Research Interests: Skeletal muscle biology, Biology, Medicine, Amyotrophic Lateral Sclerosis, Brain, and 13 moreHumans, Survivors, Female, Male, Middle Aged, microRNAs, Adult, Disease Progression, Neuromuscular Junction, Histone deacetylases, Motor Neurons, Psychology and Cognitive Sciences, and Medical and Health Sciences
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In this article, the author, artist Simon Hantai, offers a reflection on a photograph of himself and his father, Daniel Hantai, from 1956, dealing with topics including his father's work in painting, abstract painting in the mid-20th... more
In this article, the author, artist Simon Hantai, offers a reflection on a photograph of himself and his father, Daniel Hantai, from 1956, dealing with topics including his father's work in painting, abstract painting in the mid-20th century and Simon Hantai's exhibition "Pliage: The First Decade" at the Mnuchin Gallery in New York City through June 26, 2015.
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Il est maintenant bien etabli que certaines serine proteases comme les activateurs du plasminogene (PA) ou la thrombine ainsi que leurs inhibiteurs sont impliques dans le developpement du systeme nerveux central et peripherique. Nous... more
Il est maintenant bien etabli que certaines serine proteases comme les activateurs du plasminogene (PA) ou la thrombine ainsi que leurs inhibiteurs sont impliques dans le developpement du systeme nerveux central et peripherique. Nous avons montre que les PA musculaires actives apres denervation etaient capables de degrader certains composants de la lame basale musculaire. Nous avons montre egalement que plusieurs inhibiteurs de serine proteases etaient concentres au niveau de la jonction neuromusculaire. Ce sont la protease nexine I (PN1), encore appelee «glia derived nexin» (GDN), la protease nexine II (PN2), une des formes secretees du precurseur de la substance β-amyloide (APP), et l'α 1 -antichymotrypsine (ACT). Ces resultats nous ont amene a proposer un modele dans lequel les serine proteases favoriseraient la plasticite des terminaisons nerveuses au cours du developpement neuromusculaire. A l'oppose, l'action des inhibiteurs des serine proteases jouerait a l'et...
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Congenital myasthenic syndromes (CMS) are a heterogeneous group of disorders caused by genetic defects affecting neuromuscular transmission and leading to muscle weakness accentuated by exertion. Three different aspects have been... more
Congenital myasthenic syndromes (CMS) are a heterogeneous group of disorders caused by genetic defects affecting neuromuscular transmission and leading to muscle weakness accentuated by exertion. Three different aspects have been investigated by members of the national French CMS Network: the difficulties in making a proper diagnosis; the course and long-term prognosis; and the response to therapy, especially for CMS that do not respond to cholinesterase inhibitors. CMS diagnosis is late in most cases because of confusion with other entities such as: congenital myopathies, due to the frequent presentation in patients of myopathies such as permanent muscle weakness, atrophy and scoliosis, and the abnormalities of internal structure, diameter and distribution of fibers (type I predominance, type II atrophy) seen on biopsy; seronegative autoimmune myasthenia gravis, when CMS is of late onset; and metabolic myopathy, with the presence of lipidosis in muscle. The long-term prognosis of CMS was studied in a series of 79 patients recruited with the following gene mutations: CHRNA; CHRNE; DOK7; COLQ; RAPSN; AGRN; and MUSK. Disease-course patterns (progressive worsening, exacerbation, stability, improvement) could be variable throughout life in a given patient. DOK7 patients had the most severe disease course with progressive worsening: of the eight wheelchair-bound and ventilated patients, six had mutations of this gene. Pregnancy was a frequent cause of exacerbation. Anticholinesterase agents are the first-line therapy for CMS patients, except for cases of slow-channel CMS, COLQ and DOK7. In our experience, 3,4-DAP was a useful complement for several patients harboring CMS with AChR loss or RAPSN gene mutations. Ephedrine was given to 18 patients (eight DOK7, five COLQ, four AGRN and one RAPSN). Tolerability was good. Therapeutic responses were encouraging even in the most severely affected patients, particularly with DOK7 and COLQ. Salbutamol was a good alternative in one patient who was allergic to ephedrine.
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The following information was missing from the funding section: Austrian Science Fund... more
The following information was missing from the funding section: Austrian Science Fund ({"type":"entrez-protein","attrs":{"text":"P21667","term_id":"122622","term_text":"P21667"}}P21667-B09).
