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https://www.readbyqxmd.com/read/29437146/histone-deacetylase-activity-governs-diastolic-dysfunction-through-a-nongenomic-mechanism
#1
Mark Y Jeong, Ying H Lin, Sara A Wennersten, Kimberly M Demos-Davies, Maria A Cavasin, Jennifer H Mahaffey, Valmen Monzani, Chandrasekhar Saripalli, Paolo Mascagni, T Brett Reece, Amrut V Ambardekar, Henk L Granzier, Charles A Dinarello, Timothy A McKinsey
There are no approved drugs for the treatment of heart failure with preserved ejection fraction (HFpEF), which is characterized by left ventricular (LV) diastolic dysfunction. We demonstrate that ITF2357 (givinostat), a clinical-stage inhibitor of histone deacetylase (HDAC) catalytic activity, is efficacious in two distinct murine models of diastolic dysfunction with preserved EF. ITF2357 blocked LV diastolic dysfunction due to hypertension in Dahl salt-sensitive (DSS) rats and suppressed aging-induced diastolic dysfunction in normotensive mice...
February 7, 2018: Science Translational Medicine
https://www.readbyqxmd.com/read/29435569/interpreting-genetic-variants-in-titin-in-patients-with-muscle-disorders
#2
Marco Savarese, Lorenzo Maggi, Anna Vihola, Per Harald Jonson, Giorgio Tasca, Lucia Ruggiero, Luca Bello, Francesca Magri, Teresa Giugliano, Annalaura Torella, Anni Evilä, Giuseppina Di Fruscio, Olivier Vanakker, Sara Gibertini, Liliana Vercelli, Alessandra Ruggieri, Carlo Antozzi, Helena Luque, Sandra Janssens, Maria Barbara Pasanisi, Chiara Fiorillo, Monika Raimondi, Manuela Ergoli, Luisa Politano, Claudio Bruno, Anna Rubegni, Marika Pane, Filippo M Santorelli, Carlo Minetti, Corrado Angelini, Jan De Bleecker, Maurizio Moggio, Tiziana Mongini, Giacomo Pietro Comi, Lucio Santoro, Eugenio Mercuri, Elena Pegoraro, Marina Mora, Peter Hackman, Bjarne Udd, Vincenzo Nigro
Importance: Mutations in the titin gene (TTN) cause a wide spectrum of genetic diseases. The interpretation of the numerous rare variants identified in TTN is a difficult challenge given its large size. Objective: To identify genetic variants in titin in a cohort of patients with muscle disorders. Design, Setting, and Participants: In this case series, 9 patients with titinopathy and 4 other patients with possibly disease-causing variants in TTN were identified...
February 12, 2018: JAMA Neurology
https://www.readbyqxmd.com/read/29435554/understanding-titin-variants-in-the-age-of-next-generation-sequencing-a-titanic-challenge
#3
Carsten G Bönnemann
No abstract text is available yet for this article.
February 12, 2018: JAMA Neurology
https://www.readbyqxmd.com/read/29433413/the-work-of-titin-protein-folding-as-a-major-driver-in-muscle-contraction
#4
Edward C Eckels, Rafael Tapia-Rojo, Jamie Andrés Rivas-Pardo, Julio M Fernández
Single-molecule atomic force microscopy and magnetic tweezers experiments have demonstrated that titin immunoglobulin (Ig) domains are capable of folding against a pulling force, generating mechanical work that exceeds that produced by a myosin motor. We hypothesize that upon muscle activation, formation of actomyosin cross bridges reduces the force on titin, causing entropic recoil of the titin polymer and triggering the folding of the titin Ig domains. In the physiological force range of 4-15 pN under which titin operates in muscle, the folding contraction of a single Ig domain can generate 200% of the work of entropic recoil and occurs at forces that exceed the maximum stalling force of single myosin motors...
