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1
Iyer, Shama R., Sameer B. Shah, and Richard M. Lovering. "The Neuromuscular Junction: Roles in Aging and Neuromuscular Disease." International Journal of Molecular Sciences 22, no. 15 (2021): 8058. http://dx.doi.org/10.3390/ijms22158058.
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The neuromuscular junction (NMJ) is a specialized synapse that bridges the motor neuron and the skeletal muscle fiber and is crucial for conversion of electrical impulses originating in the motor neuron to action potentials in the muscle fiber. The consideration of contributing factors to skeletal muscle injury, muscular dystrophy and sarcopenia cannot be restricted only to processes intrinsic to the muscle, as data show that these conditions incur denervation-like findings, such as fragmented NMJ morphology and corresponding functional changes in neuromuscular transmission. Primary defects in the NMJ also influence functional loss in motor neuron disease, congenital myasthenic syndromes and myasthenia gravis, resulting in skeletal muscle weakness and heightened fatigue. Such findings underscore the role that the NMJ plays in neuromuscular performance. Regardless of cause or effect, functional denervation is now an accepted consequence of sarcopenia and muscle disease. In this short review, we provide an overview of the pathologic etiology, symptoms, and therapeutic strategies related to the NMJ. In particular, we examine the role of the NMJ as a disease modifier and a potential therapeutic target in neuromuscular injury and disease.
2
Panenic, Robert, and Phillip F. Gardiner. "The Case for Adaptability of the Neuromuscular Junction to Endurance Exercise Training." Canadian Journal of Applied Physiology 23, no. 4 (1998): 339–60. http://dx.doi.org/10.1139/h98-019.
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Although the adaptability of the neuromuscular junction (NMJ) has been demonstrated using the models of denervation/reinnervation, electrical stimulation, development, aging, and pathological states, relatively little is known about the effects of increased chronic voluntary use on the morphology and physiological function of the NMJ. A review of findings relating to adaptations in the various pre- and postsynaptic components of the NMJ with exercise training is presented. These findings are discussed as they pertain to NMJ function during exercise. Other physiological modulators of the NMJ, such as trophic factors released by nerve terminals and muscles, and circulating substances are discussed in terms of possible roles they may play in training-induced adaptations. Key words: neuromuscular junction, endurance exercise, adaptations, morphology, acetylcholinesterase, physiology, trophic factors
3
Lepore, Elisa, Irene Casola, Gabriella Dobrowolny, and Antonio Musarò. "Neuromuscular Junction as an Entity of Nerve-Muscle Communication." Cells 8, no. 8 (2019): 906. http://dx.doi.org/10.3390/cells8080906.
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One of the crucial systems severely affected in several neuromuscular diseases is the loss of effective connection between muscle and nerve, leading to a pathological non-communication between the two tissues. The neuromuscular junction (NMJ) represents the critical region at the level of which muscle and nerve communicate. Defects in signal transmission between terminal nerve endings and muscle membrane is a common feature of several physio-pathologic conditions including aging and Amyotrophic Lateral Sclerosis (ALS). Nevertheless, controversy exists on whether pathological events beginning at the NMJ precede or follow loss of motor units. In this review, the role of NMJ in the physio-pathologic interplay between muscle and nerve is discussed.
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Deschenes, Michael R., Rachel Flannery, Alexis Hawbaker, Leah Patek, and Mia Mifsud. "Adaptive Remodeling of the Neuromuscular Junction with Aging." Cells 11, no. 7 (2022): 1150. http://dx.doi.org/10.3390/cells11071150.
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Aging is associated with gradual degeneration, in mass and function, of the neuromuscular system. This process, referred to as “sarcopenia”, is considered a disease by itself, and it has been linked to a number of other serious maladies such as type II diabetes, osteoporosis, arthritis, cardiovascular disease, and even dementia. While the molecular causes of sarcopenia remain to be fully elucidated, recent findings have implicated the neuromuscular junction (NMJ) as being an important locus in the development and progression of that malady. This synapse, which connects motor neurons to the muscle fibers that they innervate, has been found to degenerate with age, contributing both to senescent-related declines in muscle mass and function. The NMJ also shows plasticity in response to a number of neuromuscular diseases such as amyotrophic lateral sclerosis (ALS) and Lambert-Eaton myasthenic syndrome (LEMS). Here, the structural and functional degradation of the NMJ associated with aging and disease is described, along with the measures that might be taken to effectively mitigate, if not fully prevent, that degeneration.
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Nemeth, Colin, Naren L. Banik, and Azizul Haque. "Disruption of Neuromuscular Junction Following Spinal Cord Injury and Motor Neuron Diseases." International Journal of Molecular Sciences 25, no. 6 (2024): 3520. http://dx.doi.org/10.3390/ijms25063520.
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The neuromuscular junction (NMJ) is a crucial structure that connects the cholinergic motor neurons to the muscle fibers and allows for muscle contraction and movement. Despite the interruption of the supraspinal pathways that occurs in spinal cord injury (SCI), the NMJ, innervated by motor neurons below the injury site, has been found to remain intact. This highlights the importance of studying the NMJ in rodent models of various nervous system disorders, such as amyotrophic lateral sclerosis (ALS), Charcot–Marie–Tooth disease (CMT), spinal muscular atrophy (SMA), and spinal and bulbar muscular atrophy (SBMA). The NMJ is also involved in myasthenic disorders, such as myasthenia gravis (MG), and is vulnerable to neurotoxin damage. Thus, it is important to analyze the integrity of the NMJ in rodent models during the early stages of the disease, as this may allow for a better understanding of the condition and potential treatment options. The spinal cord also plays a crucial role in the functioning of the NMJ, as the junction relays information from the spinal cord to the muscle fibers, and the integrity of the NMJ could be disrupted by SCI. Therefore, it is vital to study SCI and muscle function when studying NMJ disorders. This review discusses the formation and function of the NMJ after SCI and potential interventions that may reverse or improve NMJ dysfunction, such as exercise, nutrition, and trophic factors.
6
Minty, Gavin, Alex Hoppen, Ines Boehm, et al. "aNMJ-morph: a simple macro for rapid analysis of neuromuscular junction morphology." Royal Society Open Science 7, no. 4 (2020): 200128. http://dx.doi.org/10.1098/rsos.200128.
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Large-scale data analysis of synaptic morphology is becoming increasingly important to the field of neurobiological research (e.g. ‘connectomics’). In particular, a detailed knowledge of neuromuscular junction (NMJ) morphology has proven to be important for understanding the form and function of synapses in both health and disease. The recent introduction of a standardized approach to the morphometric analysis of the NMJ—‘NMJ-morph’—has provided the first common software platform with which to analyse and integrate NMJ data from different research laboratories. Here, we describe the design and development of a novel macro—‘automated NMJ-morph’ or ‘aNMJ-morph’—to update and streamline the original NMJ-morph methodology. ImageJ macro language was used to encode the complete NMJ-morph workflow into seven navigation windows that generate robust data for 19 individual pre-/post-synaptic variables. The aNMJ-morph scripting was first validated against reference data generated by the parent workflow to confirm data reproducibility. aNMJ-morph was then compared with the parent workflow in large-scale data analysis of original NMJ images (240 NMJs) by multiple independent investigators. aNMJ-morph conferred a fourfold increase in data acquisition rate compared with the parent workflow, with average analysis times reduced to approximately 1 min per NMJ. Strong concordance was demonstrated between the two approaches for all 19 morphological variables, confirming the robust nature of aNMJ-morph. aNMJ-morph is a freely available and easy-to-use macro for the rapid and robust analysis of NMJ morphology and offers significant improvements in data acquisition and learning curve compared to the original NMJ-morph workflow.
7
Yi, Jianxun, Ang Li, Xuejun Li, et al. "MG53 Preserves Neuromuscular Junction Integrity and Alleviates ALS Disease Progression." Antioxidants 10, no. 10 (2021): 1522. http://dx.doi.org/10.3390/antiox10101522.
