Conformation-regulated mechanosensory control via titin domains in cardiac muscle

The giant filamentous protein titin is ideally positioned in the muscle sarcomere to sense mechanical stimuli and transform them into biochemical signals, such as those triggering cardiac hypertrophy. In this review, we ponder the evidence for signaling hotspots along the titin filament involved in mechanosensory control mechanisms. On the way, we distinguish between stress and strain as triggers of mechanical signaling events at the cardiac sarcomere. Whereas the Z-disk and M-band regions of titin may be prominently involved in sensing mechanical stress, signaling hotspots within the elastic I-band titin segment may respond primarily to mechanical strain. Common to both stress and strain sensor elements is their regulation by conformational changes in protein domains.

• Publication year

  2011

• Venue

  Pflügers Archiv: European Journal of Physiology

• Publication date

  2011-02-25

• Fields of study

  Biology, Medicine, Engineering

• Identifiers
  DOI 10.1007/s00424-011-0938-1PMID 21347754PMCID 3114084
• External record

  Open on Semantic Scholar

• Source metadata

  Semantic Scholar, PubMed

• No claims are published for this paper.

• No concepts are published for this paper.

• The sarcomeric cytoskeleton: who picks up the strain?

  2011cited by this paper
• Cardiac Z-disc Signaling Network*

  2011cited by this paper
• The Giant Protein Titin: A Regulatory Node That Integrates Myocyte Signaling Pathways*

  2011cited by this paper
• Cardiac titin: a multifunctional giant.

  2010cited by this paper
• Exploring the conformation-regulated function of titin kinase by mechanical pump and probe experiments with single molecules.

  2010cited by this paper
• Myofilament length dependent activation.

  2010cited by this paper
• Functional muscle analysis of the Tcap knockout mouse

  2010cited by this paper
• Roles of Titin in the Structure and Elasticity of the Sarcomere

  2010cited by this paper
• Regulation of muscle force in the absence of actin-myosin-based cross-bridge interaction.

  2010cited by this paper
• The giant protein titin as an integrator of myocyte signaling pathways.

  2010cited by this paper
• Proposed role of the M-band in sarcomere mechanics and mechano-sensing: a model study

  2010influential reference
• Titin Diversity—Alternative Splicing Gone Wild

  2010cited by this paper
• Frank-Starling law and mass action calcium activation of the myofibril ATPase; comment on "de Tombe PP, Mateja RD, Tachampa K, Mou YA, Farman GP, Irving TC. Myofilament length dependent activation. J Mol Cell Cardiol 2010; 48: 851-8".

  2010cited by this paper
• The vertebrate muscle Z-disc: sarcomere anchor for structure and signalling

  2009cited by this paper
• Hypophosphorylation of the Stiff N2B Titin Isoform Raises Cardiomyocyte Resting Tension in Failing Human Myocardium

  2009cited by this paper
• Myocyte remodeling in response to hypertrophic stimuli requires nucleocytoplasmic shuttling of muscle LIM protein.

  2009cited by this paper
• PKC Phosphorylation of Titin’s PEVK Element: A Novel and Conserved Pathway for Modulating Myocardial Stiffness

  2009cited by this paper
• Modulation of titin-based stiffness by disulfide bonding in the cardiac titin N2-B unique sequence.

  2009cited by this paper
• In vivo phosphoproteome of human skeletal muscle revealed by phosphopeptide enrichment and HPLC-ESI-MS/MS.

  2009cited by this paper
• Truncation of Titin’s Elastic PEVK Region Leads to Cardiomyopathy With Diastolic Dysfunction

  2009cited by this paper
• The vertebrate muscle Z-disc: sarcomere anchor for structure and signalling

  2009cited by this paper
• Troponin and Titin Coordinately Regulate Length-dependent Activation in Skinned Porcine Ventricular Muscle

  2008cited by this paper
• Mutation that dramatically alters rat titin isoform expression and cardiomyocyte passive tension.

  2008cited by this paper
• The sarcomere and sarcomerogenesis.

  2008cited by this paper
• Titin Isoforms, Extracellular Matrix, and Global Chamber Remodeling in Experimental Dilated Cardiomyopathy: Functional Implications and Mechanistic Insight

  2008cited by this paper
• An FHL1-containing complex within the cardiomyocyte sarcomere mediates hypertrophic biomechanical stress responses in mice.

  2008influential reference
• Pulling single molecules of titin by AFM—recent advances and physiological implications

  2008cited by this paper
• Build it up-Tear it down: protein quality control in the cardiac sarcomere.

