The muscle ankyrin repeat proteins: CARP, ankrd2/Arpp and DARP as a family of titin filament-based stress response molecules.

CARP, ankrd-2/Arpp, and DARP, are three members of a conserved gene family, referred to here as MARPs (muscle ankyrin repeat proteins). The expression of MARPs is induced upon injury and hypertrophy (CARP), stretch or denervation (ankrd2/Arpp), and during recovery following starvation (DARP), suggesting that they are involved in muscle stress response pathways. Here, we show that MARP family members contain within their ankyrin repeat region a binding site for the myofibrillar elastic protein titin. Within the myofibril, MARPs, myopalladin, and the calpain protease p94 appear to be components of a titin N2A-based signaling complex. Ultrastructural studies demonstrated that all three endogenous MARP proteins co-localize with I-band titin N2A epitopes in adult heart muscle tissues. In cultured fetal rat cardiac myocytes, passive stretch induced differential distribution patterns of CARP and DARP: staining for both proteins was increased in the nucleus and at the I-band region of myofibrils, while DARP staining also increased at intercalated discs. We speculate that the myofibrillar MARPs are regulated by stretch, and that this links titin-N2A-based myofibrillar stress/strain signals to a MARP-based regulation of muscle gene expression.

[1]  D. Glass.  Signalling pathways that mediate skeletal muscle hypertrophy and atrophy , 2003, Nature Cell Biology.

[2]  Siegfried Labeit,et al.  The NH2 Terminus of Titin Spans the Z-Disc: Its Interaction with a Novel 19-kD Ligand (T-cap) Is Required for Sarcomeric Integrity , 1998, The Journal of cell biology.

[3]  G. Lanfranchi,et al.  Characterization of human skeletal muscle Ankrd2. , 2001, Biochemical and biophysical research communications.

[4]  J. Beckmann,et al.  Stable expression of calpain 3 from a muscle transgene in vivo: Immature muscle in transgenic mice suggests a role for calpain 3 in muscle maturation , 2002, Proceedings of the National Academy of Sciences of the United States of America.

[5]  T Delhaas,et al.  An equibiaxial strain system for cultured cells. , 1996, The American journal of physiology.

[6]  J. Sadoshima,et al.  The cellular and molecular response of cardiac myocytes to mechanical stress. , 1997, Annual review of physiology.

[7]  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.

[8]  J. Vigoreaux.  The muscle Z band: lessons in stress management , 1994, Journal of Muscle Research & Cell Motility.

[9]  J. McGhee,et al.  The GATA family (vertebrates and invertebrates). , 2002, Current opinion in genetics & development.

[10]  K. Suzuki,et al.  New aspect of the research on limb-girdle muscular dystrophy 2A: a molecular biologic and biochemical approach to pathology. , 1999, Trends in cardiovascular medicine.

[11]  C. Cognard,et al.  Identification of AnkG107, a Muscle-specific Ankyrin-G Isoform* , 2002, The Journal of Biological Chemistry.

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

[13]  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 .

[14]  H. Lehrach,et al.  HIP-I: a huntingtin interacting protein isolated by the yeast two-hybrid system. , 1997, Human molecular genetics.

[15]  Siegfried Labeit,et al.  Titin Extensibility In Situ: Entropic Elasticity of Permanently Folded and Permanently Unfolded Molecular Segments , 1998, The Journal of cell biology.

[16]  D. Pette.  Historical Perspectives: plasticity of mammalian skeletal muscle. , 2001, Journal of applied physiology.

[17]  M. Gautel,et al.  Two immunoglobulin‐like domains of the Z‐disc portion of titin interact in a conformation‐dependent way with telethonin , 1998, FEBS letters.

[18]  P. Ruiz-Lozano,et al.  Control of segmental expression of the cardiac-restricted ankyrin repeat protein gene by distinct regulatory pathways in murine cardiogenesis. , 1999, Development.

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

[20]  H. Granzier,et al.  Protein Kinase A Phosphorylates Titin’s Cardiac-Specific N2B Domain and Reduces Passive Tension in Rat Cardiac Myocytes , 2002, Circulation research.

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

[22]  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.

[23]  Siegfried Labeit,et al.  Titins: Giant Proteins in Charge of Muscle Ultrastructure and Elasticity , 1995, Science.

[24]  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.

[25]  S. Mori,et al.  Arpp, a New Homolog of Carp, Is Preferentially Expressed in Type 1 Skeletal Muscle Fibers and Is Markedly Induced by Denervation , 2002, Laboratory Investigation.

[26]  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.

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

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

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

[30]  K. Patel,et al.  Titin‐cap associates with, and regulates secretion of, Myostatin , 2002, Journal of cellular physiology.

[31]  Detlev Drenckhahn,et al.  Ischemia-induced association of the stress protein alpha B-crystallin with I-band portion of cardiac titin. , 2002, Journal of molecular and cellular cardiology.

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

[33]  S. Schiaffino,et al.  Calcineurin signaling and neural control of skeletal muscle fiber type and size. , 2002, Trends in pharmacological sciences.

[34]  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.

[35]  T. Gustafson,et al.  Hormonal regulation of myosin heavy chain and alpha-actin gene expression in cultured fetal rat heart myocytes. , 1987, The Journal of biological chemistry.

[36]  J. Sadoshima,et al.  Autocrine release of angiotensin II mediates stretch-induced hypertrophy of cardiac myocytes in vitro , 1993, Cell.

[37]  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.

[38]  K. Miyazono,et al.  Transforming Growth Factor-β/Smads Signaling Induces Transcription of the Cell Type–Restricted Ankyrin Repeat Protein CARP Gene Through CAGA Motif in Vascular Smooth Muscle Cells , 2001 .

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

[40]  D. Tenen,et al.  C/EBPα Is Required for Proteolytic Cleavage of Cyclin A by Calpain 3 in Myeloid Precursor Cells* , 2002, The Journal of Biological Chemistry.

[41]  M. Bang,et al.  Specific interaction of the potassium channel beta-subunit minK with the sarcomeric protein T-cap suggests a T-tubule-myofibril linking system. , 2001, Journal of molecular biology.

[42]  C. Ruwhof,et al.  Mechanical stress-induced cardiac hypertrophy: mechanisms and signal transduction pathways. , 2000, Cardiovascular research.

[43]  R. Nagai,et al.  Cardiac ankyrin repeat protein is a novel marker of cardiac hypertrophy: role of M-CAT element within the promoter. , 2000, Hypertension.

[44]  Paul Young,et al.  Obscurin, a giant sarcomeric Rho guanine nucleotide exchange factor protein involved in sarcomere assembly , 2001, The Journal of cell biology.

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

[46]  H. Satoh,et al.  Identification of a novel human ankyrin-repeated protein homologous to CARP. , 2001, Biochemical and biophysical research communications.

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

[48]  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.

[49]  R. Bloch,et al.  The Hydrophilic Domain of Small Ankyrin-1 Interacts with the Two N-terminal Immunoglobulin Domains of Titin* , 2003, The Journal of Biological Chemistry.

[50]  Vincenzo Sorrentino,et al.  Binding of an ankyrin-1 isoform to obscurin suggests a molecular link between the sarcoplasmic reticulum and myofibrils in striated muscles , 2003, The Journal of cell biology.

[51]  T Centner,et al.  Differential expression of cardiac titin isoforms and modulation of cellular stiffness. , 2000, Circulation research.

[52]  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.