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Respiratory failure from progressive respiratory muscle weakness is the most common cause of death in amyotrophic lateral sclerosis (ALS). Defects in neuromuscular junctions (NMJs) and progressive NMJ loss occur at early stages, thus stabilizing and preserving NMJs represents a potential therapeutic strategy to slow ALS disease progression. Here we demonstrate that NMJ damage is repaired by MG53, an intrinsic muscle protein involved in plasma membrane repair. Compromised diaphragm muscle membrane repair and NMJ integrity are early pathological events in ALS. Diaphragm muscles from ALS mouse models show increased susceptibility to injury and intracellular MG53 aggregation, which is also a hallmark of human muscle samples from ALS patients. We show that systemic administration of recombinant human MG53 protein in ALS mice protects against injury to diaphragm muscle, preserves NMJ integrity, and slows ALS disease progression. As MG53 is present in circulation in rodents and humans under physiological conditions, our findings provide proof-of-concept data supporting MG53 as a potentially safe and effective therapy to mitigate ALS progression.
8
Ohkawara, Bisei, Mikako Ito, and Kinji Ohno. "Secreted Signaling Molecules at the Neuromuscular Junction in Physiology and Pathology." International Journal of Molecular Sciences 22, no. 5 (2021): 2455. http://dx.doi.org/10.3390/ijms22052455.
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Signal transduction at the neuromuscular junction (NMJ) is affected in many human diseases, including congenital myasthenic syndromes (CMS), myasthenia gravis, Lambert–Eaton myasthenic syndrome, Isaacs’ syndrome, Schwartz–Jampel syndrome, Fukuyama-type congenital muscular dystrophy, amyotrophic lateral sclerosis, and sarcopenia. The NMJ is a prototypic cholinergic synapse between the motor neuron and the skeletal muscle. Synaptogenesis of the NMJ has been extensively studied, which has also been extrapolated to further understand synapse formation in the central nervous system. Studies of genetically engineered mice have disclosed crucial roles of secreted molecules in the development and maintenance of the NMJ. In this review, we focus on the secreted signaling molecules which regulate the clustering of acetylcholine receptors (AChRs) at the NMJ. We first discuss the signaling pathway comprised of neural agrin and its receptors, low-density lipoprotein receptor-related protein 4 (Lrp4) and muscle-specific receptor tyrosine kinase (MuSK). This pathway drives the clustering of acetylcholine receptors (AChRs) to ensure efficient signal transduction at the NMJ. We also discuss three secreted molecules (Rspo2, Fgf18, and connective tissue growth factor (Ctgf)) that we recently identified in the Wnt/β-catenin and fibroblast growth factors (FGF) signaling pathways. The three secreted molecules facilitate the clustering of AChRs by enhancing the agrin-Lrp4-MuSK signaling pathway.
9
Sugiura, Yoshie, and Weichun Lin. "Neuron–glia interactions: the roles of Schwann cells in neuromuscular synapse formation and function." Bioscience Reports 31, no. 5 (2011): 295–302. http://dx.doi.org/10.1042/bsr20100107.
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The NMJ (neuromuscular junction) serves as the ultimate output of the motor neurons. The NMJ is composed of a presynaptic nerve terminal, a postsynaptic muscle and perisynaptic glial cells. Emerging evidence has also demonstrated an existence of perisynaptic fibroblast-like cells at the NMJ. In this review, we discuss the importance of Schwann cells, the glial component of the NMJ, in the formation and function of the NMJ. During development, Schwann cells are closely associated with presynaptic nerve terminals and are required for the maintenance of the developing NMJ. After the establishment of the NMJ, Schwann cells actively modulate synaptic activity. Schwann cells also play critical roles in regeneration of the NMJ after nerve injury. Thus, Schwann cells are indispensable for formation and function of the NMJ. Further examination of the interplay among Schwann cells, the nerve and the muscle will provide insights into a better understanding of mechanisms underlying neuromuscular synapse formation and function.
10
Shyng, S. L., and M. M. Salpeter. "Degradation rate of acetylcholine receptors inserted into denervated vertebrate neuromuscular junctions." Journal of Cell Biology 108, no. 2 (1989): 647–51. http://dx.doi.org/10.1083/jcb.108.2.647.
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Many studies exist on the effect of denervation on the degradation of acetylcholine receptors (AChRs) at the vertebrate neuromuscular junction (nmj). These studies have described the behavior of either the total population of junctional receptors at different times after denervation, or of the receptors present at the time of denervation (referred to as original receptors). No experimental studies yet exist on the degradation rate of the receptors newly inserted into denervated junctions. In the previous studies, the original receptors of mouse sternomastoid muscles were found to retain the slow degradation (t 1/2) of approximately 8-10 d of innervated junctional receptors for up to 10 d after denervation before accelerating to a t 1/2 of approximately 3 d. The total junctional receptors, on the other hand, showed a progressive increase in degradation rate from a t 1/2 of 8-10 d to a t 1/2 of 1 d. To reconcile these earlier observations, the present study examines the degradation of new receptors inserted into the nmj after denervation. To avoid possible contamination of the data with postdenervation extrajunctional receptors, we used transmission electron microscope autoradiography to study only receptors located at the postjunctional fold of the nmj. We established that the new receptors inserted into denervated junctions have a t 1/2 of approximately 1 d, considerably faster than that of the original receptors and equivalent to that of postdenervation extrajunctional receptors. Both original and new receptors are interspersed at the top of the junctional folds. Thus, until all the original receptors are degraded, the postjunctional membrane contains two populations of AChRs that maintain a total steady-state site density but degrade at different rates. The progressive increase in turnover rate of total AChRs therefore reflects the combined rates of the original and new receptors, as earlier postulated by Levitt and Salpeter (1981).
11
Krakora, Dan, Corey Macrander, and Masatoshi Suzuki. "Neuromuscular Junction Protection for the Potential Treatment of Amyotrophic Lateral Sclerosis." Neurology Research International 2012 (2012): 1–8. http://dx.doi.org/10.1155/2012/379657.
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Amyotrophic lateral sclerosis (ALS) is a neuromuscular disease characterized by the progressive degeneration of upper and lower motor neurons (MNs), leading to muscular atrophy and eventual respiratory failure. ALS research has primarily focused on mechanisms regarding MN cell death; however, degenerative processes in the skeletal muscle, particularly involving neuromuscular junctions (NMJs), are observed in the early stages of and throughout disease progression. According to the “dying-back” hypothesis, NMJ degeneration may not only precede, but actively cause upper and lower MN loss. The importance of NMJ pathology has relatively received little attention in ALS, possibly because compensatory mechanisms mask NMJ loss for prolonged periods. Many mechanisms explaining NMJ degeneration have been proposed such as the disruption of anterograde/retrograde axonal transport, irregular cellular metabolism, and changes in muscle gene and protein expression. Neurotrophic factors, which are known to have neuroprotective and regenerative properties, have been intensely investigated for their therapeutic potential in both the preclinical and clinical setting. Additional research should focus on the potential of preserving NMJs in order to delay or prevent disease progression
12
Charoensook, Surapon N., Damian J. Williams, Syandan Chakraborty, Kam W. Leong, and Gordana Vunjak-Novakovic. "Bioreactor model of neuromuscular junction with electrical stimulation for pharmacological potency testing." Integrative Biology 9, no. 12 (2017): 956–67. http://dx.doi.org/10.1039/c7ib00144d.
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Dobrowolny, Gabriella, Alessandra Barbiera, Gigliola Sica, and Bianca Maria Scicchitano. "Age-Related Alterations at Neuromuscular Junction: Role of Oxidative Stress and Epigenetic Modifications." Cells 10, no. 6 (2021): 1307. http://dx.doi.org/10.3390/cells10061307.
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With advancing aging, a decline in physical abilities occurs, leading to reduced mobility and loss of independence. Although many factors contribute to the physio-pathological effects of aging, an important event seems to be related to the compromised integrity of the neuromuscular system, which connects the brain and skeletal muscles via motoneurons and the neuromuscular junctions (NMJs). NMJs undergo severe functional, morphological, and molecular alterations during aging and ultimately degenerate. The effect of this decline is an inexorable decrease in skeletal muscle mass and strength, a condition generally known as sarcopenia. Moreover, several studies have highlighted how the age-related alteration of reactive oxygen species (ROS) homeostasis can contribute to changes in the neuromuscular junction morphology and stability, leading to the reduction in fiber number and innervation. Increasing evidence supports the involvement of epigenetic modifications in age-dependent alterations of the NMJ. In particular, DNA methylation, histone modifications, and miRNA-dependent gene expression represent the major epigenetic mechanisms that play a crucial role in NMJ remodeling. It is established that environmental and lifestyle factors, such as physical exercise and nutrition that are susceptible to change during aging, can modulate epigenetic phenomena and attenuate the age-related NMJs changes. This review aims to highlight the recent epigenetic findings related to the NMJ dysregulation during aging and the role of physical activity and nutrition as possible interventions to attenuate or delay the age-related decline in the neuromuscular system.
