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Cell Reports Nov 2017The neuromuscular junction (NMJ) plays a fundamental role in transferring information from lower motor neuron to skeletal muscle to generate movement. It is also an...
The neuromuscular junction (NMJ) plays a fundamental role in transferring information from lower motor neuron to skeletal muscle to generate movement. It is also an experimentally accessible model synapse routinely studied in animal models to explore fundamental aspects of synaptic form and function. Here, we combined morphological techniques, super-resolution imaging, and proteomic profiling to reveal the detailed cellular and molecular architecture of the human NMJ. Human NMJs were significantly smaller, less complex, and more fragmented than mouse NMJs. In contrast to mice, human NMJs were also remarkably stable across the entire adult lifespan, showing no signs of age-related degeneration or remodeling. Super-resolution imaging and proteomic profiling revealed distinctive distribution of active zone proteins and differential expression of core synaptic proteins and molecular pathways at the human NMJ. Taken together, these findings reveal human-specific cellular and molecular features of the NMJ that distinguish them from comparable synapses in other mammalian species.
Topics: Aging; Animals; Humans; Motor Neurons; Muscle, Skeletal; Nervous System; Neuromuscular Junction; Proteomics; Synapses; Synaptic Transmission
PubMed: 29186674
DOI: 10.1016/j.celrep.2017.11.008 -
Neurologic Clinics May 2018Neuromuscular junctions (NMJs) form between nerve terminals of spinal cord motor neurons and skeletal muscles, and perisynaptic Schwann cells and kranocytes cap NMJs.... (Review)
Review
Neuromuscular junctions (NMJs) form between nerve terminals of spinal cord motor neurons and skeletal muscles, and perisynaptic Schwann cells and kranocytes cap NMJs. One muscle fiber has one NMJ, which is innervated by one motor nerve terminal. NMJs are excitatory synapses that use P/Q-type voltage-gated calcium channels to release the neurotransmitter acetylcholine. Acetylcholine receptors accumulate at the postsynaptic specialization called the end plate on the muscle fiber membrane, the sarcolemma. Proteins essential for the organization of end plates include agrin secreted from nerve terminals, Lrp4 and MuSK receptors for agrin, and Dok-7 and rapsyn cytosolic proteins in the muscle.
Topics: Animals; Humans; Neuromuscular Junction
PubMed: 29655446
DOI: 10.1016/j.ncl.2018.01.009 -
Cellular and Molecular Life Sciences :... Mar 2015The neuromuscular junction (NMJ) is the synaptic connection between motor neurons and muscle fibers. It is involved in crucial processes such as body movements and... (Review)
Review
The neuromuscular junction (NMJ) is the synaptic connection between motor neurons and muscle fibers. It is involved in crucial processes such as body movements and breathing. Its proper development requires the guidance of motor axons toward their specific targets, the development of multi-innervated myofibers, and a selective synapse stabilization. It first consists of the removal of excessive motor axons on myofibers, going from multi-innervation to a single innervation of each myofiber. Whereas guidance cues of motor axons toward their specific muscular targets are well characterized, only few molecular and cellular cues have been reported as clues for selecting and stabilizing specific neuromuscular junctions. We will first provide a brief summary on NMJ development. We will then review molecular cues that are involved in NMJ stabilization, in both pre- and post-synaptic compartments, considering motor neurons and Schwann cells on the one hand, and muscle on the other hand. We will provide links with pathologies and highlight advances that can be brought both by basic research on NMJ development and clinical data resulting from the analyses of neurodegeneration of synaptic connections to obtain a better understanding of this process. The goal of this review is to highlight the findings toward understanding the roles of poly- or single-innervations and the underlying mechanisms of NMJ stabilization.
Topics: Animals; Axons; Humans; Motor Neurons; Muscles; Neuromuscular Junction; Synapses
PubMed: 25359233
DOI: 10.1007/s00018-014-1768-z -
International Journal of Molecular... Feb 2019A present review is devoted to the analysis of literature data and results of own research. Skeletal muscle neuromuscular junction is specialized to trigger the striated... (Review)
Review
A present review is devoted to the analysis of literature data and results of own research. Skeletal muscle neuromuscular junction is specialized to trigger the striated muscle fiber contraction in response to motor neuron activity. The safety factor at the neuromuscular junction strongly depends on a variety of pre- and postsynaptic factors. The review focuses on the crucial role of membrane cholesterol to maintain a high efficiency of neuromuscular transmission. Cholesterol metabolism in the neuromuscular junction, its role in the synaptic vesicle cycle and neurotransmitter release, endplate electrogenesis, as well as contribution of cholesterol to the synaptogenesis, synaptic integrity, and motor disorders are discussed.
