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https://www.readbyqxmd.com/read/29452748/knockout-of-human-muscle-genes-revealed-by-large-scale-whole-exome-studies
#1
Stefano Schiaffino
Large scale whole-exome sequence studies have revealed that a number of individuals from different populations have predicted loss-of-function of different genes due to nonsense, frameshift, or canonical splice-site mutations. Surprisingly, many of these mutations do not apparently show the deleterious phenotypic consequences expected from gene knockout. These homozygous null mutations, when confirmed, can provide insight into human gene function and suggest novel approaches to correct gene dysfunction, as the lack of the expected disease phenotype may reflect the existence of modifier genes that reveal potential therapeutic targets...
February 10, 2018: Molecular Genetics and Metabolism
https://www.readbyqxmd.com/read/29452157/hypertrophic-cardiomyopathy-mutation-r58q-in-the-myosin-regulatory-light-chain-perturbs-thick-filament-based-regulation-in-cardiac-muscle
#2
Thomas Kampourakis, Saraswathi Ponnam, Malcolm Irving
Hypertrophic cardiomyopathy (HCM) is frequently linked to mutations in the protein components of the myosin-containing thick filaments leading to contractile dysfunction and ultimately heart failure. However, the molecular structure-function relationships that underlie these pathological effects remain largely obscure. Here we chose an example mutation (R58Q) in the myosin regulatory light chain (RLC) that is associated with a severe HCM phenotype and combined the results from a wide range of in vitro and in situ structural and functional studies on isolated protein components, myofibrils and ventricular trabeculae to create an extensive map of structure-function relationships...
February 13, 2018: Journal of Molecular and Cellular Cardiology
https://www.readbyqxmd.com/read/29451820/the-hcm-linked-w792r-mutation-in-cardiac-myosin-binding-protein-c-reduces-c6-fniii-domain-stability
#3
Dan F Smelter, Willem J De Lange, Wenxuan Cai, Ying Ge, John C Ralphe
Cardiac myosin binding protein-C (cMyBP-C) is a functional sarcomeric protein that regulates contractility in response to contractile demand, and many mutations in cMyBP-C lead to hypertrophic cardiomyopathy (HCM). To gain insight into the effects of disease-causing cMyBP-C missense mutations on contractile function, we expressed the pathogenic W792R mutation in mouse cardiomyocytes lacking endogenous cMyBP-C and studied the functional effects using three-dimensional engineered cardiac tissue (mECT) constructs...
February 16, 2018: American Journal of Physiology. Heart and Circulatory Physiology
https://www.readbyqxmd.com/read/29451818/overexpression-of-heart-specific-small-subunit-of-myosin-light-chain-phosphatase-results-in-heart-failure-and-conduction-disturbance
#4
Takuro Arimura, Antoine Muchir, Masayoshi Kuwahara, Sachio Morimoto, Taisuke Ishikawa, Cheng-Kun Du, Dong-Yun Zhan, Shu Nakao, Noboru Machida, Ryo Tanaka, Yoshihisa Yamane, Takeharu Hayashi, Akinori Kimura
Mutations in genes encoding components of sarcomere cause cardiomyopathy, which is often associated with abnormal Ca 2+ sensitivity of muscle contraction. We previously showed that a heart-specific myosin light chain phosphatase small subunit, hHS-M 21 , increases the Ca 2+ -sensitivity of muscle contraction. The aim of this study was to investigate the function of hHS-M 21 in vivo and the causative role of abnormal Ca 2+ sensitivity in cardiomyopathy. We generated transgenic (Tg) mice with cardiac-specific overexpression of hHS-M 21 ...
February 16, 2018: American Journal of Physiology. Heart and Circulatory Physiology
https://www.readbyqxmd.com/read/29433275/influence-of-carcass-weight-on-meat-quality-of-commercial-feedlot-steers-with-similar-feedlot-slaughter-and-post-mortem-management
#5
Babatunde Agbeniga, Edward C Webb
The effects of beef carcass weight on muscle pH/temperature profile and selected meat quality attributes were evaluated. Twenty-six carcasses from light (≤260kg, n=15) and heavy (≥290kg, n=11) feedlot steers were randomly allocated and stimulated with low voltage electrical stimulation (LVES) for 30s at 7min post-mortem (pm). Quality evaluations were carried out on samples from the Longissimus et lumborum (LL) muscle from the left side of each carcass. Heavier carcasses showed faster pH decline and slower (P<0...