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Xiao, Yatao, Jianmin Zhang, Xiaoqiu Shu, et al. "Loss of mitochondrial protein CHCHD10 in skeletal muscle causes neuromuscular junction impairment." Human Molecular Genetics 29, no. 11 (2019): 1784–96. http://dx.doi.org/10.1093/hmg/ddz154.
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Abstract The neuromuscular junction (NMJ) is a synapse between motoneurons and skeletal muscles to control motor behavior. Acetylcholine receptors (AChRs) are restricted at the synaptic region for proper neurotransmission. Mutations in the mitochondrial CHCHD10 protein have been identified in multiple neuromuscular disorders; however, the physiological roles of CHCHD10 at NMJs remain elusive. Here, we report that CHCHD10 is highly expressed at the postsynapse of NMJs in skeletal muscles. Muscle conditional knockout CHCHD10 mice showed motor defects, abnormal neuromuscular transmission and NMJ structure. Mechanistically, we found that mitochondrial CHCHD10 is required for ATP production, which facilitates AChR expression and promotes agrin-induced AChR clustering. Importantly, ATP could effectively rescue the reduction of AChR clusters in the CHCHD10-ablated muscles. Our study elucidates a novel physiological role of CHCHD10 at the peripheral synapse. It suggests that mitochondria dysfunction contributes to neuromuscular pathogenesis.
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Barbeau, Susie, Julie Tahraoui-Bories, Claire Legay, and Cécile Martinat. "Building neuromuscular junctions in vitro." Development 147, no. 22 (2020): dev193920. http://dx.doi.org/10.1242/dev.193920.
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ABSTRACTThe neuromuscular junction (NMJ) has been the model of choice to understand the principles of communication at chemical synapses. Following groundbreaking experiments carried out over 60 years ago, many studies have focused on the molecular mechanisms underlying the development and physiology of these synapses. This Review summarizes the progress made to date towards obtaining faithful models of NMJs in vitro. We provide a historical approach discussing initial experiments investigating NMJ development and function from Xenopus to mice, the creation of chimeric co-cultures, in vivo approaches and co-culture methods from ex vivo and in vitro derived cells, as well as the most recent developments to generate human NMJs. We discuss the benefits of these techniques and the challenges to be addressed in the future for promoting our understanding of development and human disease.
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Nazarian, Javad, Khaled Bouri, and Eric P. Hoffman. "Intracellular expression profiling by laser capture microdissection: three novel components of the neuromuscular junction." Physiological Genomics 21, no. 1 (2005): 70–80. http://dx.doi.org/10.1152/physiolgenomics.00227.2004.
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The neuromuscular junction (NMJ) is a regionally specialized area of myofibers defined, in part, by specific gene expression from underlying myonuclei. We sought to obtain a more complete picture of the mRNA transcripts and proteins playing a role in NMJ formation and maintenance using laser capture microdissection (LCM) and to define expression profiles of the nuclear domain at the NMJ. NMJs (800) were isolated from normal mouse tibialis anterior muscle by LCM, with an equal amount of adjacent non-NMJ regions isolated. Many known components of the NMJ were found significantly differentially expressed. Three differentially expressed potential novel components of the NMJ were chosen for further study, and each was validated by immunostaining with and without blocking peptides (3/3), quantitative RT-PCR (3/3), and in situ hybridization (1/3). The three genes validated were dual-specificity phosphatase-6 (DUSP6), ribosomal receptor-binding protein-1 (RRBP1), and vacuolar protein sorting-26 (VPS26). Query of each of these novel components in a 27-time point in vivo muscle regeneration series showed expression commensurate with previously known NMJ markers (nestin, α-ACh receptor). Understanding and discovering elements responsible for the integrity and function of NMJs is relevant to understanding neuromuscular diseases such as spinal muscular atrophy. Our LCM-based mRNA expression profiling provided us with new means of identification of specific genes potentially responsible for NMJ stability and function and new candidates for involvement in disease pathogenesis.
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Zuo, Yi, and Derron Bishop. "Glial imaging during synapse remodeling at the neuromuscular junction." Neuron Glia Biology 4, no. 4 (2008): 319–26. http://dx.doi.org/10.1017/s1740925x09990421.
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Glia are an indispensable structural and functional component of the synapse. They modulate synaptic transmission and also play important roles in synapse formation and maintenance. The vertebrate neuromuscular junction (NMJ) is a classic model synapse. Due to its large size, simplicity and accessibility, the NMJ has contributed greatly to our understanding of synapse development and organization. In the past decade, the NMJ has also emerged as an effective model for studying glia–synapse interactions, in part due to the development of various labeling techniques that permit NMJs and associated Schwann cells (the glia at NMJs) to be visualized in vitro and in vivo. These approaches have demonstrated that Schwann cells are actively involved in synapse remodeling both during early development and in post-injury reinnervation. In vivo imaging has also recently been combined with serial section transmission electron microscopic (ssTEM) reconstruction to directly examine the ultrastructural organization of remodeling NMJs. In this review, we focus on the anatomical studies of Schwann cell dynamics and their roles in formation, maturation and remodeling of vertebrate NMJs using the highest temporal and spatial resolution methods currently available.
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Giannoccaro, Maria Pia, Patrizia Avoni, and Rocco Liguori. "Presynaptic Paraneoplastic Disorders of the Neuromuscular Junction: An Update." Brain Sciences 11, no. 8 (2021): 1035. http://dx.doi.org/10.3390/brainsci11081035.
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The neuromuscular junction (NMJ) is the target of a variety of immune-mediated disorders, usually classified as presynaptic and postsynaptic, according to the site of the antigenic target and consequently of the neuromuscular transmission alteration. Although less common than the classical autoimmune postsynaptic myasthenia gravis, presynaptic disorders are important to recognize due to the frequent association with cancer. Lambert Eaton myasthenic syndrome is due to a presynaptic failure to release acetylcholine, caused by antibodies to the presynaptic voltage-gated calcium channels. Acquired neuromyotonia is a condition characterized by nerve hyperexcitability often due to the presence of antibodies against proteins associated with voltage-gated potassium channels. This review will focus on the recent developments in the autoimmune presynaptic disorders of the NMJ.
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Kamimura, Keisuke, Kohei Ueno, Jun Nakagawa, Rie Hamada, Minoru Saitoe, and Nobuaki Maeda. "Perlecan regulates bidirectional Wnt signaling at the Drosophila neuromuscular junction." Journal of Cell Biology 200, no. 2 (2013): 219–33. http://dx.doi.org/10.1083/jcb.201207036.
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Heparan sulfate proteoglycans (HSPGs) play pivotal roles in the regulation of Wnt signaling activity in several tissues. At the Drosophila melanogaster neuromuscular junction (NMJ), Wnt/Wingless (Wg) regulates the formation of both pre- and postsynaptic structures; however, the mechanism balancing such bidirectional signaling remains elusive. In this paper, we demonstrate that mutations in the gene of a secreted HSPG, perlecan/trol, resulted in diverse postsynaptic defects and overproduction of synaptic boutons at NMJ. The postsynaptic defects, such as reduction in subsynaptic reticulum (SSR), were rescued by the postsynaptic activation of the Frizzled nuclear import Wg pathway. In contrast, overproduction of synaptic boutons was suppressed by the presynaptic down-regulation of the canonical Wg pathway. We also show that Trol was localized in the SSR and promoted postsynaptic accumulation of extracellular Wg proteins. These results suggest that Trol bidirectionally regulates both pre- and postsynaptic activities of Wg by precisely distributing Wg at the NMJ.
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Smith, A. S. T., C. J. Long, K. Pirozzi, and J. J. Hickman. "A functional system for high-content screening of neuromuscular junctions in vitro." TECHNOLOGY 01, no. 01 (2013): 37–48. http://dx.doi.org/10.1142/s2339547813500015.