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The objective of our study was to investigate the cellular communication between the axon and its postsynaptic targets in the synapse. We used the neuromuscular junction (NMJ) model, which is a highly specialized structure between the... more
The objective of our study was to investigate the cellular communication between the axon and its postsynaptic targets in the synapse. We used the neuromuscular junction (NMJ) model, which is a highly specialized structure between the nerve, the muscle, and the Schwann cell terminal where the motor neuron orders the muscle to contract. We used experimental models of motor nerve
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Because injury of the CNS causes an astrogliosis, characterized by cell swelling and proliferation, similar to the effects of the serine protease thrombin on astrocytes, we hypothesized that a high level of thrombin at the site of injury... more
Because injury of the CNS causes an astrogliosis, characterized by cell swelling and proliferation, similar to the effects of the serine protease thrombin on astrocytes, we hypothesized that a high level of thrombin at the site of injury might initially induce an astrocyte reaction and later increase the expression of its specific inhibitor, thrombomodulin. Thrombomodulin could then stabilize the astroglial scar through its adhesive properties. Here, we studied the in vivo injury response of astrocytes in the anterior medullary velum of adult rat by immunostaining and in situ hybridization of thrombomodulin. Thrombomodulin was poorly expressed on astrocytes in normal tissue, increased up to 2 d after injury, and was still highly expressed at 6 d. To check that thrombin had a direct effect on thrombomodulin expression by astrocytes, we used brain cortical astrocyte primary cultures treated with either thrombin or the agonist peptide thrombin receptor-activating peptide-6, known to ac...
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Brody disease was first described as a benign pseudo-myotonic disorder with muscular stiffness, which increased with exercise. Biochemical and genetic studies have pointed out its close relationship to a functional defect of the... more
Brody disease was first described as a benign pseudo-myotonic disorder with muscular stiffness, which increased with exercise. Biochemical and genetic studies have pointed out its close relationship to a functional defect of the fast-twitch sarcoplasmic reticulum Ca(++) ATPase pump (SERCA1) encoded by the ATP2A1 gene located on chromosome 16. The histopathological features in this form of myopathy were generally described as non-specific, i.e. moderate degree of type 2 fibre atrophy and excess of internal nuclei. We here present the clinical and histopathological features of a patient with Brody disease over a 19-year follow-up period. This patient had two heterozygous ATP2A1 mutations and complained about muscle stiffness immediately after effort. He had suffered from this since early childhood and exhibited clinical symptoms mimicking myotonia. Histological, ultrastructural and cytogenetic analyses revealed morphologically abnormal nuclei with polyploidy. In this report, we discuss the possible links between the consequences of the genetic abnormality and the peculiar aspect of the nuclei.
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Congenital myasthenic syndromes (CMS) are a heterogeneous group of disorders caused by genetic defects affecting neuromuscular transmission and leading to muscle weakness accentuated by exertion. The characterization of CMS comprises two... more
Congenital myasthenic syndromes (CMS) are a heterogeneous group of disorders caused by genetic defects affecting neuromuscular transmission and leading to muscle weakness accentuated by exertion. The characterization of CMS comprises two complementary steps: establishing the diagnosis and identifying the pathophysiological type of CMS. The combination of clinical, electrophysiological, and morphological studies allows the physician to refer a given CMS to mutation(s) in one of the 18 causative genes discovered to date and, in turn, to classify the CMS according to the location of the mutated proteins at the neuromuscular junction into presynaptic compartment, synaptic basal lamina, and postsynaptic compartment CMS. This complete characterization is essential for counseling and therapy of the patient, depending on the molecular background of the respective CMS. Despite comprehensive characterization, the phenotypic expression of one given gene involved is variable, and the etiology o...
The neuromuscular junction is made up of the apposition of highly differentiated domains of three types of cell: the motor neuronal ending, the terminal Schwann cell and the muscle postsynaptic membrane. These three components are... more
The neuromuscular junction is made up of the apposition of highly differentiated domains of three types of cell: the motor neuronal ending, the terminal Schwann cell and the muscle postsynaptic membrane. These three components are surrounded by a basal lamina, dedicated to molecular signal exchanges controlling neuromuscular formation, maturation and maintenance. This functional and structural differentiated complex conducts synaptic neurotransmission to the skeletal muscle fiber. Nerve and muscle have distinct roles in synaptic compartment differentiation. The initial steps of this differentiation and the motor endplate formation require several postsynaptic molecular agents including agrin, the tyrosine kinase receptor MuSK. Neuregulin is essentially involved in Schwann cell survival and guidance for axonal growth.