Topics: Animals; Cholesterol; Humans; Neuromuscular Junction; Synaptic Transmission
PubMed: 30823359
DOI: 10.3390/ijms20051046 -
The Journal of Physiology Apr 2016Changes in the neuromuscular system affecting the ageing motor unit manifest structurally as a reduction in motor unit number secondary to motor neuron loss; fibre type... (Review)
Review
Changes in the neuromuscular system affecting the ageing motor unit manifest structurally as a reduction in motor unit number secondary to motor neuron loss; fibre type grouping due to repeating cycles of denervation-reinnervation; and instability of the neuromuscular junction that may be due to either or both of a gradual perturbation in postsynaptic signalling mechanisms necessary for maintenance of the endplate acetylcholine receptor clusters or a sudden process involving motor neuron death or traumatic injury to the muscle fibre. Functionally, these changes manifest as a reduction in strength and coordination that precedes a loss in muscle mass and contributes to impairments in fatigue. Regular muscle activation in postural muscles or through habitual physical activity can attenuate some of these structural and functional changes up to a point along the ageing continuum. On the other hand, regular muscle activation in advanced age (>75 years) loses its efficacy, and at least in rodents may exacerbate age-related motor neuron death. Transgenic mouse studies aimed at identifying potential mechanisms of motor unit disruptions in ageing muscle are not conclusive due to many different mechanisms converging on similar motor unit alterations, many of which phenocopy ageing muscle. Longitudinal studies of ageing models and humans will help clarify the cause and effect relationships and thus, identify relevant therapeutic targets to better preserve muscle function across the lifespan.
Topics: Animals; Humans; Muscle Strength; Muscle, Skeletal; Neuromuscular Junction
PubMed: 26437581
DOI: 10.1113/JP270561 -
Scientific Reports Mar 2022In needle electromyography, there are two spontaneous waveforms, miniature end plate potentials and "end plate spikes", appearing usually together. Miniature end plate...
In needle electromyography, there are two spontaneous waveforms, miniature end plate potentials and "end plate spikes", appearing usually together. Miniature end plate potentials are local, non-propagating postsynaptic waves, caused by spontaneous exocytosis of acetylcholine in the neuromuscular junction. The prevailing hypothesis states that "end plate spikes" are propagated postsynaptic action potentials of muscle fibers, caused by presynaptic irritation of the motor nerve or nerve terminal. Using several small concentric needle electrodes in parallel with the muscle fibers, most "end plate spikes" are strictly local or propagating for 2-4 mm. At the end plate zone, there are miniature end plate potentials without "end plate spikes". Local "end plate spikes" are junctional potentials of intrafusal gamma neuromuscular junctions of the nuclear bag fibers, and propagated "end plate spikes" are potentials of nuclear chain muscle fibers of muscle spindles. Miniature end plate potentials without "end plate spikes" at the end plate zone derive from alpha neuromuscular junctions. These findings contrast with the prevailing hypothesis. The history of observations and different hypotheses of the origin of end plate spikes are described.
Topics: Action Potentials; Electromyography; Motor Endplate; Muscle Spindles; Neuromuscular Junction
PubMed: 35273346
DOI: 10.1038/s41598-022-08239-4 -
Physiological Reviews Apr 2007This review is focused on purinergic neurotransmission, i.e., ATP released from nerves as a transmitter or cotransmitter to act as an extracellular signaling molecule on... (Review)
Review
This review is focused on purinergic neurotransmission, i.e., ATP released from nerves as a transmitter or cotransmitter to act as an extracellular signaling molecule on both pre- and postjunctional membranes at neuroeffector junctions and synapses, as well as acting as a trophic factor during development and regeneration. Emphasis is placed on the physiology and pathophysiology of ATP, but extracellular roles of its breakdown product, adenosine, are also considered because of their intimate interactions. The early history of the involvement of ATP in autonomic and skeletal neuromuscular transmission and in activities in the central nervous system and ganglia is reviewed. Brief background information is given about the identification of receptor subtypes for purines and pyrimidines and about ATP storage, release, and ectoenzymatic breakdown. Evidence that ATP is a cotransmitter in most, if not all, peripheral and central neurons is presented, as well as full accounts of neurotransmission and neuromodulation in autonomic and sensory ganglia and in the brain and spinal cord. There is coverage of neuron-glia interactions and of purinergic neuroeffector transmission to nonmuscular cells. To establish the primitive and widespread nature of purinergic neurotransmission, both the ontogeny and phylogeny of purinergic signaling are considered. Finally, the pathophysiology of purinergic neurotransmission in both peripheral and central nervous systems is reviewed, and speculations are made about future developments.