March 2018: Food Research International
https://www.readbyqxmd.com/read/29432755/pelvic-muscles-mechanical-response-to-strains-in-the-absence-and-presence-of-pregnancy-induced-adaptations-in-a-rat-model
#6
Tatiana Catanzarite, Shannon Bremner, Caitlin L Barlow, Laura Bou-Malham, Shawn O'Connor, Marianna Alperin
BACKGROUND: Maternal birth trauma to the pelvic floor muscles is thought to be consequent to mechanical demands placed on these muscles during fetal delivery that exceed muscle physiological limits. The above is consistent with studies of striated limb muscles that identify hyperelongation of sarcomeres, the functional muscle units, as the primary cause of mechanical muscle injury and resultant muscle dysfunction. However, pelvic floor muscles' mechanical response to strains have not been examined at a tissue level...
February 9, 2018: American Journal of Obstetrics and Gynecology
https://www.readbyqxmd.com/read/29432443/short-term-doxycycline-treatment-induces-sustained-improvement-in-myocardial-infarction-border-zone-contractility
#7
Kimberly Spaulding, Kiyoaki Takaba, Alexander Collins, Farshid Faraji, Guanying Wang, Esteban Aguayo, Liang Ge, David Saloner, Arthur W Wallace, Anthony J Baker, David H Lovett, Mark B Ratcliffe
Decreased contractility in the non-ischemic border zone surrounding a MI is in part due to degradation of cardiomyocyte sarcomeric components by intracellular matrix metalloproteinase-2 (MMP-2). We recently reported that MMP-2 levels were increased in the border zone after a MI and that treatment with doxycycline for two weeks after MI was associated with normalization of MMP-2 levels and improvement in ex-vivo contractile protein developed force in the myocardial border zone. The purpose of the current study was to determine if there is a sustained effect of short term treatment with doxycycline (Dox) on border zone function in a large animal model of antero-apical myocardial infarction (MI)...
2018: PloS One
https://www.readbyqxmd.com/read/29423427/rapid-ifm-dissection-for-visualizing-fluorescently-tagged-sarcomeric-proteins
#8
Yu Shu Xiao, Frieder Schöck, Nicanor González-Morales
Sarcomeres, the smallest contractile unit of muscles, are arguably the most impressive actomyosin structure. Yet a complete understanding of sarcomere formation and maintenance is missing. The Drosophila indirect flight muscle (IFM) has proven to be a very valuable model to study sarcomeres. Here, we present a protocol for the rapid dissection of IFM and analysis of sarcomeres using fluorescently tagged proteins.
November 20, 2017: Bio-protocol
https://www.readbyqxmd.com/read/29419405/muscle-contraction
#9
REVIEW
H Lee Sweeney, David W Hammers
SUMMARYMuscle cells are designed to generate force and movement. There are three types of mammalian muscles-skeletal, cardiac, and smooth. Skeletal muscles are attached to bones and move them relative to each other. Cardiac muscle comprises the heart, which pumps blood through the vasculature. Skeletal and cardiac muscles are known as striated muscles, because the filaments of actin and myosin that power their contraction are organized into repeating arrays, called sarcomeres, that have a striated microscopic appearance...
February 1, 2018: Cold Spring Harbor Perspectives in Biology
https://www.readbyqxmd.com/read/29416706/troponin-through-the-looking-glass-emerging-roles-beyond-regulation-of-striated-muscle-contraction
#10
REVIEW
Jamie R Johnston, P Bryant Chase, Jose Renato Pinto
Troponin is a heterotrimeric Ca2+-binding protein that has a well-established role in regulating striated muscle contraction. However, mounting evidence points to novel cellular functions of troponin, with profound implications in cancer, cardiomyopathy pathogenesis and skeletal muscle aging. Here, we highlight the non-canonical roles and aberrant expression patterns of troponin beyond the sarcomeric milieu. Utilizing bioinformatics tools and online databases, we also provide pathway, subcellular localization, and protein-protein/DNA interaction analyses that support a role for troponin in multiple subcellular compartments...
January 2, 2018: Oncotarget
https://www.readbyqxmd.com/read/29414430/surgical-pathology-of-subaortic-septal-myectomy-histology-skips-over-clinical-diagnosis
#11
João Abecasis, Rosa Gouveia, Mariana Castro, Maria João Andrade, Regina Ribeiras, Sância Ramos, Miguel Abecasis, Nuno Cardim, Victor Gil
BACKGROUND: Subaortic septal myectomy is usually performed to mitigate obstruction in patients with the obstructive form of hypertrophic cardiomyopathy (HCM) or in those with congenital subaortic stenosis. Moreover, it is combined with aortic valve replacement in patients with severe aortic valve stenosis (SAS) and asymmetrical septal hypertrophy causing concomitant left ventricular outflow tract obstruction. When both conditions coexist, it is conceptually difficult to identify a cardiomyopathy beyond an adaptive myocardial hypertrophy, strictly related to pressure overload...
