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J M Heckmann - One of the best experts on this subject based on the ideXlab platform.
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Association of transforming growth factor β-1 (TGFB1) regulatory region polymorphisms with myasthenia gravis-related ophthalmoparesis.
Journal of neuroimmunology, 2012Co-Authors: M V Akinyi, C Dandara, J Gamieldien, J M HeckmannAbstract:We investigated the association of an ophthalmoplegic complication developing in African myasthenia gravis (MG) subjects with polymorphisms in the regulatory region of TGFB1. We found significant associations with several putative functional single nucleotide polymorphisms (SNPs) (including two novel SNPs) that potentially alter transcription factor binding. Our data support a hypothesis that altered TGFB1 regulation may predispose individuals who harbour these SNPs to developing ophthalmoplegia as a result of increased TGF-β1 driven Myofibrosis as a consequence to complement-mediated damage.
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RETRACTED: Association of transforming growth factor beta-1 (TGFB1) regulatory region polymorphisms with myasthenia gravis-related ophthalmoparesis
Journal of Neuroimmunology, 2012Co-Authors: M V Akinyi, C Dandara, J Gamieldien, J M HeckmannAbstract:article i nfo We investigated the association of an ophthalmoplegic complication developing in African myasthenia gravis (MG) subjects with polymorphisms in the regulatory region of TGFB1. We found significant associations with several putative functional single nucleotide polymorphisms (SNPs) (including two novel SNPs) that poten- tially alter transcription factor binding. Our data support a hypothesis that altered TGFB1 regulation may pre- dispose individuals who harbour these SNPs to developing ophthalmoplegia as a result of increased TGF-β1 driven Myofibrosis as a consequence to complement-mediated damage.
Kay Ohlendieck - One of the best experts on this subject based on the ideXlab platform.
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proteomic analysis of the sarcolemma enriched fraction from dystrophic mdx 4cv skeletal muscle
Journal of Proteomics, 2018Co-Authors: Sandra Murphy, Rustam R. Mundegar, Margit Zweyer, Paula Meleady, Dieter Swandulla, Michael Henry, Kay OhlendieckAbstract:Abstract The highly progressive neuromuscular disorder dystrophinopathy is triggered by primary abnormalities in the Dmd gene, which causes cytoskeletal instability and loss of sarcolemmal integrity. Comparative organellar proteomics was employed to identify sarcolemma-associated proteins with an altered concentration in dystrophic muscle tissue from the mdx-4cv mouse model of dystrophinopathy. A lectin agglutination method was used to prepare a sarcolemma-enriched fraction and resulted in the identification of 190 significantly changed protein species. Proteomics established differential expression patterns for key components of the muscle plasma membrane, cytoskeletal network, extracellular matrix, metabolic pathways, cellular stress response, protein synthesis, immune response and neuromuscular junction. The deficiency in dystrophin and drastic reduction in dystrophin-associated proteins appears to trigger (i) enhanced membrane repair involving myoferlin, dysferlin and annexins, (ii) increased protein synthesis and the compensatory up-regulation of cytoskeletal proteins, (iii) the decrease in the scaffolding protein periaxin and myelin PO involved in myelination of motor neurons, (iv) complex changes in bioenergetic pathways, (v) elevated levels of molecular chaperones to prevent proteotoxic effects, (vi) increased collagen deposition causing reactive Myofibrosis, (vii) disturbed ion homeostasis at the sarcolemma and associated membrane systems, and (viii) a robust inflammatory response by the innate immune system in response to chronic muscle damage. Significance Duchenne muscular dystrophy is a devastating muscle wasting disease and represents the most frequently inherited neuromuscular disorder in humans. Genetic abnormalities in the Dmd gene cause a loss of sarcolemmal integrity and highly progressive muscle fibre degeneration. Changes in the neuromuscular system are associated with necrosis, fibrosis and inflammation. In order to evaluate secondary changes in the sarcolemma membrane system due to the lack of the membrane cytoskeletal protein dystrophin, comparative organellar proteomics was used to study the mdx-4cv mouse model of dystrophinopathy. Mass spectrometric analyses identified a variety of altered components of the extracellular matrix-sarcolemma-cytoskeleton axis in dystrophic muscles. This included proteins involved in membrane repair, cytoskeletal restoration, calcium homeostasis, cellular signalling, stress response, neuromuscular transmission and reactive Myofibrosis, as well as immune cell infiltration. These pathobiochemical alterations agree with the idea of highly complex secondary changes in X-linked muscular dystrophy and support the concept that micro-rupturing of the dystrophin-deficient plasma membrane is at the core of muscle wasting pathology.
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Proteomic profiling of mdx-4cv serum reveals highly elevated levels of the inflammation-induced plasma marker haptoglobin in muscular dystrophy.