February 10, 2018: Annual Review of Physiology
https://www.readbyqxmd.com/read/29417940/inverse-changes-in-plasma-tetranectin-and-titin-levels-in-patients-with-type-2-diabetes-mellitus-a-potential-predictor-of-acute-myocardial-infarction
#5
Mohd Aizat Abdul Rahim, Zubaidah Haji Abdul Rahim, Wan Azman Wan Ahmad, Marina Mohd Bakri, Muhammad Dzafir Ismail, Onn Haji Hashim
An early intervention using biomarkers to predict acute myocardial infarction (AMI) will effectively reduce global heart attack incidence, particularly among high-risk patients with type 2 diabetes mellitus (T2DM). This study attempted to identify potential biomarkers by detecting changes in the levels of plasma proteins in T2DM patients following onset of AMI in comparison with those without AMI. Volunteer T2DM patients without AMI (control; n=10) and T2DM patients with AMI (n=10) were recruited. Plasma samples from these patients were evaluated via two-dimensional gel electrophoresis (2DE) to screen for proteins with level changes between the two groups...
February 8, 2018: Acta Pharmacologica Sinica
https://www.readbyqxmd.com/read/29408381/autophosphorylation-is-a-mechanism-of-inhibition-in-twitchin-kinase
#6
Rhys M Williams, Barbara Franke, Mark Wilkinson, Jennifer R Fleming, Daniel J Rigden, Guy M Benian, Patrick A Eyers, Olga Mayans
Titin-like kinases are muscle-specific kinases that regulate mechanical sensing in the sarcomere. Twitchin kinase (TwcK) is the best-characterized member of this family, both structurally and enzymatically. TwcK activity is auto-inhibited by a dual intrasteric mechanism, in which N- and C-terminal tail extensions wrap around the kinase domain, blocking the hinge region, the ATP binding pocket and the peptide substrate binding groove. Physiologically, kinase activation is thought to occur by a stretch-induced displacement of the inhibitory tails from the kinase domain...
February 3, 2018: Journal of Molecular Biology
https://www.readbyqxmd.com/read/29401264/stretch-induced-compliance-a-novel-adaptive-biological-mechanism-following-acute-cardiac-load
#7
André M Leite-Moreira, João Almeida-Coelho, João S Neves, Ana L Pires, João Ferreira-Martins, Ricardo Castro-Ferreira, Ricardo Ladeiras-Lopes, Glória Conceição, Daniela Miranda-Silva, Patrícia Rodrigues, Nazha Hamdani, Melissa Herwig, Inês Falcão-Pires, Walter J Paulus, Wolfgang A Linke, André P Lourenço, Adelino F Leite-Moreira
Aims: The heart is constantly challenged with acute bouts of stretching or overload. Systolic adaptations to these challenges are known but adaptations in diastolic stiffness remain unknown. We evaluated adaptations in myocardial stiffness due to acute stretching and characterized the underlying mechanisms. Methods and Results: Left ventricles (LV) of intact rat hearts, rabbit papillary muscles and myocardial strips from cardiac surgery patients were stretched. After stretching, there was a sustained >40% decrease in end-diastolic pressure (EDP) or passive tension (PT) for 15 minutes in all species and experimental preparations...
February 1, 2018: Cardiovascular Research
https://www.readbyqxmd.com/read/29385343/two-state-folding-energy-determination-based-on-transition-points-in-non-equilibrium-single-molecule-experiments
#8
Huijuan You, Shiwen Guo, Shimin Le, Qingnan Tang, Mingxi Yao, Xiaodan Zhao, Jie Yan
Many small protein domains or nucleic acids structures undergo two-state unfolding-refolding transitions during mechanical stretching using single-molecule techniques. Here, by applying the Jarzynski equality (JE), we analytically express the folding energy of a molecule as a function of the experimentally measured transition points ξ* obtained with two typical time-varying mechanical constraints: the force constraints F(t) and the position constraints R(t) of a Hookian spring attached to one end of the molecule...