January 3, 2018: Cardiovascular Pathology: the Official Journal of the Society for Cardiovascular Pathology
https://www.readbyqxmd.com/read/29413682/rigor-bonds-cause-reduced-sarcomeric-volume-in-skinned-porcine-skeletal-muscle-under-pse-like-conditions
#12
Jiao Liu, Matthias Schwartzkopf, Anders Arner
Effects of rigor cross-bridge attachment on water holding in PSE-like conditions were investigated. A new model using permeabilised/skinned porcine longissimus thoracis et lumborum muscle fibres was established to study effects of varied pH, temperature and the presence of rigor bonds on the muscle fibre structure. Preparations were exposed during 30min to different temperatures (22 and 38°C) and pH (7.0 and 5.5) in relaxed and rigor states, followed by evaluation of active force and filament lattice spacing (using small angle X-ray scattering) at standard pH (7...
February 2, 2018: Meat Science
https://www.readbyqxmd.com/read/29408381/autophosphorylation-is-a-mechanism-of-inhibition-in-twitchin-kinase
#13
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/29404727/combined-use-of-bone-marrow-derived-mesenchymal-stromal-cells-bm-mscs-and-platelet-rich-plasma-prp-stimulates-proliferation-and-differentiation-of-myoblasts-in-vitro-new-therapeutic-perspectives-for-skeletal-muscle-repair-regeneration
#14
Chiara Sassoli, Larissa Vallone, Alessia Tani, Flaminia Chellini, Daniele Nosi, Sandra Zecchi-Orlandini
Satellite cell-mediated skeletal muscle repair/regeneration is compromised in cases of extended damage. Bone marrow mesenchymal stromal cells (BM-MSCs) hold promise for muscle healing but some criticisms hamper their clinical application, including the need to avoid animal serum contamination for expansion and the scarce survival after transplant. In this context, platelet-rich plasma (PRP) could offer advantages. Here, we compare the effects of PRP or standard culture media on C2C12 myoblast, satellite cell and BM-MSC viability, survival, proliferation and myogenic differentiation and evaluate PRP/BM-MSC combination effects in promoting myogenic differentiation...
February 5, 2018: Cell and Tissue Research
https://www.readbyqxmd.com/read/29398688/late-gadolinium-enhancement-for-prediction-of-mutation-positive-hypertrophic-cardiomyopathy-on-the-basis-of-panel-wide-sequencing
#15
Ryota Teramoto, Noboru Fujino, Tetsuo Konno, Akihiro Nomura, Yoji Nagata, Toyonobu Tsuda, Hayato Tada, Kenji Sakata, Masakazu Yamagishi, Kenshi Hayashi, Masa-Aki Kawashiri
BACKGROUND: Cardiac magnetic resonance (CMR) with late gadolinium enhancement (LGE) revealed a substantial variation in the extent of myocardial scarring, a pathological hallmark of hypertrophic cardiomyopathy (HCM). However, few data exist regarding the relationship between the presence of gene mutations and the extent of LGE. Therefore, we aimed to investigate whether variations in the extent of LGE in HCM patients can be explained by the presence or absence of disease-causing mutations...
February 3, 2018: Circulation Journal: Official Journal of the Japanese Circulation Society
https://www.readbyqxmd.com/read/29397107/platelet-function-analyzer-100-and-brain-natriuretic-peptide-as-biomarkers-in-obstructive-hypertrophic-cardiomyopathy
#16
Joseph L Blackshear, Robert E Safford, Colleen S Thomas, J Martijn Bos, Michael J Ackerman, Jeffrey B Geske, Steve R Ommen, Brian P Shapiro, Gretchen S Johns
To test dual blood biomarkers compared with electrocardiogram (ECG) for hypertrophic cardiomyopathy (HC) screening, we performed 3 analyses and cut-point assessments. First, we measured platelet function analyzer (PFA)-100 (n = 99) and normalized B-type natriuretic peptide (BNP) or NT-proBNP (BNP/upper limit of normal [ULN], n = 92) in 64 patients with HC and 29 normal controls (NCs). Second, from the regression equation between PFA and gradient (r = 0.77), we derived estimated PFA in a population of 189 patients with functional class I HC in whom measured BNP/ULN and ECG were available, and calculated single and dual biomarker sensitivity and specificity compared with ECG...