  2008cited by this paper
• Mechanoenzymatics of titin kinase

  2008cited by this paper
• Protein kinase G modulates human myocardial passive stiffness by phosphorylation of the titin springs

  2008influential reference
• Targeted deletion of titin N2B region leads to diastolic dysfunction and cardiac atrophy

  2007cited by this paper
• Structural and regulatory roles of muscle ankyrin repeat protein family in skeletal muscle.

  2007cited by this paper
• Sense and stretchability: the role of titin and titin-associated proteins in myocardial stress-sensing and mechanical dysfunction.

  2007influential reference
• Cardiac Hypertrophy and Reduced Contractility in Hearts Deficient in the Titin Kinase Region

  2007cited by this paper
• Molecular determinants for the recruitment of the ubiquitin‐ligase MuRF‐1 onto M‐line titin

  2007cited by this paper
• Expression of distinct classes of titin isoforms in striated and smooth muscles by alternative splicing, and their conserved interaction with filamins.

  2006influential reference
• Palindromic assembly of the giant muscle protein titin in the sarcomeric Z-disk

  2006cited by this paper
• Targeted homozygous deletion of M-band titin in cardiomyocytes prevents sarcomere formation

  2006cited by this paper
• Titin as a Giant Scaffold for Integrating Stress and Src Homology Domain 3-mediated Signaling Pathways

  2006cited by this paper
• Developmental changes in passive stiffness and myofilament Ca2+ sensitivity due to titin and troponin-I isoform switching are not critically triggered by birth.

  2006cited by this paper
• Transverse stiffness of myofibrils of skeletal and cardiac muscles studied by atomic force microscopy.

  2006cited by this paper
• Mechanical stress-strain sensors embedded in cardiac cytoskeleton: Z disk, titin, and associated structures.

  2006cited by this paper
• Restoring force development by titin/connectin and assessment of Ig domain unfolding

  2006cited by this paper
• From A to Z and back? Multicompartment proteins in the sarcomere.

  2006cited by this paper
• Protein kinase-A phosphorylates titin in human heart muscle and reduces myofibrillar passive tension

  2006cited by this paper
• Nebulin regulates thin filament length, contractility, and Z‐disk structure in vivo

  2006cited by this paper
• Mechanical strength of the titin Z1Z2-telethonin complex.

  2006cited by this paper
• MURF-1 and MURF-2 target a specific subset of myofibrillar proteins redundantly: towards understanding MURF-dependent muscle ubiquitination.

  2005cited by this paper
• The Kinase Domain of Titin Controls Muscle Gene Expression and Protein Turnover

  2005cited by this paper
• The kinase domain of titin controls muscle gene expression and protein turnover.

  2005cited by this paper
• The M-band: an elastic web that crosslinks thick filaments in the center of the sarcomere.

  2005influential reference
• Phosphorylation of Titin Modulates Passive Stiffness of Cardiac Muscle in a Titin Isoform-dependent Manner

  2005cited by this paper
• Developmental Control of Titin Isoform Expression and Passive Stiffness in Fetal and Neonatal Myocardium

  2004influential reference
• Differential actin binding along the PEVK domain of skeletal muscle titin

  2004cited by this paper
• Developmentally Regulated Switching of Titin Size Alters Myofibrillar Stiffness in the Perinatal Heart

  2004influential reference
• Titin isoform changes in rat myocardium during development.

  2004influential reference
• Gigantic variety: expression patterns of titin isoforms in striated muscles and consequences for myofibrillar passive stiffness

  2004cited by this paper
• Cardiac titin: molecular basis of elasticity and cellular contribution to elastic and viscous stiffness components in myocardium

  2004cited by this paper
• At the crossroads of myocardial signaling: the role of Z-discs in intracellular signaling and cardiac function.

  2004cited by this paper
• Damped elastic recoil of the titin spring in myofibrils of human myocardium

  2003cited by this paper
• The muscle ankyrin repeat proteins: CARP, ankrd2/Arpp and DARP as a family of titin filament-based stress response molecules.

  2003cited by this paper
• Calcium-dependent molecular spring elements in the giant protein titin

  2003cited by this paper
• Malleable conformation of the elastic PEVK segment of titin: non-co-operative interconversion of polyproline II helix, beta-turn and unordered structures.

  2003cited by this paper
• Transient association of titin and myosin with microtubules in nascent myofibrils directed by the MURF2 RING-finger protein

  2002cited by this paper
• The cardiac mechanical stretch sensor machinery involves a Z disc complex that is defective in a subset of human dilated cardiomyopathy.

  2002cited by this paper
• PEVK domain of titin: an entropic spring with actin-binding properties.