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Congenital Myasthenic Syndromes (CMS) are a heterogeneous group of diseases caused by genetic defects affecting neuromuscular transmission. The twenty five past Years saw major advances in identifying different types of CMS due to... more
Congenital Myasthenic Syndromes (CMS) are a heterogeneous group of diseases caused by genetic defects affecting neuromuscular transmission. The twenty five past Years saw major advances in identifying different types of CMS due to abnormal presynaptic, synaptic, and postsynaptic proteins. CMS diagnosis requires two steps: 1) positive diagnosis supported by myasthenic signs beginning in neonatal period, efficacy of anticholinesterase medications, positive family history, negative tests for anti-acetylcholine receptor (AChR) antibodies, electromyographic studies (decremental response at low frequency, repetitive CMAP after one single stimulation); 2) pathophysiological characterisation of CMS implying specific studies: light and electron microscopic analysis of endplate (EP) morphology, estimation of the number of AChR per EP, acetylcholinesterase (AChE) expression, molecular genetic analysis. Most CMS are postsynaptic due to mutations in the AChR subunits genes that alter the kinetic...
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A review of the importance of the extravascular fibrinolytic enzymes and their inhibitors in the neuromuscular system is discussed. We present data showing the role of specific serine proteases, the plasminogen activators, during... more
A review of the importance of the extravascular fibrinolytic enzymes and their inhibitors in the neuromuscular system is discussed. We present data showing the role of specific serine proteases, the plasminogen activators, during neuromuscular development as well as after nerve injury and regeneration through their action on muscle basement membrane components. We show the presence in muscle of protease nexin I, a member of the serine protease inhibitors (serpins) family, where it is highly concentrated in the neuromuscular junction. These data have lead us to propose a model where the extravascular components of the fibrinolytic cascade and cellular derived serpins, such as protease nexin I, would act in the formation and maintenance of the neuromuscular synapse. Our conclusion is that future studies with these molecules, including their regulation at several levels, are warranted in a number of neuromuscular and neuro-degenerative diseases.
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Slow and fast contracting muscles differ in their innervation and electrophysiological properties as well as in their regenerating potentialities. The purpose of the present work was to investigate the expression of plasminogen activators... more
Slow and fast contracting muscles differ in their innervation and electrophysiological properties as well as in their regenerating potentialities. The purpose of the present work was to investigate the expression of plasminogen activators and its possible relation to each type of muscle. Slow (Soleus) and fast (Extensor Digitorum Longus) muscles were obtained from white Wistar rats. Before sectioning the muscles, the euthanized rats were perfused with cold phosphate buffer saline to avoid interference by circulating proteases and inhibitors. Muscle extracts were pounded in an ice-cold Potter tube. Plasminogen activators (PAs) were assayed by fibrin zymography and by both liquid and solid-phase fibrin spectrophotometric assays for the detection of PAs activity. Both urokinase (uPA) and tissue-type plasminogen activator (tPA) activities corresponding to proteins of 38 kDa and 65 kDa molecular masses, were detected in the extracts. Slow muscles contained higher amounts of both activato...
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Immunocytochemical localization of the adhesive glycoprotein thrombospondin made in comparison with other components of extracellular matrices shows its sequential appearance in the mouse muscle endomysium during postnatal development.... more
Immunocytochemical localization of the adhesive glycoprotein thrombospondin made in comparison with other components of extracellular matrices shows its sequential appearance in the mouse muscle endomysium during postnatal development. Thrombospondin, absent at birth, in contrast to laminin, type IV collagen and fibronectin, is progressively detected during the first month of neonatal life in the whole muscle extracellular matrix. Immunoblotting of thrombospondin showed the appearance 14 days after birth of a band migrating at 180 kDa corresponding to thrombospondin. A fragment of thrombospondin at 110 kDa was already present at birth, as was also a lower molecular mass band at 70 kDa. Another band at 50 kDa also appeared during development in muscle extracts. Clonal muscle cells in culture were able to synthesize thrombospondin but only at the myotube stage, since little thrombospondin was detected at the myoblast stage. These data show a development regulation of thrombospondin ex...