Topics: Adenosine Triphosphate; Aging; Animals; Autonomic Nervous System; Central Nervous System; Ganglia, Autonomic; Humans; Nervous System Diseases; Neuroeffector Junction; Neuroglia; Neurons, Afferent; Receptors, Purinergic; Synaptic Transmission
PubMed: 17429044
DOI: 10.1152/physrev.00043.2006 -
Biological Reviews of the Cambridge... Apr 2021The coordinated movement of many organisms relies on efficient nerve-muscle communication at the neuromuscular junction (NMJ), a peripheral synapse composed of a... (Review)
Review
The coordinated movement of many organisms relies on efficient nerve-muscle communication at the neuromuscular junction (NMJ), a peripheral synapse composed of a presynaptic motor axon terminal, a postsynaptic muscle specialization, and non-myelinating terminal Schwann cells. NMJ dysfunctions are caused by traumatic spinal cord or peripheral nerve injuries as well as by severe motor pathologies. Compared to the central nervous system, the peripheral nervous system displays remarkable regenerating abilities; however, this capacity is limited by the denervation time frame and depends on the establishment of permissive regenerative niches. At the injury site, detailed information is available regarding the cells, molecules, and mechanisms involved in nerve regeneration and repair. However, a regenerative niche at the final functional step of peripheral motor innervation, i.e. at the mature neuromuscular synapse, has not been deciphered. In this review, we integrate classic and recent evidence describing the cells and molecules that could orchestrate a dynamic ecosystem to accomplish successful NMJ regeneration. We propose that such a regenerative niche must ensure at least two fundamental steps for successful NMJ regeneration: the proper arrival of incoming regenerating axons to denervated postsynaptic muscle domains, and the resilience of those postsynaptic domains, in morphological and functional terms. We here describe and combine the main cellular and molecular responses involved in each of these steps as potential targets to help successful NMJ regeneration.
Topics: Ecosystem; Nerve Regeneration; Neuromuscular Junction; Recovery of Function; Synapses
PubMed: 33336525
DOI: 10.1111/brv.12675 -
The Journal of Cell Biology Apr 2021In this issue, Wang et al. (2021. J. Cell Biol.https://doi.org/10.1083/jcb.201911114) describe a phenomenon in which neuromuscular junction synapse elimination triggers...
In this issue, Wang et al. (2021. J. Cell Biol.https://doi.org/10.1083/jcb.201911114) describe a phenomenon in which neuromuscular junction synapse elimination triggers myelination of terminal motor axon branches. They propose a mechanism initiated by synaptic pruning that depends on synaptic activity, cytoskeletal maturation, and the associated anterograde transport of trophic factors including Neuregulin 1-III.
Topics: Axons; Neuromuscular Junction; Neuronal Plasticity
PubMed: 33734302
DOI: 10.1083/jcb.202102030 -
Neuroscience Letters Sep 2021Volumetric muscle loss (VML) following a severe trauma or injury is beyond the intrinsic regenerative capacity of muscle tissues, and hence interventional therapy is... (Review)
Review
Volumetric muscle loss (VML) following a severe trauma or injury is beyond the intrinsic regenerative capacity of muscle tissues, and hence interventional therapy is required. Extensive muscle loss concomitant with damage to neuromuscular components overwhelms the muscles' remarkable regenerative capacity. The loss of nervous and vascular tissue leads to further damage and atrophy, so a combined treatment for neuromuscular junction (NMJ) along with the volumetric muscle regeneration is important. There have been immense advances in the field of tissue engineering for skeletal muscle tissue and peripheral nerve regeneration, but very few address the interdependence of the tissues and the need for combined therapies to repair and regenerate fully functional muscle tissue. This review addresses the problem and presents an overview of the biomaterials that have been studied for tissue engineering of neuromuscular tissues associated with skeletal muscles.
Topics: Animals; Biocompatible Materials; Humans; Muscle, Skeletal; Nerve Regeneration; Neuromuscular Junction; Tissue Engineering
PubMed: 34332029
DOI: 10.1016/j.neulet.2021.136145