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150 Years of Motor Endplate: Molecules, Cells, and Relevance of...
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150 Years of Motor Endplate: Molecules, Cells, and Relevance of a Model Synapse

A special issue of Cells (ISSN 2073-4409).

Deadline for manuscript submissions: closed (30 June 2019) | Viewed by 71363

Special Issue Editor

Prof. Dr. Rüdiger Rudolf

E-Mail Website
Guest Editor
1. Institute of Molecular and Cell Biology, Faculty of Biotechnology, Mannheim University of Applied Sciences, Mannheim, Germany
2. Interdisciplinary Center for Neuroscience, Heidelberg University, Heidelberg, Germany
3. Institute of Toxicology and Genetics, Karlsruhe Institute of Technology, Eggenstein-Leopoldshafen, Germany
Interests: neuromuscular junction; 3D cell culture
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

More than 150 years after the terms ‘plaques nerveuses terminales’ and ‘motorische Endplatte’ were coined by Charles Rouget and Wilhelm Krause, respectively, the neuromuscular synapse continues to be crucial for the musculoskeletal and neural sciences. Having always served as a model in terms of morphological and molecular configuration of chemical synapses, recent research has renewed an interest in the involvement of the motor endplate in general systemic functions of muscle beyond inducing contraction. Along these lines, the endplate has lately also attracted increasing attention with respect to its role in pathophysiology and aging.

This Special Issue of Cells will focus on the progress in understanding the molecular and cellular frameworks that regulate and mediate formation, maintenance, and repair of the motor endplate in normal physiology and upon pathological conditions. Further, it will address consequences of these insights on treatment of neuromuscular diseases and muscle wasting conditions.

Dr. Rüdiger Rudolf
Guest Editor

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Keywords

  • neuromuscular synapse
  • muscle innervation
  • neuromuscular disorders
  • muscle wasting
  • muscle regeneration

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Published Papers (11 papers)