  2002cited by this paper
• Reverse engineering of the giant muscle protein titin

  2002cited by this paper
• Titin Isoform Switch in Ischemic Human Heart Disease

  2002influential reference
• Subcellular targeting of metabolic enzymes to titin in heart muscle may be mediated by DRAL/FHL-2

  2002cited by this paper
• 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

  2002cited by this paper
• 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

  2001influential reference
• Titin-Based Modulation of Calcium Sensitivity of Active Tension in Mouse Skinned Cardiac Myocytes

  2001cited by this paper
• Unfolding of titin domains explains the viscoelastic behavior of skeletal myofibrils.

  2001cited by this paper
• Identification of muscle specific ring finger proteins as potential regulators of the titin kinase domain.

  2001cited by this paper
• Interaction Between PEVK-Titin and Actin Filaments: Origin of a Viscous Force Component in Cardiac Myofibrils

  2001cited by this paper
• The complete gene sequence of titin, expression of an unusual approximately 700-kDa titin isoform, and its interaction with obscurin identify a novel Z-line to I-band linking system.

  2001cited by this paper
• Identification of new repeating motifs in titin

  2001cited by this paper
• Titin-actin interaction in mouse myocardium: passive tension modulation and its regulation by calcium/S100A1.

  2001cited by this paper
• Series of exon-skipping events in the elastic spring region of titin as the structural basis for myofibrillar elastic diversity.

  2000cited by this paper
• I-Band Titin in Cardiac Muscle Is a Three-Element Molecular Spring and Is Critical for Maintaining Thin Filament Structure

  1999influential reference
• Structural basis for activation of the titin kinase domain during myofibrillogenesis

  1998cited by this paper
• Nature of PEVK-titin elasticity in skeletal muscle.

  1998cited by this paper
• Titin Extensibility In Situ: Entropic Elasticity of Permanently Folded and Permanently Unfolded Molecular Segments

  1998cited by this paper
• Molecular structure of the sarcomeric Z‐disk: two types of titin interactions lead to an asymmetrical sorting of α‐actinin

  1998cited by this paper
• Actin-titin interaction in cardiac myofibrils: probing a physiological role.

  1997cited by this paper
• Tissue-specific expression and alpha-actinin binding properties of the Z-disc titin: implications for the nature of vertebrate Z-discs.

  1997cited by this paper
• Single Molecule Force Spectroscopy on Polysaccharides by Atomic Force Microscopy

  1997cited by this paper
• Molecular structure of the sarcomeric M band: mapping of titin and myosin binding domains in myomesin and the identification of a potential regulatory phosphorylation site in myomesin

  1997cited by this paper
• Folding-unfolding transitions in single titin molecules characterized with laser tweezers.

  1997cited by this paper
• Elasticity and unfolding of single molecules of the giant muscle protein titin

  1997cited by this paper
• Actin removal from cardiac myocytes shows that near Z line titin attaches to actin while under tension.

  1997cited by this paper
• Towards a molecular understanding of the elasticity of titin.

  1996cited by this paper
• Genomic organization of M line titin and its tissue-specific expression in two distinct isoforms.

  1996cited by this paper
• The central Z-disk region of titin is assembled from a novel repeat in variable copy numbers.

  1996cited by this paper
• Characterization of a 5.4 kb cDNA fragment from the Z-line region of rabbit cardiac titin reveals phosphorylation sites for proline-directed kinases.

  1995cited by this paper
• Titins: Giant Proteins in Charge of Muscle Ultrastructure and Elasticity

  1995cited by this paper
• Phosphorylation of KSP motifs in the C‐terminal region of titin in differentiating myoblasts.

  1993cited by this paper
• Role of the Z band in the mechanical properties of the heart

  1991influential reference
• Two structural states of Z-bands in cardiac muscle.

  1989cited by this paper
• Elastic behavior of connectin filaments during thick filament movement in activated skeletal muscle

  1989cited by this paper

• The titin N2A-MARP signalosome constrains muscle longitudinal hypertrophy in response to stretch

  2025cites this paper
• Exploring TTN variants as genetic insights into cardiomyopathy pathogenesis and potential emerging clues to molecular mechanisms in cardiomyopathies

  2024cites this paper
• Principles and regulation of mechanosensing.

  2024cites this paper
• The TTN p. Tyr4418Ter mutation causes cardiomyopathy in human and mice

  2024cites this paper
• The harder the climb the better the view: The impact of substrate stiffness on cardiomyocyte fate.

  2022cites this paper
• Proteomic and phosphoproteomic profiling in heart failure with preserved ejection fraction (HFpEF)

  2022cites this paper
• Titin N2A Domain and Its Interactions at the Sarcomere

  2021cites this paper
• Precision Medicine and Dilated Cardiomyopathy.