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Congenital myasthenic syndromes (CMS) are rare genetic diseases affecting the neuromuscular junction (NMJ) and are characterized by a dysfunction of the neurotransmission. They are heterogeneous at their pathophysiological level and can... more
Congenital myasthenic syndromes (CMS) are rare genetic diseases affecting the neuromuscular junction (NMJ) and are characterized by a dysfunction of the neurotransmission. They are heterogeneous at their pathophysiological level and can be classified in three categories according to their presynaptic, synaptic and postsynaptic origins. We report here the first case of a human neuromuscular transmission dysfunction due to mutations in the gene encoding a postsynaptic molecule, the muscle-specific receptor tyrosine kinase (MuSK). Gene analysis identified two heteroallelic mutations, a frameshift mutation (c.220insC) and a missense mutation (V790M). The muscle biopsy showed dramatic pre- and postsynaptic structural abnormalities of the neuromuscular junction and severe decrease in acetylcholine receptor (AChR) epsilon-subunit and MuSK expression. In vitro and in vivo expression experiments were performed using mutant MuSK reproducing the human mutations. The frameshift mutation led to ...
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Research Interests: Genetics, Cognitive Science, Immunology, Clinical Neuroscience, Neuroimmunology, and 15 moreHumans, Mutation, Animals, Acetylcholinesterase, Differential Diagnosis, Electromyography, Medical Physiology, Cholinesterase inhibitors, Child Neurology, Clinical Sciences, Genotype, Neuromuscular Disorders, Genetic Analysis, Neuromuscular Junction, and cholinergic mechanisms
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Page 1. Workshop report 126th International Workshop: Congenital Myasthenic Syndromes, 24–26 September 2004, Naarden, The Netherlands David Beeson a , Daniel Hantaı b , Hanns Lochmüller c,*, Andrew G. Engeld aNeurosciences ...
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A staining technique is presented in order to facilitate the automatic analysis of muscle biopsies. It renders possible the visualization on the same section of the myofibrillary adenosine-triphosphatase (ATPase) activity under the... more
A staining technique is presented in order to facilitate the automatic analysis of muscle biopsies. It renders possible the visualization on the same section of the myofibrillary adenosine-triphosphatase (ATPase) activity under the microscope with transmitted light, and of the fluorescent staining of fibronectin which marks the outlines of the muscle fibers by a simple switch to ultraviolet (UV) light.
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The distribution pattern of fibronectin, laminin and type IV collagen in the striated muscle fiber of adult rat was studied using immunofluorescence staining and electron microscopy. The results indicate that fibronectin as well as... more
The distribution pattern of fibronectin, laminin and type IV collagen in the striated muscle fiber of adult rat was studied using immunofluorescence staining and electron microscopy. The results indicate that fibronectin as well as laminin and type IV collagen precisely delineate each muscle fiber. Fibronectin is present on the sarcolemma extending from the cell membrane to the intercellular collagen fibers beyond the basal lamina lucida externa. This suggests a role for fibronectin in making contact between the cell membrane and the intercellular matrix.
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Research Interests: Genetics, Cognitive Science, Electrophysiology, Kinetics, Patch-clamp and imaging techniques, and 15 moreCell line, Humans, Mutation, Acetylcholine, Medical Physiology, Neuron, SIGNAL PEPTIDE, Amino Acid Sequence, Base Sequence, Resting State, Neurosciences, Patch Clamp, Binding affinity, Molecular Sequence Data, and Molecular probes
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Tubular aggregates are morphological abnormalities characterized by the accumulation of densely packed tubules in skeletal muscle fibres. To improve knowledge of tubular aggregates, the formation and role of which are still unclear, the... more
Tubular aggregates are morphological abnormalities characterized by the accumulation of densely packed tubules in skeletal muscle fibres. To improve knowledge of tubular aggregates, the formation and role of which are still unclear, the present study reports the electron microscopic analysis and protein characterization of tubular aggregates in six patients with 'tubular aggregate myopathy'. Three of the six patients also presented with myasthenic features. A large panel of immunochemical markers located in the sarcoplasmic reticulum, T-tubules, mitochondria, and nucleus was used. Despite differences in clinical phenotype, the composition of tubular aggregates, which contained proteins normally segregated differently along the sarcoplasmic reticulum architecture, was similar in all patients. All of these proteins, calsequestrin, RyR, triadin, SERCAs, and sarcalumenin, are involved in calcium uptake, storage, and release. The dihydropyridine receptor, DHPR, specifically located in the T-tubule, was also present in tubular aggregates in all patients. COX-2 and COX-7 mitochondrial proteins were not found in tubular aggregates, despite being observed close to them in the muscle fibre. The nuclear membrane protein emerin was found in only one case. Electron microscopy revealed vesicular budding from nuclei, and the presence of SAR-1 GTPase protein in tubular aggregates shown by immunochemistry, in all patients, suggests that tubular aggregates could arise from endoplasmic reticulum exit sites. Taken together, these results cast new light on the composition and significance of tubular aggregates.