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Research

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16 pages, 2900 KiB  
Article
Loss of Protein Kinase Csnk2b/CK2β at Neuromuscular Junctions Affects Morphology and Dynamics of Aggregated Nicotinic Acetylcholine Receptors, Neuromuscular Transmission, and Synaptic Gene Expression
by Nane Eiber, Michael Rehman, Bojana Kravic, Rüdiger Rudolf, Marco Sandri and Said Hashemolhosseini
Cells 2019, 8(8), 940; https://doi.org/10.3390/cells8080940 - 20 Aug 2019
Cited by 12 | Viewed by 3944
Abstract
The protein kinase Csnk2/CK2 is important for cell proliferation, differentiation, and survival. Previously, we showed that CK2 binds distinctive proteins at neuromuscular junctions (NMJs) of mice and phosphorylates some of them. CK2 likely stabilizes clustered nicotinic acetylcholine receptors (AChRs). In the absence of [...] Read more.
The protein kinase Csnk2/CK2 is important for cell proliferation, differentiation, and survival. Previously, we showed that CK2 binds distinctive proteins at neuromuscular junctions (NMJs) of mice and phosphorylates some of them. CK2 likely stabilizes clustered nicotinic acetylcholine receptors (AChRs). In the absence of the β-subunit of CK2 in skeletal muscle fibers, mice develop an age-dependent decrease of grip strength accompanied by NMJ fragmentation and impairments of neuromuscular transmission. However, the precise role of CK2β regarding the clustering of AChRs and downstream signaling at NMJs is unknown. Here, we compared conditional CK2β-deficient mice with controls and found in the mutants (1) a lower decrement of endplate potentials after repetitive stimulation and decrements of nerve-evoked compound muscle action potentials decayed more rapidly after synaptic transmission was partially blocked, (2) that their muscle weakness was partially rescued by administration of an acetylcholine esterase inhibitor, (3) fragmented NMJs and impaired AChR clustering was detected in muscles and cultured muscle cells, (4) enlarged myonuclei, (5) impaired synaptic gene expression, and (6) a high turnover rate of their AChR clusters in vivo. Altogether, our data demonstrate a role for CK2 at the NMJ by maintaining a high density of AChRs and ensuring physiological synaptic gene expression. Full article
(This article belongs to the Special Issue 150 Years of Motor Endplate: Molecules, Cells, and Relevance of a Model Synapse)
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20 pages, 2954 KiB  
Article
Modulation of Agrin and RhoA Pathways Ameliorates Movement Defects and Synapse Morphology in MYO9A-Depleted Zebrafish
by Emily O’Connor, George Cairns, Sally Spendiff, David Burns, Stefan Hettwer, Armin Mäder, Juliane Müller, Rita Horvath, Clarke Slater, Andreas Roos and Hanns Lochmüller
Cells 2019, 8(8), 848; https://doi.org/10.3390/cells8080848 - 7 Aug 2019
Cited by 27 | Viewed by 5079
Abstract
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 [...] Read more.
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. Full article
(This article belongs to the Special Issue 150 Years of Motor Endplate: Molecules, Cells, and Relevance of a Model Synapse)
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22 pages, 2851 KiB  
Article
Regulation of Acetylcholine Quantal Release by Coupled Thrombin/BDNF Signaling in Mouse Motor Synapses
by Alexander Gaydukov, Polina Bogacheva, Ekaterina Tarasova, Anastasia Molchanova, Anna Miteva, Ekaterina Pravdivceva and Olga Balezina
Cells 2019, 8(7), 762; https://doi.org/10.3390/cells8070762 - 22 Jul 2019
Cited by 16 | Viewed by 4750
Abstract
The aim of this study was to compare the acute effects of thrombin and brain-derived neurotrophic factor (BDNF) on spontaneous miniature endplate potentials (MEPPs) and multiquantal evoked endplate potentials (EPPs) in mouse neuromuscular junctions (NMJs) of m. diaphragma and m. EDL. Intracellular microelectrode [...] Read more.
The aim of this study was to compare the acute effects of thrombin and brain-derived neurotrophic factor (BDNF) on spontaneous miniature endplate potentials (MEPPs) and multiquantal evoked endplate potentials (EPPs) in mouse neuromuscular junctions (NMJs) of m. diaphragma and m. EDL. Intracellular microelectrode recordings of MEPPs and EPPs were used to evaluate the changes in acetylcholine (ACh) release in mature and newly-formed mouse NMJs. Thrombin (1 nM) increased the amplitude of MEPPs and EPPs by 25–30% in mature and newly-formed NMJs. This effect was due to an enhanced loading of synaptic vesicles with ACh and increase of ACh quantal size, since it was fully prevented by blocking of vesicular ACh transporter. It was also prevented by tropomyosin-related kinase B (TrkB) receptors inhibitor ANA12. Exogenous BDNF (1 nM) mimicked thrombin effect and increased the amplitude of MEPPs and EPPs by 25–30%. It required involvement of protein kinase A (PKA) and mitogen-activated protein kinase (MEK1/2)-mediated pathway, but not phospholipase C (PLC). Blocking A2A adenosine receptors by ZM241385 abolished the effect of BDNF, whereas additional stimulation of A2A receptors by CGS21680 increased MEPP amplitudes, which was prevented by MEK1/2 inhibitor U0126. At mature NMJs, BDNF enhanced MEPPs frequency by 30–40%. This effect was selectively prevented by inhibition of PLC, but not PKA or MEK1/2. It is suggested that interrelated effects of thrombin/BDNF in mature and newly-formed NMJs are realized via enhancement of vesicular ACh transport and quantal size increase. BDNF-induced potentiation of synaptic transmission involves the functional coupling between A2A receptor-dependent active PKA and neurotrophin-triggered MAPK pathway, as well as PLC-dependent increase in frequency of MEPPs. Full article
(This article belongs to the Special Issue 150 Years of Motor Endplate: Molecules, Cells, and Relevance of a Model Synapse)
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Review

