scholarly journals An Agonist of the CXCR4 Receptor Strongly Promotes Regeneration of Degenerated Motor Axon Terminals

Cells ◽  
2019 ◽  
Vol 8 (10) ◽  
pp. 1183 ◽  
Author(s):  
Negro ◽  
Zanetti ◽  
Mattarei ◽  
Valentini ◽  
Megighian ◽  
...  
Keyword(s):  
Functional Recovery ◽  
Neuromuscular Junctions ◽  
Recovery Of Function ◽  
Motor Axon ◽  
Cxcr4 Antagonist ◽  
Axon Terminals ◽  
Stem Cell Migration ◽  
Natural Ligand ◽  
Nerve Recovery ◽  
Strong Candidate

The activation of the G-protein coupled receptor CXCR4 by its ligand CXCL12α is involved in a large variety of physiological and pathological processes, including the growth of B cells precursors and of motor axons, autoimmune diseases, stem cell migration, inflammation, and several neurodegenerative conditions. Recently, we demonstrated that CXCL12α potently stimulates the functional recovery of damaged neuromuscular junctions via interaction with CXCR4. This result prompted us to test the neuroregeneration activity of small molecules acting as CXCR4 agonists, endowed with better pharmacokinetics with respect to the natural ligand. We focused on NUCC-390, recently shown to activate CXCR4 in a cellular system. We designed a novel and convenient chemical synthesis of NUCC-390, which is reported here. NUCC-390 was tested for its capability to induce the regeneration of motor axon terminals completely degenerated by the presynaptic neurotoxin α-Latrotoxin. NUCC-390 was found to strongly promote the functional recovery of the neuromuscular junction, as assayed by electrophysiology and imaging. This action is CXCR4 dependent, as it is completely prevented by AMD3100, a well-characterized CXCR4 antagonist. These data make NUCC-390 a strong candidate to be tested in human therapy to promote nerve recovery of function after different forms of neurodegeneration.

scholarly journals The mechanism of agrin-induced acetylcholine receptor aggregation

1991 ◽  
Vol 331 (1261) ◽  
pp. 273-280 ◽  
Keyword(s):  
Neuromuscular Junction ◽  
Tyrosine Phosphorylation ◽  
Acetylcholine Receptor ◽  
Acetylcholine Receptors ◽  
Neuromuscular Junctions ◽  
Electric Organ ◽  
Motor Axon ◽  
Β Subunit ◽  
Axon Terminals ◽  
Receptor Aggregation

Agrin, a protein isolated from the synapse-rich electric organ of Torpedo californica , induces the formation of specializations on myotubes in culture which resemble the post-synaptic apparatus at the vertebrate skeletal neuromuscular junction. For example, the specializations contain aggregates of acetylcholine receptors and acetylcholinesterase. This report summarizes the evidence that the formation of the postsynaptic apparatus at developing and regenerating neuromuscular junctions is triggered by the release of agrin from motor axon terminals and describes results of recent experiments which suggest that agrininduced tyrosine phosphorylation of the β subunit of the acetylcholine receptor may play a role in receptor aggregation.

Proportion of muscles spindles supplied by skeletofusimotor axons (beta-axons) in peroneus brevis muscle of the cat

1975 ◽  
Vol 38 (6) ◽  
pp. 1390-1394 ◽  
Author(s):  
F. Emonet-Denand ◽  
Y. Laporte
Keyword(s):  
Neuromuscular Junctions ◽  
Muscle Fibers ◽  
Repetitive Stimulation ◽  
Motor Axon ◽  
Dynamic Sensitivity ◽  
Conduction Velocities ◽  
Peroneus Brevis ◽  
Stimulation Of

Of 32 cat peroneus brevis spindles, 23 (72%) were found to be supplied by a least 1 skeletofusimotor or beta-axon. A motor axon was identified as skeletofusimotor when repetitive stimulation of it elicited both the contraction of extrafusal muscle fibers and as acceleration of the discharge of primary ending, which persisted after selective block of the neuromuscular junctions of extrafusal muscle fibers. The block was obtained by stimulating single axons at 400-500/s for a few seconds. Of 135 axons supplying extrafusal muscle fibers, 24 (18%) were shown to be beta-axons; 22 beta-axons had conduction velocities ranging from 45 to 75 m/s. All but three beta-axons increased the dynamic sensitivity of primary endings. Beta-innervated spindles may also be supplied by dynamic gamma-axons.

scholarly journals Acetylcholinesterase from the motor nerve terminal accumulates on the synaptic basal lamina of the myofiber.