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Research Interests: Skeletal muscle biology, Cell Biology, Energy Metabolism, Biological Sciences, Glucose, and 15 moreMutation, Mice, Electroporation, Female, Animals, Rats, Age Factors, Experimental Medicine, Muscle contraction, The cell, Dystrophin, Sirolimus, Glycogen, Severity of Illness Index, and Medical and Health Sciences
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Protease nexin I is a 43-50 kDa glycoprotein capable of inhibiting a number of serine proteases. In cultured differentiated human skeletal muscle (myotubes), we previously found that protease nexin I was localized in patches at their... more
Protease nexin I is a 43-50 kDa glycoprotein capable of inhibiting a number of serine proteases. In cultured differentiated human skeletal muscle (myotubes), we previously found that protease nexin I was localized in patches at their surface where it was active and able to inhibit thrombin. To understand the role of skeletal muscle protease nexin I after injury or in inflammatory conditions where thrombin might be extravasated by blood vessels, we examined the role of inflammatory factors on protease nexin I synthesis and secretion by myotubes in culture. By enzyme-linked immunosorbent assay (ELISA) and Western blotting, we found that this serine protease inhibitor is secreted by cultured human myotubes. Protease nexin I secretion is stimulated by tumor necrosis factor-alpha, transforming growth factor-beta and interleukin-1. Complex formation experiments with labeled thrombin reveal active protease nexin I bound to the surface of the treated cells. Secreted protease nexin I-thrombin complex was enhanced in the presence of transforming growth factor-beta and tumor necrosis factor-alpha. Protease nexin I mRNA was detected by reverse transcription-polymerase chain reaction (RT-PCR) and Northern blot analysis. Whatever the conditions, no significantly different levels were observed, indicating that the changes in cell and media protease nexin I concentration are elicited at the translational/posttranslational levels. Immunocytochemical studies on human skeletal muscle biopsies of patients suffering from inflammatory myopathies showed an overexpression of protease nexin I together with the above inflammatory factors. These findings suggest that skeletal muscle protease nexin I might play a role after injury or inflammatory pathologies.
Research Interests: Skeletal muscle biology, Wound Healing, Biopsy, Western blotting, Thrombin, and 12 moreHumans, Iodine, Cellular Physiology, Medical Physiology, Cell nucleus, Tumor necrosis factor-alpha, Transforming Growth Factor Beta, Culture Media, Enzyme Linked Immunosorbent Assay, Interleukin, Amyloid Beta Precursor Protein, and reverse transcriptase polymerase chain reaction
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... MUTAGENÈSE DIRIGÉE Dans le domaine intracellulaire, les séquences entre le rat et l'homme sont fortement homologues (Valenzuela et al., 1995). Ceci nous a permis d'utiliser un vecteur pcDNA 3 contenant... more
... MUTAGENÈSE DIRIGÉE Dans le domaine intracellulaire, les séquences entre le rat et l'homme sont fortement homologues (Valenzuela et al., 1995). Ceci nous a permis d'utiliser un vecteur pcDNA 3 contenant l'ADNc de MuSK de rat (don de Werner Hoch, Université de ...
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Research Interests: Genetics, Electron Microscopy, Locomotion, Biological Sciences, Protein Structure and Function, and 15 moreHumans, Mutation, Mice, Female, Animals, Male, Human Molecular Genetics, Animal Model, Synaptic Transmission, Mouse Model, Muscle contraction, Neuromuscular Junction, Kyphosis, Axons, and Medical and Health Sciences
Regulation of thrombin activity may be required during skeletal muscle differentiation since the thrombin tissue inhibitor protease nexin-1 appears at the myotube stage before being localized at the neuromuscular synapse. Here, we have... more
Regulation of thrombin activity may be required during skeletal muscle differentiation since the thrombin tissue inhibitor protease nexin-1 appears at the myotube stage before being localized at the neuromuscular synapse. Here, we have used a model of rat fetal myotube primary cultures to study the effect of thrombin on acetylcholine receptor (AChR) expression, which is enhanced at the myotube stage. Our results show that thrombin decreases both the number of surface AChRs (AChRn) and AChR alpha-subunit gene expression. Using the agonist peptide SFLLRN, we establish that the AChRn decrease is mediated by the G protein-coupled thrombin receptor "protease-activated receptor-1" (PAR-1). Moreover, the specific thrombin inhibitor hirudin increases AChRn by inhibiting the thrombin intrinsically present in the cultures. We further demonstrate that the activation of PAR-1 by thrombin induces intracellular calcium movements that are blocked by 2-APB, an inhibitor of inositol 1,4,5-...