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High-content phenotypic screening systems are the logical extension of the current efficient, yet low information content, pre-clinical screens for drug discovery. A physiologically accurate in vitro neuromuscular junction (NMJ) screening system would therefore be of tremendous benefit to the study of peripheral neuropathies as well as for basic and applied neuromuscular research. To date, no fully-defined, selective assay system has been developed which would allow investigators to determine the functional output of cultured muscle fibers (myotubes) when stimulated via the NMJ in real time for both acute and chronic applications. Here we present the development of such a phenotypic screening model, along with evidence of NMJ formation and motoneuron initiated neuromuscular transmission in an automated system. Myotubes assembled on silicon cantilevers allowed for measurement of substrate deflection in response to contraction and provided the basis for monitoring the effect of controlled motoneuron stimulation on the contractile behavior. The effect was blocked by treatment with D-tubocurarine, confirming NMJ functionality in this highly multiplexed assay system.
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D’Este, Giorgia, Marco Stazi, Samuele Negro, et al. "Latrotoxin-Induced Neuromuscular Junction Degeneration Reveals Urocortin 2 as a Critical Contributor to Motor Axon Terminal Regeneration." International Journal of Molecular Sciences 23, no. 3 (2022): 1186. http://dx.doi.org/10.3390/ijms23031186.
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We used α-Latrotoxin (α-LTx), the main neurotoxic component of the black widow spider venom, which causes degeneration of the neuromuscular junction (NMJ) followed by a rapid and complete regeneration, as a molecular tool to identify by RNA transcriptomics factors contributing to the structural and functional recovery of the NMJ. We found that Urocortin 2 (UCN2), a neuropeptide involved in the stress response, is rapidly expressed at the NMJ after acute damage and that inhibition of CRHR2, the specific receptor of UCN2, delays neuromuscular transmission rescue. Experiments in neuronal cultures show that CRHR2 localises at the axonal tips of growing spinal motor neurons and that its expression inversely correlates with synaptic maturation. Moreover, exogenous UCN2 enhances the growth of axonal sprouts in cultured neurons in a CRHR2-dependent manner, pointing to a role of the UCN2-CRHR2 axis in the regulation of axonal growth and synaptogenesis. Consistently, exogenous administration of UCN2 strongly accelerates the regrowth of motor axon terminals degenerated by α-LTx, thereby contributing to the functional recovery of neuromuscular transmission after damage. Taken together, our results posit a novel role for UCN2 and CRHR2 as a signalling axis involved in NMJ regeneration.
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Connor, Nadine P., Tatsutoshi Suzuki, Gregory K. Sewall, Kyungah Lee, and Dennis M. Heisey. "Neuromuscular Junction Changes in Aged Rat Thyroarytenoid Muscle." Annals of Otology, Rhinology & Laryngology 111, no. 7 (2002): 579–86. http://dx.doi.org/10.1177/000348940211100703.
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Dynamic remodeling of neuromuscular junction (NMJ) structure is postulated as a cause of age-related muscular atrophy. Direct study of NMJ morphology in laryngeal muscles is important to our understanding of age-related decrements in voice and swallowing. The morphology of NMJs was studied in a rat model to compare young and old specimens of thyroarytenoid muscle — a muscle critical to airway protection and phonation. Fluorescent, triple-label immunohistochemical analysis and confocal microscopic visualization were used to analyze the structure of NMJs. We found that laryngeal NMJs underwent significant changes that were similar to those observed after denervation. Specifically, the axon terminal area was significantly reduced, there were a number of postsynaptic acetylcholine receptor areas unoccupied by nerve terminals, and there was increased variability in end plate architecture in the old muscles. The results of this study increase our understanding of the age-related morphological changes in the larynx, and may serve as a baseline to test the effectiveness of future interventions.
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Prakash, Y. S., L. E. Gosselin, W. Z. Zhan, and G. C. Sieck. "Alterations of diaphragm neuromuscular junctions with hypothyroidism." Journal of Applied Physiology 81, no. 3 (1996): 1240–48. http://dx.doi.org/10.1152/jappl.1996.81.3.1240.
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Hypothyroidism (HYPO) often manifests as neuromuscular symptoms; however, little is known about its effects on the neuromuscular junction (NMJ). The present study examined changes in NMJ morphology and neuromuscular transmission failure (NTF) in the rat diaphragm muscle (Dimus) after 3 wk of HYPO. Three-color fluorescence immunocytochemistry and confocal microscopy were used to simultaneously visualize nerve terminals and axons, motor end plates, and myosin heavy chain isoform expression in Dimus fibers. NTF was assessed in vitro by comparing muscle fatigue induced by nerve with that induced by direct muscle stimulation. Diameters of axons innervating type I fibers were 30% smaller in the HYPO Dimus than in control (CTL). Planar areas of nerve terminals and end plates on type I and IIa fibers were 15-35% smaller in HYPO than in CTL. The extent of overlap between nerve terminals and end plates of type I fibers was 10% less in HYPO. Susceptibility to NTF during repetitive nerve stimulation was 20% greater in the CTL Dimus than in HYPO; however, changes in NMJ morphology could not fully account or the effect of HYPO on NTF.
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Sieck, Gary C., Roland H. H. Van Balkom, Y. S. Prakash, Wen-Zhi Zhan, and P. N. Richard Dekhuijzen. "Corticosteroid effects on diaphragm neuromuscular junctions." Journal of Applied Physiology 86, no. 1 (1999): 114–22. http://dx.doi.org/10.1152/jappl.1999.86.1.114.
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The effects of corticosteroid (CS) treatment (prednisolone continuously administered subcutaneously at a flow rate of 2.5 μl/h, daily dose 5.6 mg/kg, for 3 wk) on neuromuscular junction (NMJ) morphology and neuromuscular transmission in rat diaphragm muscle (Dimus) were compared with weight-matched (Sham) and ad libitum fed control (Ctl) groups. Fibers were classified on the basis of myosin heavy chain (MHC) isoform expression. CS treatment caused significant atrophy of fibers expressing MHC2X(type IIx), either alone or with MHC2B(type IIx/b). Fibers expressing MHCslow(type I) and MHC2A(type IIa) were unaffected by CS. The planar areas of nerve terminals and motor endplates at type IIx/b fibers were smaller in CS-treated Dimuscompared with Sham and Ctl. However, CS-induced atrophy of type IIx/b fibers exceeded changes in NMJ morphology. Thus, when normalized for fiber diameter, NMJs were relatively larger in the CS-treated group compared with Ctl. Neuromuscular transmission failure, assessed in vitro by comparing force loss during repetitive (40 Hz) nerve vs. direct muscle stimulation, was less in CS-treated Dimus. These results indicate that alterations in NMJ morphology after CS treatment are dependent on fiber type and may contribute to improved neuromuscular transmission.
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Hui, Tiankun, Hongyang Jing, Tian Zhou, et al. "Increasing LRP4 diminishes neuromuscular deficits in a mouse model of Duchenne muscular dystrophy." Human Molecular Genetics 30, no. 17 (2021): 1579–90. http://dx.doi.org/10.1093/hmg/ddab135.
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Abstract Duchenne muscular dystrophy (DMD) is an X-linked neuromuscular disease characterized by progressive wasting of skeletal muscles. The neuromuscular junction (NMJ) is a synapse between motor neurons and skeletal muscle fibers, critical for the control of muscle contraction. The NMJ decline is observed in DMD patients, but the mechanism is unclear. LRP4 serves as a receptor for agrin, a proteoglycan secreted by motor neurons to induce NMJ, and plays a critical role in NMJ formation and maintenance. Interestingly, we found that protein levels of LRP4 were reduced both in muscles of the DMD patients and DMD model mdx mice. We explored whether increasing LRP4 is beneficial for DMD and crossed muscle-specific LRP4 transgenic mice with mdx mice (mdx; HSA-LRP4). The LRP4 transgene increased muscle strength, together with improved neuromuscular transmission in mdx mice. Furthermore, we found the LRP4 expression mitigated NMJ fragments and denervation in mdx mice. Mechanically, we showed that overexpression of LRP4 increased the activity of MuSK and expression of dystrophin-associated glycoprotein complex proteins in the mdx mice. Overall, our findings suggest that increasing LRP4 improves both function and structure of NMJ in the mdx mice and Agrin signaling might serve as a new therapeutic strategy in DMD.
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Cipriani, Silvia, Vietxuan Phan, Jean-Jacques Médard, et al. "Neuromuscular Junction Changes in a Mouse Model of Charcot-Marie-Tooth Disease Type 4C." International Journal of Molecular Sciences 19, no. 12 (2018): 4072. http://dx.doi.org/10.3390/ijms19124072.