1991 ◽  
Vol 115 (3) ◽  
pp. 755-764 ◽  
Author(s):  
L Anglister
Keyword(s):  
Basal Lamina ◽  
Ache Activity ◽  
Neuromuscular Junctions ◽  
Motor Nerve ◽  
Synaptic Cleft ◽  
Motor Nerve Terminal ◽  
Nerve Terminals ◽  
Axon Terminals ◽  
Muscle Nerve ◽  
Almost All

Acetylcholinesterase (AChE) in skeletal muscle is concentrated at neuromuscular junctions, where it is found in the synaptic cleft between muscle and nerve, associated with the synaptic portion of the myofiber basal lamina. This raises the question of whether the synaptic enzyme is produced by muscle, nerve, or both. Studies on denervated and regenerating muscles have shown that myofibers can produce synaptic AChE, and that the motor nerve may play an indirect role, inducing myofibers to produce synaptic AChE. The aim of this study was to determine whether some of the AChE which is known to be made and transported by the motor nerve contributes directly to AChE in the synaptic cleft. Frog muscles were surgically damaged in a way that caused degeneration and permanent removal of all myofibers from their basal lamina sheaths. Concomitantly, AChE activity was irreversibly blocked. Motor axons remained intact, and their terminals persisted at almost all the synaptic sites on the basal lamina in the absence of myofibers. 1 mo after the operation, the innervated sheaths were stained for AChE activity. Despite the absence of myofibers, new AChE appeared in an arborized pattern, characteristic of neuromuscular junctions, and its reaction product was concentrated adjacent to the nerve terminals, obscuring synaptic basal lamina. AChE activity did not appear in the absence of nerve terminals. We concluded therefore, that the newly formed AChE at the synaptic sites had been produced by the persisting axon terminals, indicating that the motor nerve is capable of producing some of the synaptic AChE at neuromuscular junctions. The newly formed AChE remained adherent to basal lamina sheaths after degeneration of the terminals, and was solubilized by collagenase, indicating that the AChE provided by nerve had become incorporated into the basal lamina as at normal neuromuscular junctions.

The fate of foreign endplates in cross-innervated rat soleus muscle

1980 ◽  
Vol 208 (1171) ◽  
pp. 189-222 ◽  
Keyword(s):  
Muscle Fibre ◽  
Proximal Region ◽  
Presynaptic Terminal ◽  
Motor Axon ◽  
Muscle Fibres ◽  
Nerve Terminals ◽  
Axon Terminals ◽  
Adult Rat ◽  
Rat Soleus Muscle ◽  
Postsynaptic Site

After transplantation of the superficial fibular and the medial plantar nerve to neighbouring sites in the proximal region of adult rat soleus muscles many muscle fibres were initially innervated by axons in both foreign nerves after resection of the original soleus nerve. The foreign endplates were formed at ectopic sites and were often separately locatedon individual muscle fibres. After 3-4 weeks many endplates had been eliminated and most muscle fibres were innervated by only a single foreign axon. Many muscle fibres still had multiple esterase-staining endplate sites in the region innervated by the foreign nerve. On exami­nation by electronmicroscopy, some of these sites were seen to have lost their presynaptic terminal while the postsynaptic structure of the endplate remained intact. Other sites were only partially occupied by motor axon terminals. On each muscle fibre there was always at least one fully occupied endplate region. In some instances separate endplate sites on the same muscle fibre were innervated by branches of the same motor axon. We conclude that the elimination of endplates is due to a competitive interaction between motor axons innervating the same muscle fibre. Morphologically, the elimination of functional endplates is caused by a retraction of nerve terminals from the postsynaptic site.

scholarly journals Restoration of Neurological Function Following Peripheral Nerve Trauma

2020 ◽  
Vol 21 (5) ◽  
pp. 1808 ◽  
Author(s):  
Damien P. Kuffler ◽  
Christian Foy
Keyword(s):  
Peripheral Nerve ◽  
Functional Recovery ◽  
Recovery Of Function ◽  
Sensory Nerve ◽  
Standard Technique ◽  
Neurological Function ◽  
Neurological Recovery ◽  
Nerve Grafts ◽  
Peripheral Nerve Trauma ◽  
Nerve Trauma