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9 pages, 5567 KiB  
Review
The Metabolic Stability of the Nicotinic Acetylcholine Receptor at the Neuromuscular Junction
by Isabel Martinez-Pena y Valenzuela and Mohammed Akaaboune
Cells 2021, 10(2), 358; https://doi.org/10.3390/cells10020358 - 9 Feb 2021
Cited by 23 | Viewed by 5220
Abstract
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 [...] Read more.
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. Full article
(This article belongs to the Special Issue 150 Years of Motor Endplate: Molecules, Cells, and Relevance of a Model Synapse)
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23 pages, 8540 KiB  
Review
Mitochondrial Mechanisms of Neuromuscular Junction Degeneration with Aging
by Maria-Eleni Anagnostou and Russell T. Hepple
Cells 2020, 9(1), 197; https://doi.org/10.3390/cells9010197 - 13 Jan 2020
Cited by 38 | Viewed by 8713
Abstract
Skeletal muscle deteriorates with aging, contributing to physical frailty, poor health outcomes, and increased risk of mortality. Denervation is a major driver of changes in aging muscle. This occurs through transient denervation-reinnervation events throughout the aging process that remodel the spatial domain of [...] Read more.
Skeletal muscle deteriorates with aging, contributing to physical frailty, poor health outcomes, and increased risk of mortality. Denervation is a major driver of changes in aging muscle. This occurs through transient denervation-reinnervation events throughout the aging process that remodel the spatial domain of motor units and alter fiber type. In advanced age, reinnervation wanes, leading to persistent denervation that accelerates muscle atrophy and impaired muscle contractility. Alterations in the muscle fibers and motoneurons are both likely involved in driving denervation through destabilization of the neuromuscular junction. In this respect, mitochondria are implicated in aging and age-related neurodegenerative disorders, and are also likely key to aging muscle changes through their direct effects in muscle fibers and through secondary effects mediated by mitochondrial impairments in motoneurons. Indeed, the large abundance of mitochondria in muscle fibers and motoneurons, that are further concentrated on both sides of the neuromuscular junction, likely renders the neuromuscular junction especially vulnerable to age-related mitochondrial dysfunction. Manifestations of mitochondrial dysfunction with aging include impaired respiratory function, elevated reactive oxygen species production, and increased susceptibility to permeability transition, contributing to reduced ATP generating capacity, oxidative damage, and apoptotic signaling, respectively. Using this framework, in this review we summarize our current knowledge, and relevant gaps, concerning the potential impact of mitochondrial impairment on the aging neuromuscular junction, and the mechanisms involved. Full article
(This article belongs to the Special Issue 150 Years of Motor Endplate: Molecules, Cells, and Relevance of a Model Synapse)
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12 pages, 1676 KiB  
Review
Glutamate at the Vertebrate Neuromuscular Junction: From Modulation to Neurotransmission
by Maria Nicol Colombo and Maura Francolini
Cells 2019, 8(9), 996; https://doi.org/10.3390/cells8090996 - 28 Aug 2019
Cited by 31 | Viewed by 5408
Abstract
Although acetylcholine is the major neurotransmitter operating at the skeletal neuromuscular junction of many invertebrates and of vertebrates, glutamate participates in modulating cholinergic transmission and plastic changes in the last. Presynaptic terminals of neuromuscular junctions contain and release glutamate that contribute to the [...] Read more.
Although acetylcholine is the major neurotransmitter operating at the skeletal neuromuscular junction of many invertebrates and of vertebrates, glutamate participates in modulating cholinergic transmission and plastic changes in the last. Presynaptic terminals of neuromuscular junctions contain and release glutamate that contribute to the regulation of synaptic neurotransmission through its interaction with pre- and post-synaptic receptors activating downstream signaling pathways that tune synaptic efficacy and plasticity. During vertebrate development, the chemical nature of the neurotransmitter at the vertebrate neuromuscular junction can be experimentally shifted from acetylcholine to other mediators (including glutamate) through the modulation of calcium dynamics in motoneurons and, when the neurotransmitter changes, the muscle fiber expresses and assembles new receptors to match the nature of the new mediator. Finally, in adult rodents, by diverting descending spinal glutamatergic axons to a denervated muscle, a functional reinnervation can be achieved with the formation of new neuromuscular junctions that use glutamate as neurotransmitter and express ionotropic glutamate receptors and other markers of central glutamatergic synapses. Here, we summarize the past and recent experimental evidences in support of a role of glutamate as a mediator at the synapse between the motor nerve ending and the skeletal muscle fiber, focusing on the molecules and signaling pathways that are present and activated by glutamate at the vertebrate neuromuscular junction. Full article
(This article belongs to the Special Issue 150 Years of Motor Endplate: Molecules, Cells, and Relevance of a Model Synapse)
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15 pages, 1420 KiB  
Review
Neuromuscular Junction as an Entity of Nerve-Muscle Communication
by Elisa Lepore, Irene Casola, Gabriella Dobrowolny and Antonio Musarò
Cells 2019, 8(8), 906; https://doi.org/10.3390/cells8080906 - 16 Aug 2019
Cited by 59 | Viewed by 11089
Abstract
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 [...] Read more.
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. Full article
(This article belongs to the Special Issue 150 Years of Motor Endplate: Molecules, Cells, and Relevance of a Model Synapse)
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35 pages, 2870 KiB  
Review
Myasthenia Gravis: Pathogenic Effects of Autoantibodies on Neuromuscular Architecture
by Inga Koneczny and Ruth Herbst
Cells 2019, 8(7), 671; https://doi.org/10.3390/cells8070671 - 2 Jul 2019
Cited by 108 | Viewed by 15124
Abstract
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 [...] Read more.
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. Full article
(This article belongs to the Special Issue 150 Years of Motor Endplate: Molecules, Cells, and Relevance of a Model Synapse)
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20 pages, 1301 KiB  
Review
Motor Endplate—Anatomical, Functional, and Molecular Concepts in the Historical Perspective
by Rüdiger Rudolf, Muzamil Majid Khan and Veit Witzemann
Cells 2019, 8(5), 387; https://doi.org/10.3390/cells8050387 - 27 Apr 2019
Cited by 29 | Viewed by 7123
Abstract
By mediating voluntary muscle movement, vertebrate neuromuscular junctions (NMJ) play an extraordinarily important role in physiology. While the significance of the nerve-muscle connectivity was already conceived almost 2000 years back, the precise cell and molecular biology of the NMJ have been revealed in [...] Read more.
By mediating voluntary muscle movement, vertebrate neuromuscular junctions (NMJ) play an extraordinarily important role in physiology. While the significance of the nerve-muscle connectivity was already conceived almost 2000 years back, the precise cell and molecular biology of the NMJ have been revealed in a series of fascinating research activities that started around 180 years ago and that continues. In all this time, NMJ research has led to fundamentally new concepts of cell biology, and has triggered groundbreaking advancements in technologies. This review tries to sketch major lines of thought and concepts on NMJ in their historical perspective, in particular with respect to anatomy, function, and molecular components. Furthermore, along these lines, it emphasizes the mutual benefit between science and technology, where one drives the other. Finally, we speculate on potential major future directions for studies on NMJ in these fields. Full article
(This article belongs to the Special Issue 150 Years of Motor Endplate: Molecules, Cells, and Relevance of a Model Synapse)
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Other

