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Holly Tiffany, Kanchan Sonkar, Matthew J Gage
The giant sarcomere protein titin is the third filament in muscle and is integral to maintaining sarcomere integrity as well as contributing to both active and passive tension. Titin is a multi-domain protein that contains regions of repeated structural elements. The N2A region sits at the boundary between the proximal Ig region of titin that is extended under low force and the PEVK region that is extended under high force. Multiple binding interactions have been associated with the N2A region and it has been proposed that this region acts as a mechanical stretch sensor...
October 11, 2016: Biochimica et Biophysica Acta
Nicolas Jaé, Stefanie Dimmeler
No abstract text is available yet for this article.
October 14, 2016: Circulation Research
Akira Hanashima, Ken Hashimoto, Yoshihiro Ujihara, Takeshi Honda, Tomoko Yobimoto, Aya Kodama, Satoshi Mohri
Connectin, also called titin, is the largest protein with a critical function as a molecular spring during contraction and relaxation of striated muscle; its mutation leads to severe myopathy and cardiomyopathy. To uncover the cause of this pathogenesis, zebrafish have recently been used as disease models because they are easier to genetically modify than mice. Although the gene structures and putative primary structures of zebrafish connectin have been determined, the actual primary structures of zebrafish connectin in heart and skeletal muscles remain unclear because of its large size and the PCR amplification-associated difficulties...
October 7, 2016: Gene
Scott D Wagner, Tomofumi Kurobe, Bruce G Hammock, Chelsea H Lam, Gary Wu, Natalia Vasylieva, Shirley J Gee, Bruce D Hammock, Swee J Teh
Pesticides in urban runoff are a major source of pollutants in aquatic ecosystems. Fipronil, a phenylpyrazole insecticide, found in structural pest control products, turf grass control, and home pet flea medication, has recently increased in use and is commonly detected in urban runoff. However, little is known about the effects of fipronil on aquatic organisms at early developmental stages. Here, we evaluated toxicity of fipronil to embryos of Japanese Medaka (Oryzias latipes, Qurt strain) using a high-throughput 96-well plate toxicity test...
January 2017: Chemosphere
Edvina Galié, Rosaria Renna, Domenico Plantone, Andrea Pace, Mirella Marino, Bruno Jandolo, Tatiana Koudriavtseva
Morvan's syndrome (MoS) is a rare, complex neurological disorder characterized by neuromyotonia, neuropsychiatric features, dysautonomia and neuropathic pain. The majority of MoS cases have a paraneoplastic aetiology, usually occurring prior to the diagnosis of the underlying tumour and showing improvement following its treatment. The present study reports the case of a 35-year-old Caucasian male patient who was diagnosed with stage IVA thymoma. Thymectomy, lung resection, diaphragmatic pleurectomy and pericardio-phrenectomy were performed 6 months after neoadjuvant chemotherapy...
October 2016: Oncology Letters
Julius Bogomolovas, Jennifer R Fleming, Brian R Anderson, Rhys Williams, Stephan Lange, Bernd Simon, Muzamil M Khan, Rüdiger Rudolf, Barbara Franke, Belinda Bullard, Daniel J Rigden, Henk Granzier, Siegfried Labeit, Olga Mayans
Missense single-nucleotide polymorphisms (mSNPs) in titin are emerging as a main causative factor of heart failure. However, distinguishing between benign and disease-causing mSNPs is a substantial challenge. Here, we research the question of whether a single mSNP in a generic domain of titin can affect heart function as a whole and, if so, how. For this, we studied the mSNP T2850I, seemingly linked to arrhythmogenic right ventricular cardiomyopathy (ARVC). We used structural biology, computational simulations and transgenic muscle in vivo methods to track the effect of the mutation from the molecular to the organismal level...
September 2016: Open Biology
Sebastian Kötter, Malgorzata Kazmierowska, Christian Andresen, Katharina Bottermann, Maria Grandoch, Simone Gorressen, Andre Heinen, Jens M Moll, Jürgen Scheller, Axel Gödecke, Jens W Fischer, Joachim P Schmitt, Martina Krüger
RATIONALE: Myocardial infarction (MI) increases the wall stress in the viable myocardium and initiates early adaptive remodeling in the left ventricle to maintain cardiac output. Later remodeling processes include fibrotic reorganization that eventually leads to cardiac failure. Understanding the mechanisms that support cardiac function in the early phase post MI and identifying the processes that initiate transition to maladaptive remodeling are of major clinical interest. OBJECTIVE: To characterize MI-induced changes in titin-based cardiac myocyte stiffness and to elucidate the role of titin in ventricular remodeling of remote myocardium in the early phase after MI...