January 31, 2018: Journal of Physical Chemistry Letters
https://www.readbyqxmd.com/read/29377983/titin-cardiomyopathy-leads-to-altered-mitochondrial-energetics-increased-fibrosis-and-long-term-life-threatening-arrhythmias
#9
Job A J Verdonschot, Mark R Hazebroek, Kasper W J Derks, Arantxa Barandiarán Aizpurua, Jort J Merken, Ping Wang, Jörgen Bierau, Arthur van den Wijngaard, Simon M Schalla, Myrurgia A Abdul Hamid, Marc van Bilsen, Vanessa P M van Empel, Christian Knackstedt, Hans-Peter Brunner-La Rocca, Han G Brunner, Ingrid P C Krapels, Stephane R B Heymans
Aims: Truncating titin variants (TTNtv) are the most prevalent genetic cause of dilated cardiomyopathy (DCM). We aim to study clinical parameters and long-term outcomes related to the TTNtv genotype and determine the related molecular changes at tissue level in TTNtv DCM patients. Methods and results: A total of 303 consecutive and extensively phenotyped DCM patients (including cardiac imaging, Holter monitoring, and endomyocardial biopsy) underwent DNA sequencing of 47 cardiomyopathy-associated genes including TTN, yielding 38 TTNtv positive (13%) patients...
January 25, 2018: European Heart Journal
https://www.readbyqxmd.com/read/29377162/serological-and-experimental-studies-in-different-forms-of-myasthenia-gravis
#10
REVIEW
Angela Vincent, Saif Huda, Michelangelo Cao, Hakan Cetin, Inga Koneczny, Pedro Rodriguez-Cruz, Leslie Jacobson, Stuart Viegas, Saiju Jacob, Mark Woodhall, Akiko Nagaishi, Angelina Maniaol, Valentina Damato, M Isabel Leite, Judith Cossins, Richard Webster, Jacqueline Palace, David Beeson
Antibodies to the acetylcholine receptor (AChR) have been recognized for over 40 years and have been important in the diagnosis of myasthenia gravis (MG), and its recognition in patients of different ages and thymic pathologies. The 10-20% of patients who do not have AChR antibodies are now known to comprise different subgroups, the most commonly reported of which is patients with antibodies to muscle-specific kinase (MuSK). The use of cell-based assays has extended the repertoire of antibody tests to clustered AChRs, low-density lipoprotein receptor-related protein 4, and agrin...
January 29, 2018: Annals of the New York Academy of Sciences
https://www.readbyqxmd.com/read/29373340/residual-force-enhancement-is-preserved-for-conditions-of-reduced-contractile-force
#11
Atsuki Fukutani, Walter Herzog
INTRODUCTION: The isometric muscle force attained after active stretch is greater than that attained in a purely isometric contraction. This property is referred to as residual force enhancement (RFE). Since RFE is thought to be caused by a titin-based passive force, it should be preserved in reduced contractile force states. Therefore, we evaluated the magnitude of RFE in normal and reduced contractile force states. METHODS: Skinned fibers of rabbit psoas and soleus (N = 60) were used in all experiments...
January 26, 2018: Medicine and Science in Sports and Exercise
https://www.readbyqxmd.com/read/29361395/hereditary-myopathy-with-early-respiratory-failure-hmerf-still-rare-but-common-enough
#12
REVIEW
Giorgio Tasca, Bjarne Udd
Phenotypic and genetic/allelic heterogeneity is a feature of many neuromuscular disorders, titinopathies being one of them. Hereditary Myopathy with Early Respiratory Failure (HMERF) has been considered an extremely rare disease with definite clinicopathologic hallmarks, and geographically restricted to the Northern European population with one single titin gene defect identified in previous years. The recent availability of massive parallel sequencing techniques, allowing the screening of all coding regions of the genome in undiagnosed patients, together with a growing awareness of the main muscle MRI features of the disease, has led to the discovery of a number of HMERF families and new titin mutations in the last five years...