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The neuromuscular junction (NMJ) appears to be a site of pathology in a number of peripheral nerve diseases. Charcot-Marie-Tooth (CMT) 4C is an autosomal recessive, early onset, demyelinating neuropathy. Numerous mutations in the SH3TC2 gene have been shown to underlie the condition often associated with scoliosis, foot deformities, and reduced nerve conduction velocities. Mice with exon 1 of the Sh3tc2 gene knocked out demonstrate many of the features seen in patients. To determine if NMJ pathology is contributory to the pathomechanisms of CMT4C we examined NMJs in the gastrocnemius muscle of SH3TC2-deficient mice. In addition, we performed proteomic assessment of the sciatic nerve to identify protein factors contributing to the NMJ alterations and the survival of demyelinated axons. Morphological and gene expression analysis of NMJs revealed a lack of continuity between the pre- and post-synaptic apparatus, increases in post-synaptic fragmentation and dispersal, and an increase in expression of the gamma subunit of the acetylcholine receptor. There were no changes in axonal width or the number of axonal inputs to the NMJ. Proteome investigations of the sciatic nerve revealed altered expression of extracellular matrix proteins important for NMJ integrity. Together these observations suggest that CMT4C pathology includes a compromised NMJ even in the absence of changes to the innervating axon.
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Wu, Min-Yi, Wen-Jun Zou, Daehoon Lee, Lin Mei, and Wen-Cheng Xiong. "APP in the Neuromuscular Junction for the Development of Sarcopenia and Alzheimer’s Disease." International Journal of Molecular Sciences 24, no. 9 (2023): 7809. http://dx.doi.org/10.3390/ijms24097809.
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Sarcopenia, an illness condition usually characterized by a loss of skeletal muscle mass and muscle strength or function, is often associated with neurodegenerative diseases, such as Alzheimer’s disease (AD), a common type of dementia, leading to memory loss and other cognitive impairment. However, the underlying mechanisms for their associations and relationships are less well understood. The App, a Mendelian gene for early-onset AD, encodes amyloid precursor protein (APP), a transmembrane protein enriched at both the neuromuscular junction (NMJ) and synapses in the central nervous system (CNS). Here, in this review, we highlight APP and its family members’ physiological functions and Swedish mutant APP (APPswe)’s pathological roles in muscles and NMJ. Understanding APP’s pathophysiological functions in muscles and NMJ is likely to uncover insights not only into neuromuscular diseases but also AD. We summarize key findings from the burgeoning literature, which may open new avenues to investigate the link between muscle cells and brain cells in the development and progression of AD and sarcopenia.
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Stanga, Serena, Marina Boido, and Pascal Kienlen-Campard. "How to Build and to Protect the Neuromuscular Junction: The Role of the Glial Cell Line-Derived Neurotrophic Factor." International Journal of Molecular Sciences 22, no. 1 (2020): 136. http://dx.doi.org/10.3390/ijms22010136.
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The neuromuscular junction (NMJ) is at the crossroad between the nervous system (NS) and the muscle. Following neurotransmitter release from the motor neurons (MNs), muscle contraction occurs and movement is generated. Besides eliciting muscle contraction, the NMJ represents a site of chemical bidirectional interplay between nerve and muscle with the active participation of Schwann cells. Indeed, signals originating from the muscle play an important role in synapse formation, stabilization, maintenance and function, both in development and adulthood. We focus here on the contribution of the Glial cell line-Derived Neurotrophic Factor (GDNF) to these processes and to its potential role in the protection of the NMJ during neurodegeneration. Historically related to the maintenance and survival of dopaminergic neurons of the substantia nigra, GDNF also plays a fundamental role in the peripheral NS (PNS). At this level, it promotes muscle trophism and it participates to the functionality of synapses. Moreover, compared to the other neurotrophic factors, GDNF shows unique peculiarities, which make its contribution essential in neurodegenerative disorders. While describing the known structural and functional changes occurring at the NMJ during neurodegeneration, we highlight the role of GDNF in the NMJ–muscle cross-talk and we review its therapeutic potential in counteracting the degenerative process occurring in the PNS in progressive and severe diseases such as Alzheimer’s disease (AD), Amyotrophic Lateral Sclerosis (ALS) and Spinal Muscular Atrophy (SMA). We also describe functional 3D neuromuscular co-culture systems that have been recently developed as a model for studying both NMJ formation in vitro and its involvement in neuromuscular disorders.
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Koneczny, Inga, and Ruth Herbst. "Myasthenia Gravis: Pathogenic Effects of Autoantibodies on Neuromuscular Architecture." Cells 8, no. 7 (2019): 671. http://dx.doi.org/10.3390/cells8070671.
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Myasthenia gravis (MG) is an autoimmune disease of the neuromuscular junction (NMJ). Autoantibodies target key molecules at the NMJ, such as the nicotinic acetylcholine receptor (AChR), muscle-specific kinase (MuSK), and low-density lipoprotein receptor-related protein 4 (Lrp4), that lead by a range of different pathogenic mechanisms to altered tissue architecture and reduced densities or functionality of AChRs, reduced neuromuscular transmission, and therefore a severe fatigable skeletal muscle weakness. In this review, we give an overview of the history and clinical aspects of MG, with a focus on the structure and function of myasthenic autoantigens at the NMJ and how they are affected by the autoantibodies’ pathogenic mechanisms. Furthermore, we give a short overview of the cells that are implicated in the production of the autoantibodies and briefly discuss diagnostic challenges and treatment strategies.
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Fahim, Mohamed A. "Endurance exercise modulates neuromuscular junction of C57BL/6NNia aging mice." Journal of Applied Physiology 83, no. 1 (1997): 59–66. http://dx.doi.org/10.1152/jappl.1997.83.1.59.
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Fahim, Mohamed A. Endurance exercise modulates neuromuscular junction of C57BL/6NNia aging mice. J. Appl. Physiol. 83(1): 59–66, 1997.—The effect of age and endurance exercise on the physiology and morphology of neuromuscular junctions (NMJ) of gluteus maximus muscle was studied in C57BL/6NNia mice. Mice were exercised, starting at 7 or 25 mo of age, at 28 m/min for 60 min/day, 5 days/wk for 12 wk, on a rodent treadmill. Intracellular recordings of spontaneous miniature endplate potentials (MEPP) and the quantal content of endplate potentials (EPP) were recorded from NMJ of 10- and 28-mo-old control and exercised mice. Endurance exercise resulted in significant increases in MEPP amplitudes (23%), quantal content, and safety margin, and a significant decrease in MEPP frequency of young mice, with no change in resting membrane potential or membrane capacitance. Three months of endurance exercise resulted in an increase in MEPP frequency (41%) and decreases in MEPP amplitudes (15%), quantal content, and safety margin of old mice. Endurance exercise resulted in significantly larger nerve terminals (24%) in young animals, suggesting functional adaptation. Nerve terminals in exercised 28-mo-old mice were smaller than in the corresponding control mice, an indication that exercise minimized age-related nerve terminal elaboration. It is concluded that the different physiological responses of young and old gluteus maximus muscles to endurance exercise parallel their morphological responses. This suggests that the mouse NMJ undergoes a process of physiological and morphological remodeling during aging, and such plasticity could be modulated differently by endurance exercise.
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Khosa, Shaweta, Bhavesh Trikamji, Gurveer S. Khosa, Hadi M. Khanli, and Shri K. Mishra. "An Overview of Neuromuscular Junction Aging Findings in Human and Animal Studies." Current Aging Science 12, no. 1 (2019): 28–34. http://dx.doi.org/10.2174/1874609812666190603165746.
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Background: Aging is a complex irreversible process that is not only related to an individual’s genetic make-up but also to lifestyle choices and environmental exposures. Like every other structure in human body, the Neuromuscular Junction (NMJ) is not averse to aging. Objectives: The prime objective is to analyse the microscopic and macroscopic changes at the NMJs with aging. Methods: For the purpose of review we evaluated data from resources like Pubmed, Ovid, UCLA libraries and USC libraries. Results: We review various morphological, physiological, immunological, and biochemical changes in NMJs with aging and their management. Conclusion: The alterations in NMJs secondary to aging are inevitable. It is vital that neurologists clearly understand the pathophysiology of NMJ aging and differentiate between physiological and pathological effects of aging. With the current knowledge of science, the changes in NMJ aging can be better prevented rather than cured.