October 14, 2016: Circulation Research
Jamie Douglas, Simon Pearson, Angus Ross, Mike McGuigan
An eccentric contraction involves the active lengthening of muscle under an external load. The molecular and neural mechanisms underpinning eccentric contractions differ from those of concentric and isometric contractions and remain less understood. A number of molecular theories have been put forth to explain the unexplained observations during eccentric contractions that deviate from the predictions of the established theories of muscle contraction. Postulated mechanisms include a strain-induced modulation of actin-myosin interactions at the level of the cross-bridge, the activation of the structural protein titin, and the winding of titin on actin...
September 15, 2016: Sports Medicine
Martin M LeWinter, Michael R Zile
No abstract text is available yet for this article.
October 11, 2016: Circulation
Mei Methawasin, Joshua G Strom, Rebecca E Slater, Vanessa Fernandez, Chandra Saripalli, Henk Granzier
BACKGROUND: Left ventricular (LV) stiffening contributes to heart failure with preserved ejection fraction (HFpEF), a syndrome with no effective treatment options. Increasing the compliance of titin in the heart has become possible recently through inhibition of the splicing factor RNA binding motif-20. Here, we investigated the effects of increasing the compliance of titin in mice with diastolic dysfunction. METHODS: Mice in which the RNA recognition motif (RRM) of one of the RNA binding motif-20 alleles was floxed and that expressed the MerCreMer transgene under control of the αMHC promoter (referred to as cRbm20(ΔRRM) mice) were used...
October 11, 2016: Circulation
Erik P Rader, Rolf Turk, Tobias Willer, Daniel Beltrán, Kei-Ichiro Inamori, Taylor A Peterson, Jeffrey Engle, Sally Prouty, Kiichiro Matsumura, Fumiaki Saito, Mary E Anderson, Kevin P Campbell
Dystroglycan (DG) is a highly expressed extracellular matrix receptor that is linked to the cytoskeleton in skeletal muscle. DG is critical for the function of skeletal muscle, and muscle with primary defects in the expression and/or function of DG throughout development has many pathological features and a severe muscular dystrophy phenotype. In addition, reduction in DG at the sarcolemma is a common feature in muscle biopsies from patients with various types of muscular dystrophy. However, the consequence of disrupting DG in mature muscle is not known...
September 27, 2016: Proceedings of the National Academy of Sciences of the United States of America
Rahul C Deo
BACKGROUND: -Truncating mutations in the giant sarcomeric gene Titin are the most common type of genetic alteration in dilated cardiomyopathy (DCM). Detailed studies have amassed a wealth of information regarding truncating variant position in cases and controls. Nonetheless, considerable confusion exists as to how to interpret the pathogenicity of these variants, hindering our ability to make useful recommendations to patients. METHODS AND RESULTS: -Building on our recent discovery of a conserved internal promoter within the Titin gene, we sought to develop an integrative statistical model to explain the observed pattern of TTN truncation variants in DCM patients and population controls...
September 13, 2016: Circulation. Cardiovascular Genetics
Robert Hastings, Carin de Villiers, Charlotte Hooper, Liz Ormondroyd, Alistair Pagnamenta, Stefano Lise, Silvia Salatino, Samantha J L Knight, Jenny C Taylor, Kate L Thomson, Linda Arnold, Spyros D Chatziefthimiou, Petr V Konarev, Matthias Wilmanns, Elisabeth Ehler, Andrea Ghisleni, Mathias Gautel, Edward Blair, Hugh Watkins, Katja Gehmlich
BACKGROUND: -High throughput next generation sequencing techniques have made whole genome sequencing accessible in clinical practice, however, the abundance of variation in the human genomes makes the identification of a disease-causing mutation on a background of benign rare variants challenging. METHODS AND RESULTS: -Here we combine whole genome sequencing with linkage analysis in a three-generation family affected by cardiomyopathy with features of autosomal dominant left-ventricular non-compaction cardiomyopathy...
September 13, 2016: Circulation. Cardiovascular Genetics
M I Stefanou, L Komorowski, S Kade, A Bornemann, U Ziemann, M Synofzik
BACKGROUND: Myasthenia gravis is an autoimmune neuromuscular disorder, which has only rarely been reported to co-manifest with myositis. The diagnosis of concomitant myositis in patients with myasthenia gravis is clinically challenging, and requires targeted investigations for the differential diagnosis, including EMG, autoantibody assays, muscle biopsy and, importantly, imaging of the mediastinum for thymoma screening. CASE PRESENTATION: This report presents a case-vignette of a 72-year-old woman with progressive proximal muscle weakness and myalgias, diagnosed with thymoma-associated myasthenia and bioptically verified granulomatous myositis, with positive autoantibody status for ryanodine receptor and titin antibodies...