December 12, 2017: Neuromuscular Disorders: NMD
https://www.readbyqxmd.com/read/29353351/the-multiple-roles-of-titin-in-muscle-contraction-and-force-production
#13
REVIEW
Walter Herzog
Titin is a filamentous protein spanning the half-sarcomere, with spring-like properties in the I-band region. Various structural, signaling, and mechanical functions have been associated with titin, but not all of these are fully elucidated and accepted in the scientific community. Here, I discuss the primary mechanical functions of titin, including its accepted role in passive force production, stabilization of half-sarcomeres and sarcomeres, and its controversial contribution to residual force enhancement, passive force enhancement, energetics, and work production in shortening muscle...
January 20, 2018: Biophysical Reviews
https://www.readbyqxmd.com/read/29343782/protein-phosphatase-5-regulates-titin-phosphorylation-and-function-at-a-sarcomere-associated-mechanosensor-complex-in-cardiomyocytes
#14
Judith Krysiak, Andreas Unger, Lisa Beckendorf, Nazha Hamdani, Marion von Frieling-Salewsky, Margaret M Redfield, Cris G Dos Remedios, Farah Sheikh, Ulrich Gergs, Peter Boknik, Wolfgang A Linke
Serine/threonine protein phosphatase 5 (PP5) is ubiquitously expressed in eukaryotic cells; however, its function in cardiomyocytes is unknown. Under basal conditions, PP5 is autoinhibited, but enzymatic activity rises upon binding of specific factors, such as the chaperone Hsp90. Here we show that PP5 binds and dephosphorylates the elastic N2B-unique sequence (N2Bus) of titin in cardiomyocytes. Using various binding and phosphorylation tests, cell-culture manipulation, and transgenic mouse hearts, we demonstrate that PP5 associates with N2Bus in vitro and in sarcomeres and is antagonistic to several protein kinases, which phosphorylate N2Bus and lower titin-based passive tension...
January 17, 2018: Nature Communications
https://www.readbyqxmd.com/read/29335617/cardiovascular-function-of-modern-pigs-does-not-comply-with-allometric-scaling-laws
#15
Gerard J van Essen, Maaike Te Lintel Hekkert, Oana Sorop, Ilkka Heinonen, Jolanda van der Velden, Daphne Merkus, Dirk J Duncker
Growing concerns have been expressed regarding cardiovascular performance in modern farm pigs, which has been proposed as a critical factor contributing to the reduced adaptability of modern pigs to stress. Here we tested the hypothesis that cardiac dimensions and pump function in modern heavy farm pigs are disproportionally low for their body weight, and investigated potential underlying mechanisms. The results from the present study indeed demonstrate disproportionally low values for stroke volume and cardiac output in pigs with bodyweights over 150 kg...
January 15, 2018: Scientific Reports
https://www.readbyqxmd.com/read/29332246/an-historical-perspective-of-the-discovery-of-titin-filaments-part-2
#16
REVIEW
Cristobal G Dos Remedios
In 2017, a Special Issue of Biophysical Reviews was devoted to "Titin and Its Binding Partners. The issue contained a review: "An historical perspective of the discovery of titin filaments" by dos Remedios and Gilmour that was intended to be a history of the discovery of the giant protein titin, previously named connectin. The review took readers back to the earliest discovery of the so-called third filament component of skeletal and cardiac muscle sarcomeres and ended in 1969. Recently, my colleague Shin'ichi Ishiwata gently reminded me of two papers published in 1990 and 1993 that were unwittingly omitted from the original historical perspective...
January 13, 2018: Biophysical Reviews
https://www.readbyqxmd.com/read/29331499/hspb7-is-a-cardioprotective-chaperone-facilitating-sarcomeric-proteostasis
#17
Emily J Mercer, Yi-Fan Lin, Leona Cohen-Gould, Todd Evans
Small heat shock proteins are chaperones with variable mechanisms of action. The function of cardiac family member Hspb7 is unknown, despite being identified through GWAS as a potential cardiomyopathy risk gene. We discovered that zebrafish hspb7 mutants display mild focal cardiac fibrosis and sarcomeric abnormalities. Significant mortality was observed in adult hspb7 mutants subjected to exercise stress, demonstrating a genetic and environmental interaction that determines disease outcome. We identified large sarcomeric proteins FilaminC and Titin as Hspb7 binding partners in cardiac cells...