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3 pages, 182 KiB  
Reply
mtDNA Mutation Accumulation in Muscle Is Not a Major Cause of Fiber Loss. Reply to “Comment on: Mitochondrial Mechanisms of Neuromuscular Junction Degeneration with Aging. Cells 2020, 9, 197”
by Russell T. Hepple
Cells 2020, 9(8), 1821; https://doi.org/10.3390/cells9081821 - 1 Aug 2020
Cited by 1 | Viewed by 1771
Abstract
I thank you for your comment on our review paper [...] Full article
(This article belongs to the Special Issue 150 Years of Motor Endplate: Molecules, Cells, and Relevance of a Model Synapse)
4 pages, 206 KiB  
Comment
Comment on: “Mitochondrial Mechanisms of Neuromuscular Junction Degeneration with Aging. Cells 2020, 9, 197”
by Allen Herbst, Judd M. Aiken, Debbie McKenzie and Jonathan Wanagat
Cells 2020, 9(8), 1796; https://doi.org/10.3390/cells9081796 - 29 Jul 2020
Cited by 1 | Viewed by 1984
Abstract
“The main conclusions are that the ageing atrophy begins as early as around 25 years of age and thereafter accelerates and, for this muscle, is caused mainly by a loss of fibers and to a lesser extent by a reduction in fiber size [...] Read more.
“The main conclusions are that the ageing atrophy begins as early as around 25 years of age and thereafter accelerates and, for this muscle, is caused mainly by a loss of fibers and to a lesser extent by a reduction in fiber size [...] Full article
(This article belongs to the Special Issue 150 Years of Motor Endplate: Molecules, Cells, and Relevance of a Model Synapse)
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