September 13, 2016: BMC Neurology
Yu Hong, Hai-Feng Li, Geir Olve Skeie, Fredrik Romi, Hong-Jun Hao, Xu Zhang, Xiang Gao, Jone Furlund Owe, Nils Erik Gilhus
Myasthenia gravis (MG) is an autoimmune disorder with heterogeneity. Antibodies against acetylcholine receptor (AChR), muscle-specific kinase (MuSK), titin and ryanodine receptor (RyR) were examined in 437 adult Chinese MG patients. The AChR, MuSK, titin and RyR antibodies were found in 82.2%, 2.3%, 28.4% and 23.8% of all patients. Autoantibody profiles vary among different MG subgroups. Thymoma MG patients had high frequencies of AChR (99.2%), titin (50.8%) and RyR antibodies (46.9%). The titin and RyR antibodies also showed high frequencies in late onset patients (54...
September 15, 2016: Journal of Neuroimmunology
Md Shenuarin Bhuiyan, Patrick McLendon, Jeanne James, Hanna Osinska, James Gulick, Bidur Bhandary, John N Lorenz, Jeffrey Robbins
Cardiac myosin-binding protein C (cMyBP-C) is an integral part of the sarcomeric machinery in cardiac muscle that enables normal function. cMyBP-C regulates normal cardiac contraction by functioning as a brake through interactions with the sarcomere's thick, thin, and titin filaments. cMyBP-C's precise effects as it binds to the different filament systems remain obscure, particularly as it impacts on the myosin heavy chain's head domain, contained within the subfragment 2 (S2) region. This portion of the myosin heavy chain also contains the ATPase activity critical for myosin's function...
October 2016: Pflügers Archiv: European Journal of Physiology
Pilar Cossio, Gerhard Hummer, Attila Szabo
Ductile materials can absorb spikes in mechanical force, whereas brittle ones fail catastrophically. Here we develop a theory to quantify the kinetic ductility of single molecules from force spectroscopy experiments, relating force-spike resistance to the differential responses of the intact protein and the unfolding transition state to an applied mechanical force. We introduce a class of unistable one-dimensional potential surfaces that encompass previous models as special cases and continuously cover the entire range from ductile to brittle...
August 23, 2016: Biophysical Journal
Karine Charton, Laurence Suel, Sara F Henriques, Jean-Paul Moussu, Matteo Bovolenta, Miguel Taillepierre, Céline Becker, Karelia Lipson, Isabelle Richard
The giant protein titin is the third most abundant protein in striated muscle. Mutations in its gene are responsible for diseases affecting the cardiac and/or the skeletal muscle. Titin has been reported to be expressed in multiple isoforms with considerable variability in the I-band, ensuring the modulation of the passive mechanical properties of the sarcomere. In the M-line, only the penultimate Mex5 exon coding for the specific is7 domain has been reported to be subjected to alternative splicing. Using the CRISPR-Cas9 editing technology, we generated a mouse model where we stably prevent the expression of alternative spliced variant(s) carrying the corresponding domain...
August 23, 2016: Human Molecular Genetics
Amy E M Beedle, Steven Lynham, Sergi Garcia-Manyes
The post-translational modification S-sulfenylation functions as a key sensor of oxidative stress. Yet the dynamics of sulfenic acid in proteins remains largely elusive due to its fleeting nature. Here we use single-molecule force-clamp spectroscopy and mass spectrometry to directly capture the reactivity of an individual sulfenic acid embedded within the core of a single Ig domain of the titin protein. Our results demonstrate that sulfenic acid is a crucial short-lived intermediate that dictates the protein's fate in a conformation-dependent manner...
2016: Nature Communications
Ji-Shi Liu, Liang-Liang Fan, Hao Zhang, Xiaoxian Liu, Hao Huang, Li-Jian Tao, Kun Xia, Rong Xiang
OBJECTIVES: Dilated cardiomyopathy (DCM) is a leading cause of sudden cardiac death. So far, only 127 mutations of Titin(TTN) have been reported in patients with different phenotypes such as isolated cardiomyopathies, purely skeletal muscle phenotypes or complex overlapping disorders of muscles. METHODS: We applied whole-exome sequencing (WES) to investigate cardiomyopathy patients and a cardiomyopathy-related gene-filtering strategy was used to analyze the disease-causing mutations...
August 20, 2016: Cardiology
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