International journal of molecular medicine, 2017Co-Authors: Sandra Murphy, Rustam R. Mundegar, Margit Zweyer, Paula Meleady, Dieter Swandulla, Michael Henry, Paul Dowling, Kay OhlendieckAbstract:X-linked muscular dystrophy is caused by primary abnormalities in the Dmd gene and is characterized by the almost complete loss of the membrane cytoskeletal protein dystrophin, which triggers sarcolemmal instability, abnormal calcium homeostasis, increased proteolysis and impaired excitation‑contraction coupling. In addition to progressive necrosis, crucial secondary pathologies are represented by Myofibrosis and the invasion of immune cells in damaged muscle fibres. In order to determine whether these substantial changes within the skeletal musculature are reflected by an altered rate of protein release into the circulatory system or other plasma fluctuations, we used label‑free mass spectrometry to characterize serum from the mdx‑4cv model of Duchenne muscular dystrophy. Comparative proteomics revealed a large number of increased vs. decreased protein species in mdx‑4cv serum. A serum component with greatly elevated levels was identified as the inflammation‑inducible plasma marker haptoglobin. This acute phase response protein is usually secreted in relation to tissue damage and sterile inflammation. Both immunoblot analyses and enzyme‑linked immunosorbent assays confirmed the increased concentration of haptoglobin in crude mdx‑4cv serum. This suggests that haptoglobin, in conjunction with other altered serum proteins, represents a novel diagnostic, prognostic and/or therapy‑monitoring biomarker candidate to evaluate the inflammatory response in the mdx‑4cv animal model of dystrophinopathy.
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Proteomic profiling of the dystrophin complex and membrane fraction from dystrophic mdx muscle reveals decreases in the cytolinker desmoglein and increases in the extracellular matrix stabilizers biglycan and fibronectin
Journal of Muscle Research and Cell Motility, 2017Co-Authors: Sandra Murphy, Paula Meleady, Michael Henry, Heinrich Brinkmeier, Mirjam Krautwald, Kay OhlendieckAbstract:The almost complete loss of the membrane cytoskeletal protein dystrophin and concomitant drastic reduction in dystrophin-associated glycoproteins are the underlying mechanisms of the highly progressive neuromuscular disorder Duchenne muscular dystrophy. In order to identify new potential binding partners of dystrophin or proteins in close proximity to the sarcolemmal dystrophin complex, proteomic profiling of the isolated dystrophin–glycoprotein complex was carried out. Subcellular membrane fractionation and detergent solubilisation, in combination with ion exchange, lectin chromatography and density gradient ultracentrifugation, was performed to isolate a dystrophin complex-enriched fraction. Following gradient gel electrophoresis and on-membrane digestion, the protein constituents of the dystrophin fraction were determined by peptide mass spectrometry. This proteomic strategy resulted in the novel identification of desmoglein and desmoplakin, which act as cytolinker proteins and possibly exist in close proximity to the dystrophin complex in the sarcolemma membrane. Interestingly, comparative immunoblotting showed a significant reduction in desmoglein in dystrophin-deficient mdx skeletal muscles, reminiscent of the pathobiochemical fate of the dystrophin-associated core proteins in muscular dystrophy. Comparative membrane proteomics was used to correlate this novel finding to large-scale changes in the dystrophic phenotype. A drastic increase in the extracellular stabilizers biglycan and fibronectin was shown by both mass spectrometric analysis and immunoblotting. The reduced expression of desmoglein in dystrophin-deficient skeletal muscles, and simultaneous increase in components of the extracellular matrix, suggest that muscular dystrophy is associated with plasmalemmal disintegration, loss of cellular linkage and reactive Myofibrosis.
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Molekulare Pathogenese der Fibrose bei Muskeldystrophie vom Typ Duchenne
Der Pathologe, 2017Co-Authors: Kay Ohlendieck, Dieter SwandullaAbstract:Progressive Myofibrosis plays a key role in Duchenne muscular dystrophy. The dystrophic loss of contractile cells triggers a relatively nonspecific restructuring of the surrounding mesenchyme. The increase in connective and fatty tissue leads to muscular weakness and is therefore of critical importance for the cellular pathogenesis of muscular dystrophy. The systematic biochemical analysis of fibrosis using comparative proteomics has identified a number of extracellular matrix proteins that are indirectly involved in muscular dystrophy. An increased concentration was established for collagen I, collagen IV, collagen VI, periostin, dermatopontin, fibronectin, biglycan, asporin, decorin, prolargin, mimecan and lumican. Based on these findings, the identified matrix proteins can now be characterized biochemically and their exact pathophysiological role in Duchenne muscular dystrophy determined. Die progrediente Myofibrose spielt eine entscheidende Rolle bei der Pathogenese der Muskeldystrophie vom Typ Duchenne. Die dystrophiebedingte Lückenbildung im Muskelgewebe erzeugt eine relativ unspezifische Umstrukturierung des umgebenden Mesenchyms. Der Anstieg an Bindegewebe und Fettgewebe führt zu einer progressiven Muskelschwäche und ist somit von zentraler Bedeutung für die zelluläre Pathogenese der Muskeldystrophie. Die systematische biochemische Analyse der Fibrose mithilfe der vergleichenden Proteomanalyse hat zur Identifizierung einer Vielzahl von extrazellulären Matrixproteinen geführt, welche indirekt an der Ausprägung der Muskeldystrophie beteiligt sind. Eine erhöhte Konzentration wurde für Kollagen I, Kollagen IV, Kollagen VI, Periostin, Dermatopontin, Fibronektin, Biglykan, Asporin, Decorin, Prolargin, Mimecan und Lumican etabliert. Basierend auf diesen Befunden können die identifizierten Matrixproteine nun biochemisch charakterisiert werden und ihre genaue pathophysiologische Rolle bei der Duchenne-Muskeldystrophie bestimmt werden.