January 10, 2018: Developmental Biology
https://www.readbyqxmd.com/read/29330363/disulfide-isomerization-reactions-in-titin-immunoglobulin%C3%A2-domains-enable-a-mode-of-protein-elasticity
#18
David Giganti, Kevin Yan, Carmen L Badilla, Julio M Fernandez, Jorge Alegre-Cebollada
The response of titin to mechanical forces is a major determinant of the function of the heart. When placed under a pulling force, the unstructured regions of titin uncoil while its immunoglobulin (Ig) domains unfold and extend. Using single-molecule atomic force microscopy, we show that disulfide isomerization reactions within Ig domains enable a third mechanism of titin elasticity. Oxidation of Ig domains leads to non-canonical disulfide bonds that stiffen titin while enabling force-triggered isomerization reactions to more extended states of the domains...
January 12, 2018: Nature Communications
https://www.readbyqxmd.com/read/29316444/force-generation-via-%C3%AE-cardiac-myosin-titin-and-%C3%AE-actinin-drives-cardiac-sarcomere-assembly-from-cell-matrix-adhesions
#19
Anant Chopra, Matthew L Kutys, Kehan Zhang, William J Polacheck, Calvin C Sheng, Rebeccah J Luu, Jeroen Eyckmans, J Travis Hinson, Jonathan G Seidman, Christine E Seidman, Christopher S Chen
Truncating mutations in the sarcomere protein titin cause dilated cardiomyopathy due to sarcomere insufficiency. However, it remains mechanistically unclear how these mutations decrease sarcomere content in cardiomyocytes. Utilizing human induced pluripotent stem cell-derived cardiomyocytes, CRISPR/Cas9, and live microscopy, we characterize the fundamental mechanisms of human cardiac sarcomere formation. We observe that sarcomerogenesis initiates at protocostameres, sites of cell-extracellular matrix adhesion, where nucleation and centripetal assembly of α-actinin-2-containing fibers provide a template for the fusion of Z-disk precursors, Z bodies, and subsequent striation...
January 8, 2018: Developmental Cell
https://www.readbyqxmd.com/read/29290336/genome-wide-study-of-atrial-fibrillation-identifies-seven-risk-loci-and-highlights-biological-pathways-and-regulatory-elements-involved-in-cardiac-development
#20
Jonas B Nielsen, Lars G Fritsche, Wei Zhou, Tanya M Teslovich, Oddgeir L Holmen, Stefan Gustafsson, Maiken E Gabrielsen, Ellen M Schmidt, Robin Beaumont, Brooke N Wolford, Maoxuan Lin, Chad M Brummett, Michael H Preuss, Lena Refsgaard, Erwin P Bottinger, Sarah E Graham, Ida Surakka, Yunhan Chu, Anne Heidi Skogholt, Håvard Dalen, Alan P Boyle, Hakan Oral, Todd J Herron, Jacob Kitzman, José Jalife, Jesper H Svendsen, Morten S Olesen, Inger Njølstad, Maja-Lisa Løchen, Aris Baras, Omri Gottesman, Anthony Marcketta, Colm O'Dushlaine, Marylyn D Ritchie, Tom Wilsgaard, Ruth J F Loos, Timothy M Frayling, Michael Boehnke, Erik Ingelsson, David J Carey, Frederick E Dewey, Hyun M Kang, Gonçalo R Abecasis, Kristian Hveem, Cristen J Willer
Atrial fibrillation (AF) is a common cardiac arrhythmia and a major risk factor for stroke, heart failure, and premature death. The pathogenesis of AF remains poorly understood, which contributes to the current lack of highly effective treatments. To understand the genetic variation and biology underlying AF, we undertook a genome-wide association study (GWAS) of 6,337 AF individuals and 61,607 AF-free individuals from Norway, including replication in an additional 30,679 AF individuals and 278,895 AF-free individuals...
December 27, 2017: American Journal of Human Genetics
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