  2020cites this paper
• Tissue-Specific Cell Signaling

  2020cites this paper
• Pathophysiology and pathological remodelling associated with dilated cardiomyopathy in broiler chickens predisposed to heart pump failure

  2020cites this paper
• Expression of titin-linked putative mechanosensing proteins in skeletal muscle after power resistance exercise in resistance-trained men.

  2020cites this paper
• Cellular Basis for Heart Failure

  2020cites this paper
• Phosphoinositide Signaling and Mechanotransduction in Cardiovascular Biology and Disease

  2020cites this paper
• Key Signaling Pathways in the Cardiovascular System

  2020cites this paper
• Zinc Signaling in Skeletal Muscle

  2019cites this paper
• Change in the content of titin and nebulin and their phosphorylation level in the quadriceps femoris muscle in chronic alcoholic myopathy

  2019cites this paper
• Regulating myofilament power: The determinant of health.

  2019cites this paper
• A 3-Day Functional Unloading is Accompanied by an Increase in the TTN Gene Expression in the Rat Soleus Muscle without Changes in Alternative Splicing from Exon 50 to Exon 111

  2019cites this paper
• Precision Medicine

  2019cites this paper
• Titin‐based mechanosensing modulates muscle hypertrophy

  2018cites this paper
• Peculiarities of SDS-PAGE of Titin/Connectin

  2018cites this paper
• The insertion sequence of the N2A region of titin exists in an extended structure with helical characteristics.

  2017cites this paper
• Undersized Mitral Annuloplasty Increases Strain in the Proximal Lateral Left Ventricular Wall.

  2017cites this paper
• Amyloid properties of titin

  2017cites this paper
• Expression and purification of a difficult sarcomeric protein: Telethonin.

  2017influential citation
• Increased Autolysis of &mgr;‐Calpain in Skeletal Muscles of Chronic Alcohol‐Fed Rats

  2017cites this paper
• Smooth muscle titin forms in vitro amyloid aggregates

  2016cites this paper
• Immunohistochemical studies of obscurin in failing and non-failing human hearts

  2016cites this paper
• Pathophysiological concepts in the congenital myopathies: blurring the boundaries, sharpening the focus.

  2015cites this paper
• Expression patterns of sarcomeric α-actin, α-actinin and UCP2 in the myocardium of Kunming mice after exposure to c-terminal polypeptide of cardiotrophin-1

  2014cites this paper
• Low-force transitions in single titin molecules reflect a memory of contractile history

  2014influential citation
• Cardiac titin, the giant sarcomeric protein in health and disease.

  2014cites this paper
• Conditionally and transiently disordered proteins: awakening cryptic disorder to regulate protein function.

  2014cites this paper
• Probing Muscle Ankyrin‐Repeat Protein (MARP) Structure and Function

  2014cites this paper
• Titin-mediated control of cardiac myofibrillar function.

  2014cites this paper
• Changes in gene expression and titin (connectin) content in striated muscles of chronically alcoholized rats

  2013cites this paper
• Identification of novel sarcomeric modifiers of hypertrophy in hypertrophic cardiomyopathy using the yeast two-hybrid system

  2013cites this paper
• cGMP-dependent protein kinases (cGK).

  2013cites this paper
• Impact of titin isoform on length dependent activation and cross-bridge cycling kinetics in rat skeletal muscle.

  2013cites this paper
• Molecular pathomechanisms of muscular dystrophies

  2013cites this paper
• Myofibroblast-mediated mechanisms of pathological remodelling of the heart

  2013cites this paper
• Doubly heterozygous LMNA and TTN mutations revealed by exome sequencing in a severe form of dilated cardiomyopathy

  2013cites this paper
• Multiple Causes of Fatigue during Shortening Contractions in Rat Slow Twitch Skeletal Muscle

  2013cites this paper
• The interactome of LIM domain proteins: The contributions of LIM domain proteins to heart failure and heart development

  2012cites this paper
• Characterization and regulation of mechanical loading-induced compensatory muscle hypertrophy.

  2012cites this paper
• Chapter 14 – Cardiovascular Mechanotransduction

  2012cites this paper
• New titin (connectin) isoforms and their functional role in striated muscles of mammals: Facts and suppositions

  2012cites this paper
• Single-molecule mechanoenzymatics.

  2012cites this paper
• Spontaneous Dimerization of Titin Protein Z1Z2 Domains Induces Strong Nanomechanical Anchoring*

  2012cites this paper
• The cytoskeleton and the cellular transduction of mechanical strain in the heart: a special issue

  2011cites this paper
• Muscle ankyrin repeat proteins: their role in striated muscle function in health and disease

  2011cites this paper
• Analysis of 3-D Ultrasound of Calf Muscle Geometry in Children : Growth, Spasticity, Mechanisms and Treatment

  2011cites this paper