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We report the first case of a human neuromuscular transmission dysfunction due to mutations in the gene encoding the muscle-specific receptor tyrosine kinase (MuSK). Gene analysis identified two heteroallelic mutations, a frameshift... more
We report the first case of a human neuromuscular transmission dysfunction due to mutations in the gene encoding the muscle-specific receptor tyrosine kinase (MuSK). Gene analysis identified two heteroallelic mutations, a frameshift mutation (c.220insC) and a missense mutation (V790M). The muscle biopsy showed dramatic pre- and postsynaptic structural abnormalities of the neuromuscular junction and severe decrease in acetylcholine receptor (AChR) epsilon-subunit and MuSK expression. In vitro and in vivo expression experiments were performed using mutant MuSK reproducing the human mutations. The frameshift mutation led to the absence of MuSK expression. The missense mutation did not affect MuSK catalytic kinase activity but diminished expression and stability of MuSK leading to decreased agrin-dependent AChR aggregation, a critical step in the formation of the neuromuscular junction. In electroporated mouse muscle, overexpression of the missense mutation induced, within a week, a phe...
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The turnover of basement membrane macromolecules in injured skeletal muscle has not been studied in contrast to other biologic systems undergoing remodeling. Plasminogen activators and other neutral proteases that are able to degrade... more
The turnover of basement membrane macromolecules in injured skeletal muscle has not been studied in contrast to other biologic systems undergoing remodeling. Plasminogen activators and other neutral proteases that are able to degrade these basement membrane macromolecules are secreted by cultured muscle cells. We sought to determine if locally released plasminogen activators could act on basement membrane components. Such degradation might be implicated in the disadhesion of nerve from muscle after motor nerve denervation. To test this hypothesis, we first undertook a study of the sensitivity of muscle extracellular matrix antigens following in vitro exposure to various proteases on frozen muscle sections. Fibronectin was found to be most sensitive, followed by type IV collagen and laminin. Of serine proteases, trypsin was the most active but was not selective, digesting matrix and sarcoplasmic components alike in less than 30 min. Purified urokinase was inactive unless plasminogen (also inactive alone) was previously added to tissue sections, at which time only matrix antigens were digested. Little if any observable degradation of sarcoplasmic proteins took place under these conditions. Using a highly sensitive and selective assay, we found that plasminogen activators were present in muscle tissue and increased 8- to 10-fold after 10 days of denervation. Using an extract of denervated muscle in the presence of plasminogen, we observed degradation of matrix antigens. No degradation was observed with control muscle extract. We next evaluated the degradation of these antigens in denervated muscle during a temporal study. The results, analyzed by quantitative image analysis, indicates that with increasing time after denervation a marked decrease of fibronectin and type IV collagen, followed by laminin occurred but, again, only in the present of plasminogen. These results indicate a selective sensitivity of basement membrane antigens of muscle and a role for plasminogen activators in the degradation of these adhesive basement membranes macromolecules after denervation.