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Walter, Lisa A., Lauren P. Blake, Yann S. Gallot, et al. "Effect of Denervation on XBP1 in Skeletal Muscle and the Neuromuscular Junction." International Journal of Molecular Sciences 23, no. 1 (2021): 169. http://dx.doi.org/10.3390/ijms23010169.
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Denervation of skeletal muscle is a debilitating consequence of injury of the peripheral nervous system, causing skeletal muscle to experience robust atrophy. However, the molecular mechanisms controlling the wasting of skeletal muscle due to denervation are not well understood. Here, we demonstrate that transection of the sciatic nerve in Sprague–Dawley rats induced robust skeletal muscle atrophy, with little effect on the neuromuscular junction (NMJ). Moreover, the following study indicates that all three arms of the unfolded protein response (UPR) are activated in denervated skeletal muscle. Specifically, ATF4 and ATF6 are elevated in the cytoplasm of skeletal muscle, while XBP1 is elevated in the nuclei of skeletal muscle. Moreover, XBP1 is expressed in the nuclei surrounding the NMJ. Altogether, these results endorse a potential role of the UPR and, specifically, XBP1 in the maintenance of both skeletal muscle and the NMJ following sciatic nerve transection. Further investigations into a potential therapeutic role concerning these mechanisms are needed.
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Shimizu, Kazunori, Haruo Kassai, Yuhei Kamei, et al. "Alignment of Skeletal Muscle Cells Facilitates Acetylcholine Receptor Clustering and Neuromuscular Junction Formation with Co-Cultured Human iPSC-Derived Motor Neurons." Cells 11, no. 23 (2022): 3760. http://dx.doi.org/10.3390/cells11233760.
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In vitro neuromuscular junction (NMJ) models are powerful tools for studying neuromuscular disorders. Although linearly patterned culture surfaces have been reported to be useful for the formation of in vitro NMJ models using mouse motor neuron (MNs) and skeletal muscle (SkM) myotubes, it is unclear how the linearly patterned culture surface increases acetylcholine receptor (AChR) clustering, one of the steps in the process of NMJ formation, and whether this increases the in vitro NMJ formation efficiency of co-cultured human MNs and SkM myotubes. In this study, we investigated the effects of a linearly patterned culture surface on AChR clustering in myotubes and examined the possible mechanism of the increase in AChR clustering using gene expression analysis, as well as the effects of the patterned surface on the efficiency of NMJ formation between co-cultured human SkM myotubes and human iPSC-derived MNs. Our results suggest that better differentiation of myotubes on the patterned surface, compared to the flat surface, induced gene expression of integrin α7 and AChR ε-subunit, thereby increasing AChR clustering. Furthermore, we found that the number of NMJs between human SkM cells and MNs increased upon co-culture on the linearly patterned surface, suggesting the usefulness of the patterned surface for creating in vitro human NMJ models.
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O’Connor, Kaela, Sally Spendiff, Hanns Lochmüller, and Rita Horvath. "Mitochondrial Mutations Can Alter Neuromuscular Transmission in Congenital Myasthenic Syndrome and Mitochondrial Disease." International Journal of Molecular Sciences 24, no. 10 (2023): 8505. http://dx.doi.org/10.3390/ijms24108505.
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Congenital myasthenic syndromes (CMS) are a group of rare, neuromuscular disorders that usually present in childhood or infancy. While the phenotypic presentation of these disorders is diverse, the unifying feature is a pathomechanism that disrupts neuromuscular transmission. Recently, two mitochondrial genes—SLC25A1 and TEFM—have been reported in patients with suspected CMS, prompting a discussion about the role of mitochondria at the neuromuscular junction (NMJ). Mitochondrial disease and CMS can present with similar symptoms, and potentially one in four patients with mitochondrial myopathy exhibit NMJ defects. This review highlights research indicating the prominent roles of mitochondria at both the pre- and postsynapse, demonstrating the potential for mitochondrial involvement in neuromuscular transmission defects. We propose the establishment of a novel subcategorization for CMS—mitochondrial CMS, due to unifying clinical features and the potential for mitochondrial defects to impede transmission at the pre- and postsynapse. Finally, we highlight the potential of targeting the neuromuscular transmission in mitochondrial disease to improve patient outcomes.
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Webster, Richard G., An E. Vanhaesebrouck, Susan E. Maxwell, et al. "Effect of salbutamol on neuromuscular junction function and structure in a mouse model of DOK7 congenital myasthenia." Human Molecular Genetics 29, no. 14 (2020): 2325–36. http://dx.doi.org/10.1093/hmg/ddaa116.
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Abstract Congenital myasthenic syndromes (CMS) are characterized by fatigable muscle weakness resulting from impaired neuromuscular transmission. β2-adrenergic agonists are an effective treatment for DOK7-CMS. DOK7 is a component within the AGRN-LRP4-MUSK-DOK7 signalling pathway that is key for the formation and maintenance of the synaptic structure of the neuromuscular junction (NMJ). The precise mechanism of action of β2-adrenergic agonists at the NMJ is not fully understood. In this study, we investigated whether β2-adrenergic agonists improve both neurotransmission and structural integrity of the NMJ in a mouse model of DOK7-CMS. Ex-vivo electrophysiological techniques and microscopy of the NMJ were used to study the effect of salbutamol, a β2-adrenergic agonist, on synaptic structure and function. DOK7-CMS model mice displayed a severe phenotype with reduced weight gain and perinatal lethality. Salbutamol treatment improved weight gain and survival in DOK7 myasthenic mice. Model animals had fewer active NMJs, detectable by endplate recordings, compared with age-matched wild-type littermates. Salbutamol treatment increased the number of detectable NMJs during endplate recording. Correspondingly, model mice had fewer acetylcholine receptor-stained NMJs detected by fluorescent labelling, but following salbutamol treatment an increased number were detectable. The data demonstrate that salbutamol can prolong survival and increase NMJ number in a severe model of DOK7-CMS.
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Ollivier-Lanvin, Karen, Michel A. Lemay, Alan Tessler, and Anthony S. Burns. "Neuromuscular transmission failure and muscle fatigue in ankle muscles of the adult rat after spinal cord injury." Journal of Applied Physiology 107, no. 4 (2009): 1190–94. http://dx.doi.org/10.1152/japplphysiol.00282.2009.
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Current evidence suggests that significant morphological changes occur in nerve-muscle connections caudal to spinal cord injury (SCI). To determine whether neuromuscular junction (NMJ) function is compromised after SCI, we investigated the contribution of NMJ failure to hindlimb muscle fatigue in control and spinalized adult rats. Repetitive supramaximal nerve stimulation was applied to two muscle-nerve preparations: medial gastrocnemius (MG)-tibial and tibialis anterior (TA)-peroneal. NMJ transmission failure was evident in control and SCI animals after repetitive stimulation. At 2 wk post-SCI, NMJ transmission failure was greater in SCI animals compared with controls, but the difference was not significant ( P = 0.205 for the MG and P = 0.053 for the TA). At 6 wk post-SCI, there was a significant but small difference in NMJ transmission failure for the TA between control and spinal animals. These results demonstrate that, although there may be a mild decrement in NMJ function, NMJ transmission remains largely intact for supramaximal nerve stimulation.
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Deschenes, Michael R., Mia K. Mifsud, Leah G. Patek, and Rachel E. Flannery. "Cellular and Subcellular Characteristics of Neuromuscular Junctions in Muscles with Disparate Duty Cycles and Myofiber Profiles." Cells 12, no. 3 (2023): 361. http://dx.doi.org/10.3390/cells12030361.