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The Extracellular Matrix Complexome from Skeletal Muscle
Composition and Function of the Extracellular Matrix in the Human Body, 2016Co-Authors: Sandra Murphy, Kay OhlendieckAbstract:The various layers of the extracellular matrix, forming the endomysium, perimysium and epimysium of skeletal muscles, provide essential structural and mechanical support to contractile fibres. Crucial aspects of muscle elasticity and fibre contractility are depend‐ ent on proper cell–matrix interactions. A complex network of collagen fibres, nonfibrillar collagens, proteoglycans, matricellular proteins, matrix metalloproteinases, adhesion receptors and signalling molecules maintain the physical structure for force transmission within motor units, embed critical cellular structures such as capillaries and motor neurons, and enable essential sarcolemma-matrix adhesion processes and signalling cascades. The systems biological concept of protein complexomes, which assumes the existence of interconnectivities between large protein assemblies, can be readily applied to the proteins within the extracellular space of muscles. Recent proteomic studies confirm that the extracellular matrix complexome has considerable influence on the integrity and cellular functions of skeletal muscle fibres. Adaptations or changes in the organization of the extracellular matrix play a crucial role during fibre regeneration following injury, extensive neuromuscular activity or pathophysiological insults. This chapter outlines the molecular components of the matrisome from skeletal muscles and discusses the extracellular matrix in relation to myogenesis, maturation of motor units, adaptation to changed functional demands and Myofibrosis in muscular disorders.
M V Akinyi - One of the best experts on this subject based on the ideXlab platform.
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Association of transforming growth factor β-1 (TGFB1) regulatory region polymorphisms with myasthenia gravis-related ophthalmoparesis.
Journal of neuroimmunology, 2012Co-Authors: M V Akinyi, C Dandara, J Gamieldien, J M HeckmannAbstract:We investigated the association of an ophthalmoplegic complication developing in African myasthenia gravis (MG) subjects with polymorphisms in the regulatory region of TGFB1. We found significant associations with several putative functional single nucleotide polymorphisms (SNPs) (including two novel SNPs) that potentially alter transcription factor binding. Our data support a hypothesis that altered TGFB1 regulation may predispose individuals who harbour these SNPs to developing ophthalmoplegia as a result of increased TGF-β1 driven Myofibrosis as a consequence to complement-mediated damage.
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RETRACTED: Association of transforming growth factor beta-1 (TGFB1) regulatory region polymorphisms with myasthenia gravis-related ophthalmoparesis
Journal of Neuroimmunology, 2012Co-Authors: M V Akinyi, C Dandara, J Gamieldien, J M HeckmannAbstract:article i nfo We investigated the association of an ophthalmoplegic complication developing in African myasthenia gravis (MG) subjects with polymorphisms in the regulatory region of TGFB1. We found significant associations with several putative functional single nucleotide polymorphisms (SNPs) (including two novel SNPs) that poten- tially alter transcription factor binding. Our data support a hypothesis that altered TGFB1 regulation may pre- dispose individuals who harbour these SNPs to developing ophthalmoplegia as a result of increased TGF-β1 driven Myofibrosis as a consequence to complement-mediated damage.
Pravin C. Singhal - One of the best experts on this subject based on the ideXlab platform.
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Myonecrosis and Myofibrosis in Sickle Cell Anemia
Annals of internal medicine, 1991Co-Authors: Joseph Mattana, Pravin C. SinghalAbstract:Excerpt To the Editors:Valeriano-Marcet and Kerr (1) report myonecrosis and Myofibrosis in four patients with painful crises of sickle cell disease. Presumably, sickling of red blood cells causes m...
Leslie Dubin Kerr - One of the best experts on this subject based on the ideXlab platform.
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Myonecrosis and Myofibrosis as Complications of Sickle Cell Anemia
Annals of internal medicine, 1991Co-Authors: Joanne Valeriano-marcet, Leslie Dubin KerrAbstract:▪ Painful crises in sickle cell anemia are associated with infarction and subsequent fibrosis of many different organs. Myonecrosis secondary to muscle infarction during a crisis and subsequent fib...