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Research Interests: Skeletal muscle biology, Calcium, Immunohistochemistry, Gene expression, Cell Culture, and 15 moreCell Differentiation, Thrombin, Humans, Calcium Signaling, Peptides, Inflammatory disease, Clinical Sciences, Skeletal Muscle, Myositis, Neuromuscular Junction, Serine Protease, Biochemistry and cell biology, Interleukin, Proteolytic activity, and reverse transcriptase polymerase chain reaction
In the course of studies on thrombin and its inhibitor(s) in synaptic plasticity, we addressed the question of their roles in the formation of neuromuscular junctions (NMJ) and used a model of rat neuron-myotube cocultures. We report that... more
In the course of studies on thrombin and its inhibitor(s) in synaptic plasticity, we addressed the question of their roles in the formation of neuromuscular junctions (NMJ) and used a model of rat neuron-myotube cocultures. We report that the size of acetylcholinesterase (AChE) patches used as a marker of neuromuscular contacts was decreased in the presence of either thrombin or SFLLRN, the agonist peptide of the thrombin receptor PAR-1, whereas it was increased with hirudin, a specific thrombin inhibitor. In an attempt to relate these neuromuscular contact size variations to molecular changes, we studied muscle-specific tyrosine kinase receptor (MuSK), acetylcholine receptor (AChR) and rapsyn expression in the presence of thrombin. We showed that thrombin did not change rapsyn gene and protein expression. However, the expression of MuSK and surface AChR proteins was diminished in both myotube cultures and neuron-myotube cocultures. These reductions in protein expression were associated with a decrease in MuSK and AChR alpha-subunit gene expression in myotube cultures but not in neuron-myotube cocultures. Moreover, the expression of the AChR epsilon-subunit gene, specifically enhanced by neuron-released factors, was not modified by thrombin in neuron-myotube cocultures. This suggests that thrombin did not affect the expression of synaptic AChRs enhanced by neuron-released factors but rather reduced the level of extrasynaptic AChRs. Taken together, these results indicate that thrombin in balance with its inhibitor(s) could modulate the formation of neuromuscular contacts in vitro by affecting the expression of two essential molecules in NMJ postsynaptic differentiation, MuSK and AChR.
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Research Interests: Genetics, Cognitive Science, Immunology, Clinical Neuroscience, Neuroimmunology, and 15 moreHumans, Mutation, Animals, Acetylcholinesterase, Differential Diagnosis, Electromyography, Medical Physiology, Cholinesterase inhibitors, Child Neurology, Clinical Sciences, Genotype, Neuromuscular Disorders, Genetic Analysis, Neuromuscular Junction, and cholinergic mechanisms
The distribution pattern of fibronectin, laminin, type I, III and IV collagens in human skeletal muscle was studied by immunofluorescence. In normal muscle, as well as in congenital myopathies (CM), type I and III collagens were localized... more
The distribution pattern of fibronectin, laminin, type I, III and IV collagens in human skeletal muscle was studied by immunofluorescence. In normal muscle, as well as in congenital myopathies (CM), type I and III collagens were localized in the endomysium and the perimysium. Laminin and type IV collagen delineated precisely each muscle fiber but did not stain the perimysium. In Duchenne's muscular dystrophy (DMD) as well as in congenital muscular dystrophies (CMD) the extensive proliferation of connective tissue consisted mainly of fibronectin and type I and III collagens. Laminin and type IV collagen delineated principally the basal lamina but suprisingly were found to be distributed to some extent all over the extracellular matrix. No disease--specific accumulation of components of the extracellular matrix was found which would enable us to differentiate these last two diseases, though the immunofluorescence reactions for all components were stronger in DMD than in CMD.
Research Interests: Biomedical Engineering, Adolescent, Extracellular Matrix, Humans, Child, and 15 moreBasement Membrane, Collagen, Muscular Dystrophy, Female, Muscular Dystrophies, Male, Connective tissue, Muscles, Clinical Sciences, Middle Aged, Adult, Laminin, Congenital muscular dystrophy, Child preschool, and Tissue distribution
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In addition to muscle changes due to peripheral nervous system involvement, primary myopathic changes associated with the human immunodeficiency virus (HIV) have also been described. We studied seven cases: two had developed an acquired... more
In addition to muscle changes due to peripheral nervous system involvement, primary myopathic changes associated with the human immunodeficiency virus (HIV) have also been described. We studied seven cases: two had developed an acquired immunodeficiency syndrome (AIDS), four had seroconverted to HIV but were otherwise asymptomatic, one was HIV seronegative when the biopsy was performed and one was biopsied twice. Besides the HIV no other infectious agent was detected. Muscle biopsies showed: (a) muscle fiber necrosis and regeneration; (b) inflammatory changes with moderate perivascular infiltration; and (c) unusual myofibrillary disorganization. Immunocytochemical techniques using anti-HIV monoclonal antibodies showed the presence of the virus in one biopsy. HIV-RNA was detected by in situ hybridization in the same biopsy. With both techniques the HIV was detected in isolated mononuclear cells in the muscle endomysium and not within the muscle fibers. Muscle involvement associated with HIV infection may be related, at least in some cases, to the presence of the virus in interstitial cells.