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The neuromuscular system accounts for a large portion (~40%) of whole body mass while enabling body movement, including physical work and exercise. At the core of this system is the neuromuscular junction (NMJ) which is the vital synapse transducing electrical impulses from the motor neurons to their post-synaptic myofibers. Recent findings suggest that subcellular features (active zones) of the NMJ are distinctly sensitive to changes in activity relative to cellular features (nerve terminal branches, vesicles, receptors) of the NMJ. In the present investigation, muscles with different recruitment patterns, functions, and myofiber type profiles (soleus, plantaris, extensor digitorum longus [EDL]) were studied to quantify both cellular and subcellular NMJ characteristics along with myofiber type profiles. Results indicated that, in general, dimensions of subcellular components of NMJs mirrored cellular NMJ features when examining inter-muscle NMJ architecture. Typically, it was noted that the NMJs of the soleus, with its most pronounced recruitment pattern, were larger (p < 0.05) than NMJs of less recruited muscles. Moreover, it was revealed that myofiber size did not dictate NMJ size as soleus muscles displayed the smallest fibers (p < 0.05) while the plantaris muscles exhibited the largest fibers. In total, these data show that activity determines the size of NMJs and that generally, size dimensions of cellular and subcellular components of the NMJ are matched, and that the size of NMJs and their underlying myofibers are uncoupled.
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O’Connor, Emily, George Cairns, Sally Spendiff, et al. "Modulation of Agrin and RhoA Pathways Ameliorates Movement Defects and Synapse Morphology in MYO9A-Depleted Zebrafish." Cells 8, no. 8 (2019): 848. http://dx.doi.org/10.3390/cells8080848.
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Congenital myasthenic syndromes (CMS) are a group of rare, inherited disorders characterised by impaired function of the neuromuscular junction (NMJ). This is due to defects in one of the many proteins associated with the NMJ. In three patients with CMS, missense mutations in a gene encoding an unconventional myosin protein, MYO9A, were identified as likely causing their disorder. Preliminary studies revealed a potential involvement of the RhoA/ROCK pathway and of a key NMJ protein, agrin, in the pathophysiology of MYO9A-depletion. In this study, a CRISPR/Cas9 approach was used to generate genetic mutants of MYO9A zebrafish orthologues, myo9aa/ab, to expand and refine the morphological analysis of the NMJ. Injection of NT1654, a synthetic agrin fragment compound, improved NMJ structure and zebrafish movement in the absence of Myo9aa/ab. In addition, treatment of zebrafish with fasudil, a ROCK inhibitor, also provided improvements to the morphology of NMJs in early development, as well as rescuing movement defects, but not to the same extent as NT1654 and not at later time points. Therefore, this study highlights a role for MYO9A at the NMJ, the first unconventional myosin motor protein associated with a neuromuscular disease, and provides a potential mechanism of action of MYO9A-pathophysiology.
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Levitan, E. S., and D. Shakiryanova. "Imaging Neuropeptide Release in the Drosophila Neuromuscular Junction (NMJ)." Cold Spring Harbor Protocols 2010, no. 12 (2010): pdb.prot5529. http://dx.doi.org/10.1101/pdb.prot5529.
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Yu, Zheng, Meiying Zhang, Hongyang Jing, et al. "Characterization of LRP4/Agrin Antibodies From a Patient With Myasthenia Gravis." Neurology 97, no. 10 (2021): e975-e987. http://dx.doi.org/10.1212/wnl.0000000000012463.
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Background and ObjectiveTo determine whether human anti-LRP4/agrin antibodies are pathogenic in mice and to investigate underpinning pathogenic mechanisms.MethodsImmunoglobulin (Ig) was purified from a patient with myasthenia gravis (MG) with anti-LRP4/agrin antibodies and transferred to mice. Mice were characterized for body weight, muscle strength, twitch and tetanic force, neuromuscular junction (NMJ) functions including compound muscle action potential (CMAP) and endplate potentials, and NMJ structure. Effects of the antibodies on agrin-elicited muscle-specific tyrosine kinase (MuSK) activation and AChR clustering were studied and the epitopes of these antibodies were identified.ResultsPatient Ig-injected mice had MG symptoms, including weight loss and muscle weakness. Decreased CMAPs, reduced twitch and tetanus force, compromised neuromuscular transmission, and NMJ fragmentation and distortion were detected in patient Ig-injected mice. Patient Ig inhibited agrin-elicited MuSK activation and AChR clustering. The patient Ig recognized the β3 domain of LRP4 and the C-terminus of agrin and reduced agrin-enhanced LRP4–MuSK interaction.DiscussionAnti-LRP4/agrin antibodies in the patient with MG is pathogenic. It impairs the NMJ by interrupting agrin-dependent LRP4–MuSK interaction.
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Carlson, Bruce M., Jean A. Carlson, Eduard I. Dedkov, and Ian S. McLennan. "Concentration of Caveolin-3 at the Neuromuscular Junction in Young and Old Rat Skeletal Muscle Fibers." Journal of Histochemistry & Cytochemistry 51, no. 9 (2003): 1113–18. http://dx.doi.org/10.1177/002215540305100901.
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Caveolin-3, a muscle-specific member of the caveolin family, is strongly localized to the neuromuscular junction (NMJ) in adult rat muscle fibers, where it co-localizes with α-bungarotoxin staining. In 24-month-old rats, less distinct staining corresponds with the normal aging changes in the NMJ. After denervation, the pattern and intensity of staining begin to break up as early as 3 days, and by 10 days little staining remains. The functional implications of this concentration of caveolin-3 at the NMJ remain obscure, but it is possible that its absence could account for some of the phenotypic characteristics of individuals with caveolin-3 mutations.
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Jones, Ross A., Caitlan D. Reich, Kosala N. Dissanayake, et al. "NMJ-morph reveals principal components of synaptic morphology influencing structure–function relationships at the neuromuscular junction." Open Biology 6, no. 12 (2016): 160240. http://dx.doi.org/10.1098/rsob.160240.
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The ability to form synapses is one of the fundamental properties required by the mammalian nervous system to generate network connectivity. Structural and functional diversity among synaptic populations is a key hallmark of network diversity, and yet we know comparatively little about the morphological principles that govern variability in the size, shape and strength of synapses. Using the mouse neuromuscular junction (NMJ) as an experimentally accessible model synapse, we report on the development of a robust, standardized methodology to facilitate comparative morphometric analysis of synapses (‘NMJ-morph’). We used NMJ-morph to generate baseline morphological reference data for 21 separate pre- and post-synaptic variables from 2160 individual NMJs belonging to nine anatomically distinct populations of synapses, revealing systematic differences in NMJ morphology between defined synaptic populations. Principal components analysis revealed that overall NMJ size and the degree of synaptic fragmentation, alongside pre-synaptic axon diameter, were the most critical parameters in defining synaptic morphology. ‘Average’ synaptic morphology was remarkably conserved between comparable synapses from the left and right sides of the body. Systematic differences in synaptic morphology predicted corresponding differences in synaptic function that were supported by physiological recordings, confirming the robust relationship between synaptic size and strength.
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Shen, Wei, and Barry Ganetzky. "Autophagy promotes synapse development in Drosophila." Journal of Cell Biology 187, no. 1 (2009): 71–79. http://dx.doi.org/10.1083/jcb.200907109.
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Autophagy, a lysosome-dependent degradation mechanism, mediates many biological processes, including cellular stress responses and neuroprotection. In this study, we demonstrate that autophagy positively regulates development of the Drosophila melanogaster larval neuromuscular junction (NMJ). Autophagy induces an NMJ overgrowth phenotype closely resembling that of highwire (hiw), an E3 ubiquitin ligase mutant. Moreover, like hiw, autophagy-induced NMJ overgrowth is suppressed by wallenda (wnd) and by a dominant-negative c-Jun NH2-terminal kinase (bskDN). We show that autophagy promotes NMJ growth by reducing Hiw levels. Thus, autophagy and the ubiquitin–proteasome system converge in regulating synaptic development. Because autophagy is triggered in response to many environmental cues, our findings suggest that it is perfectly positioned to link environmental conditions with synaptic growth and plasticity.
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Han, Tae Hee, Poorva Dharkar, Mark L. Mayer, and Mihaela Serpe. "Functional reconstitution of Drosophila melanogaster NMJ glutamate receptors." Proceedings of the National Academy of Sciences 112, no. 19 (2015): 6182–87. http://dx.doi.org/10.1073/pnas.1500458112.
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The Drosophila larval neuromuscular junction (NMJ), at which glutamate acts as the excitatory neurotransmitter, is a widely used model for genetic analysis of synapse function and development. Despite decades of study, the inability to reconstitute NMJ glutamate receptor function using heterologous expression systems has complicated the analysis of receptor function, such that it is difficult to resolve the molecular basis for compound phenotypes observed in mutant flies. We find that Drosophila Neto functions as an essential component required for the function of NMJ glutamate receptors, permitting analysis of glutamate receptor responses in Xenopus oocytes. In combination with a crystallographic analysis of the GluRIIB ligand binding domain, we use this system to characterize the subunit dependence of assembly, channel block, and ligand selectivity for Drosophila NMJ glutamate receptors.