December 25, 2017: American Journal of Cardiology
https://www.readbyqxmd.com/read/29382717/structures-of-human-calpain-3-protease-core-with-and-without-bound-inhibitor-reveal-mechanisms-of-calpain-activation
#17
Qilu Ye, Robert L Campbell, Peter L Davies
Limb-girdle muscular dystrophy type 2a arises from mutations in the Ca2+-activated intracellular cysteine protease calpain-3. This calpain isoform is abundant in skeletal muscle and differs from the main isoforms, calpain-1 and -2, in being a homodimer and having two short insertion sequences. The first of these, IS1, interrupts the protease core and must be cleaved for activation and substrate binding. Here, to learn how calpain-3 can be regulated and inhibited, we determined the structures of the calpain-3 protease core with IS1 present or proteolytically excised...
January 30, 2018: Journal of Biological Chemistry
https://www.readbyqxmd.com/read/29382361/trypanosoma-cruzi-activates-mouse-cardiac-fibroblasts-in-vitro-leading-to-fibroblast-myofibroblast-transition-and-increase-in-expression-of-extracellular-matrix-proteins
#18
Laura Lacerda Coelho, Isabela Resende Pereira, Mirian Claudia de Souza Pereira, Liliane Mesquita, Joseli Lannes-Vieira, Daniel Adesse, Luciana Ribeiro Garzoni
BACKGROUND: Cardiac fibrosis is a consequence of chronic chagasic cardiomyopathy (CCC). In other cardiovascular diseases, the protagonist role of fibroblasts in cardiac fibrosis is well established. However, the role of cardiac fibroblasts (CFs) in fibrosis during the CCC is not clear. Here, our aim was to investigate the effect of Trypanosoma cruzi, the etiological agent of Chagas disease on CFs activation. METHODS: Cardiac fibroblasts were purified from primary cultures of mouse embryo cardiac cells...
January 30, 2018: Parasites & Vectors
https://www.readbyqxmd.com/read/29374849/zebrafish-embryonic-slow-muscle-is-a-rapid-system-for-genetic-analysis-of-sarcomere-organization-by-crispr-cas9-but-not-ngago
#19
Mengxin Cai, Yufeng Si, Jianshe Zhang, Zhenjun Tian, Shaojun Du
Zebrafish embryonic slow muscle cells, with their superficial localization and clear sarcomere organization, provide a useful model system for genetic analysis of muscle cell differentiation and sarcomere assembly. To develop a quick assay for testing CRISPR-mediated gene editing in slow muscles of zebrafish embryos, we targeted a red fluorescence protein (RFP) reporter gene specifically expressed in slow muscles of myomesin-3-RFP (Myom3-RFP) zebrafish embryos. We demonstrated that microinjection of RFP-sgRNA with Cas9 protein or Cas9 mRNA resulted in a mosaic pattern in loss of RFP expression in slow muscle fibers of the injected zebrafish embryos...
January 27, 2018: Marine Biotechnology
https://www.readbyqxmd.com/read/29374072/asb2%C3%AE-filamin-a-axis-is-essential-for-actin-cytoskeleton-remodeling-during-heart-development
#20
Arnaud Métais, Isabelle Lamsoul, Armelle Melet, Sandrine Uttenweiler-Joseph, Renaud Poincloux, Sonia Stefanovic, Amélie Valière, Anne Gonzalez de Peredo, Alexandre Stella, Odile Burlet-Schiltz, Stephane Zaffran, Pierre G Lutz, Christel Moog-Lutz
Rationale: Heart development involves differentiation of cardiac progenitors and assembly of the contractile sarcomere apparatus of cardiomyocytes. However, little is known about the mechanisms that regulate actin cytoskeleton remodeling during cardiac cell differentiation. Objective: The Asb2α Cullin5 RING E3 ubiquitin ligase triggers polyubiquitylation and subsequent degradation by the proteasome of filamins. Here, we investigate the role of Asb2α in heart development and its mechanisms of action. Methods and Results: : Using ASB2 knockout embryos, we show that Asb2 is an essential gene, critical to heart morphogenesis and function, although its loss does not interfere with the overall patterning of the embryonic heart tube...
January 26, 2018: Circulation Research
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