis-Associated Iκbα/Nuclear Factor κb Pathway Perturbation in Mice , 2000, The Journal of cell biology.

[34]  C. Auffray,et al.  ALP and MLP distribution during myofibrillogenesis in cultured cardiomyocytes. , 2003, Cell motility and the cytoskeleton.

[35]  H. Sorimachi,et al.  Muscle-specific Calpain, p94, Responsible for Limb Girdle Muscular Dystrophy Type 2A, Associates with Connectin through IS2, a p94-specific Sequence (*) , 1995, The Journal of Biological Chemistry.

[36]  M. Beckerle,et al.  Striated muscle cytoarchitecture: an intricate web of form and function. , 2002, Annual review of cell and developmental biology.

[37]  L. Peltonen,et al.  Secondary calpain3 deficiency in 2q-linked muscular dystrophy , 2001, Neurology.

[38]  M. Fukayama,et al.  Carp, a cardiac ankyrin-repeated protein, and its new homologue, Arpp, are differentially expressed in heart, skeletal muscle, and rhabdomyosarcomas. , 2002, The American journal of pathology.

[39]  H. Jockusch,et al.  Overshooting production of satellite cells in murine skeletal muscle affected by the mutation ”muscular dystrophy with myositis” (mdm, Chr 2) , 1996, Cell and Tissue Research.

[40]  Christian C Witt,et al.  The muscle ankyrin repeat proteins: CARP, ankrd2/Arpp and DARP as a family of titin filament-based stress response molecules. , 2003, Journal of molecular biology.

[41]  Christian C Witt,et al.  Conditional Expression of Mutant M-line Titins Results in Cardiomyopathy with Altered Sarcomere Structure* , 2003, The Journal of Biological Chemistry.