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Kautu, Bwarenaba B., Juliana Phillips, Kellie Steele, M. Shawn Mengarelli, and Eric A. Nord. "A Behavioral Survey of the Effects of Kavalactones on Caenorhabditis elegans Neuromuscular Transmission." Journal of Experimental Neuroscience 11 (January 1, 2017): 117906951770538. http://dx.doi.org/10.1177/1179069517705384.
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Kava is a plant root extract that is widely consumed by Pacific Islanders. Kava contains a class of lactone compounds called kavalactones. The sedative and anxiolytic effects of kava are likely attributed to the efficacies of kavalactones on the nervous system. Although some studies have implicated the potencies of certain kavalactone species on γ-aminobutyric acid transmission, evidence supporting the action of kavalactones on the eukaryotic neuromuscular junction (NMJ) and acetylcholine (ACh) transmission is scant. Here, we used behavioral assays to demonstrate the effects of kavalactones at the Caenorhabditis elegans NMJ. Our results suggest that kavalactones disrupt the inhibitory-excitatory balance at the NMJ. Such perturbation of NMJ activity is likely due to excess or prolonged ACh transmission. In addition, we found that kavain, a major constituent of kava, induced worm paralysis but not convulsions. Hence, the modulatory action of kavain could be distinct from the other kavalactone species.
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Martinez-Pena y Valenzuela, Isabel, and Mohammed Akaaboune. "The Metabolic Stability of the Nicotinic Acetylcholine Receptor at the Neuromuscular Junction." Cells 10, no. 2 (2021): 358. http://dx.doi.org/10.3390/cells10020358.
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The clustering and maintenance of nicotinic acetylcholine receptors (AChRs) at high density in the postsynaptic membrane is a hallmark of the mammalian neuromuscular junction (NMJ). The regulation of receptor density/turnover rate at synapses is one of the main thrusts of neurobiology because it plays an important role in synaptic development and synaptic plasticity. The state-of-the-art imaging revealed that AChRs are highly dynamic despite the overall structural stability of the NMJ over the lifetime of the animal. This review highlights the work on the metabolic stability of AChRs at developing and mature NMJs and discusses the role of synaptic activity and the regulatory signaling pathways involved in the dynamics of AChRs.
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Deconinck, Anne E., Allyson C. Potter, Jonathon M. Tinsley, et al. "Postsynaptic Abnormalities at the Neuromuscular Junctions of Utrophin-deficient Mice." Journal of Cell Biology 136, no. 4 (1997): 883–94. http://dx.doi.org/10.1083/jcb.136.4.883.
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Utrophin is a dystrophin-related cytoskeletal protein expressed in many tissues. It is thought to link F-actin in the internal cytoskeleton to a transmembrane protein complex similar to the dystrophin protein complex (DPC). At the adult neuromuscular junction (NMJ), utrophin is precisely colocalized with acetylcholine receptors (AChRs) and recent studies have suggested a role for utrophin in AChR cluster formation or maintenance during NMJ differentiation. We have disrupted utrophin expression by gene targeting in the mouse. Such mice have no utrophin detectable by Western blotting or immunocytochemistry. Utrophindeficient mice are healthy and show no signs of weakness. However, their NMJs have reduced numbers of AChRs (α-bungarotoxin [α-BgTx] binding reduced to ∼60% normal) and decreased postsynaptic folding, though only minimal electrophysiological changes. Utrophin is thus not essential for AChR clustering at the NMJ but may act as a component of the postsynaptic cytoskeleton, contributing to the development or maintenance of the postsynaptic folds. Defects of utrophin could underlie some forms of congenital myasthenic syndrome in which a reduction of postsynaptic folds is observed.
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Pęziński, Marcin, Kamila Maliszewska-Olejniczak, Patrycja Daszczuk, Paula Mazurek, Paweł Niewiadomski, and Maria Jolanta Rędowicz. "Tks5 Regulates Synaptic Podosome Formation and Stabilization of the Postsynaptic Machinery at the Neuromuscular Junction." International Journal of Molecular Sciences 22, no. 21 (2021): 12051. http://dx.doi.org/10.3390/ijms222112051.
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Currently, the etiology of many neuromuscular disorders remains unknown. Many of them are characterized by aberrations in the maturation of the neuromuscular junction (NMJ) postsynaptic machinery. Unfortunately, the molecular factors involved in this process are still largely unknown, which poses a great challenge for identifying potential therapeutic targets. Here, we identified Tks5 as a novel interactor of αdystrobrevin-1, which is a crucial component of the NMJ postsynaptic machinery. Tks5 has been previously shown in cancer cells to be an important regulator of actin-rich structures known as invadosomes. However, a role of this scaffold protein at a synapse has never been studied. We show that Tks5 is crucial for remodeling of the NMJ postsynaptic machinery by regulating the organization of structures similar to the invadosomes, known as synaptic podosomes. Additionally, it is involved in the maintenance of the integrity of acetylcholine receptor (AChR) clusters and regulation of their turnover. Lastly, our data indicate that these Tks5 functions may be mediated by its involvement in recruitment of actin filaments to the postsynaptic machinery. Collectively, we show for the first time that the Tks5 protein is involved in regulation of the postsynaptic machinery.
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Massaro, Catherine M., Jan Pielage, and Graeme W. Davis. "Molecular mechanisms that enhance synapse stability despite persistent disruption of the spectrin/ankyrin/microtubule cytoskeleton." Journal of Cell Biology 187, no. 1 (2009): 101–17. http://dx.doi.org/10.1083/jcb.200903166.
Full textAbstract:
Loss of spectrin or ankyrin in the presynaptic motoneuron disrupts the synaptic microtubule cytoskeleton and leads to disassembly of the neuromuscular junction (NMJ). Here, we demonstrate that NMJ disassembly after loss of α-spectrin can be suppressed by expression of a WldS transgene, providing evidence for a Wallerian-type degenerative mechanism. We then identify a second signaling system. Enhanced MAPK-JNK-Fos signaling suppresses NMJ disassembly despite loss of presynaptic α-spectrin or ankyrin2-L. This signaling system is activated after an acute cytoskeletal disruption, suggesting an endogenous role during neurological stress. This signaling system also includes delayed, negative feedback via the JNK phosphatase puckered, which inhibits JNK-Fos to allow NMJ disassembly in the presence of persistent cytoskeletal stress. Finally, the MAPK-JNK pathway is not required for baseline NMJ stabilization during normal NMJ growth. We present a model in which signaling via JNK-Fos functions as a stress response system that is transiently activated after cytoskeletal disruption to enhance NMJ stability, and is then shut off allowing NMJ disassembly during persistent cytoskeletal disruption.
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Ginebaugh, Scott P., Yomna Badawi, Tyler B. Tarr, and Stephen D. Meriney. "Neuromuscular Active Zone Structure and Function in Healthy and Lambert-Eaton Myasthenic Syndrome States." Biomolecules 12, no. 6 (2022): 740. http://dx.doi.org/10.3390/biom12060740.
Full textAbstract:
The mouse neuromuscular junction (NMJ) has long been used as a model synapse for the study of neurotransmission in both healthy and disease states of the NMJ. Neurotransmission from these neuromuscular nerve terminals occurs at highly organized structures called active zones (AZs). Within AZs, the relationships between the voltage-gated calcium channels and docked synaptic vesicles govern the probability of acetylcholine release during single action potentials, and the short-term plasticity characteristics during short, high frequency trains of action potentials. Understanding these relationships is important not only for healthy synapses, but also to better understand the pathophysiology of neuromuscular diseases. In particular, we are interested in Lambert-Eaton myasthenic syndrome (LEMS), an autoimmune disorder in which neurotransmitter release from the NMJ decreases, leading to severe muscle weakness. In LEMS, the reduced neurotransmission is traditionally thought to be caused by the antibody-mediated removal of presynaptic voltage-gated calcium channels. However, recent experimental data and AZ computer simulations have predicted that a disruption in the normally highly organized active zone structure, and perhaps autoantibodies to other presynaptic proteins, contribute significantly to pathological effects in the active zone and the characteristics of chemical transmitters.