Following peripheral nerve trauma that damages a length of the nerve, recovery of function is generally limited. This is because no material tested for bridging nerve gaps promotes good axon regeneration across the gap under conditions associated with common nerve traumas. While many materials have been tested, sensory nerve grafts remain the clinical “gold standard” technique. This is despite the significant limitations in the conditions under which they restore function. Thus, they induce reliable and good recovery only for patients < 25 years old, when gaps are <2 cm in length, and when repairs are performed <2–3 months post trauma. Repairs performed when these values are larger result in a precipitous decrease in neurological recovery. Further, when patients have more than one parameter larger than these values, there is normally no functional recovery. Clinically, there has been little progress in developing new techniques that increase the level of functional recovery following peripheral nerve injury. This paper examines the efficacies and limitations of sensory nerve grafts and various other techniques used to induce functional neurological recovery, and how these might be improved to induce more extensive functional recovery. It also discusses preliminary data from the clinical application of a novel technique that restores neurological function across long nerve gaps, when repairs are performed at long times post-trauma, and in older patients, even under all three of these conditions. Thus, it appears that function can be restored under conditions where sensory nerve grafts are not effective.

scholarly journals Activity-Driven Synaptic and Axonal Degeneration in Canine Motor Neuron Disease

2004 ◽  
Vol 92 (2) ◽  
pp. 1175-1181 ◽  
Author(s):  
Dario I. Carrasco ◽  
Mark M. Rich ◽  
Qingbo Wang ◽  
Timothy C. Cope ◽  
Martin J. Pinter
Keyword(s):  
Motor Neuron ◽  
Motor Neuron Disease ◽  
Motor Unit ◽  
Neuromuscular Junctions ◽  
Muscular Atrophy ◽  
Motor Axon ◽  
Medial Gastrocnemius ◽  
Neuron Activity ◽  
Functional Changes ◽  
Unit Function

The role of neuronal activity in the pathogenesis of neurodegenerative disease is largely unknown. In this study, we examined the effects of increasing motor neuron activity on the pathogenesis of a canine version of inherited motor neuron disease (hereditary canine spinal muscular atrophy). Activity of motor neurons innervating the ankle extensor muscle medial gastrocnemius (MG) was increased by denervating close synergist muscles. In affected animals, 4 wk of synergist denervation accelerated loss of motor-unit function relative to control muscles and decreased motor axon conduction velocities. Slowing of axon conduction was greatest in the most distal portions of motor axons. Morphological analysis of neuromuscular junctions (NMJs) showed that these functional changes were associated with increased loss of intact innervation and with the appearance of significant motor axon and motor terminal sprouting. These effects were not observed in the MG muscles of age-matched, normal animals with synergist denervation for 5 wk. The results indicate that motor neuron action potential activity is a major contributing factor to the loss of motor-unit function and degeneration in inherited canine motor neuron disease.

Form and classification of motor endings in mammalian muscle spindles

1985 ◽  
Vol 225 (1239) ◽  
pp. 195-212 ◽  
Keyword(s):  
Muscle Fibre ◽  
Fibre Type ◽  
Muscle Spindles ◽  
Muscle Fibre Type ◽  
Motor Axon ◽  
Muscle Fibres ◽  
Intrafusal Muscle ◽  
Axon Terminals ◽  
Hindlimb Muscle

The presynaptic features of 234 motor endings supplied to cat hindlimb muscle spindles have been studied in teased, silver preparations, and the postsynaptic features of a further 27 endings have been studied in serial, 1 μm thick, transverse sections. In the presynaptic study motor endings received by the three types of intrafusal muscle fibre were compared with the endings supplied to spindles by the various functional categories of motor axon. Three forms of motor ending were found that had significantly different presynaptic features. These forms correspond closely to those previously identified in the literature as p 1 (β), p 2 (dynamic γ) and trail (static γ). The results of the postsynaptic study showed that the degree of indentation of the intrafusal muscle fibres by motor axon terminals increases with greater distance from the primary ending, irrespective of muscle-fibre type. We conclude that the postsynaptic form of intrafusal motor endings is determined by distance from primary ending and muscle-fibre type. It is not determined by type of motor axon, and cannot be correlated with presynaptic form so as to produce a unified classification of intrafusal motor endings.

scholarly journals Morphological peculiarities of neuromuscular junctions among different fiber types: Effect of exercise

2017 ◽  
Vol 27 (3) ◽  
Author(s):  
Teet Seene ◽  
Maria Umnova ◽  
Priit Kaasik
Keyword(s):  
Axon Terminal ◽  
Neuromuscular Junctions ◽  
Muscle Fibers ◽  
Cross Sectional Area ◽  
Fiber Types ◽  
Sectional Area ◽  
Cross Sectional ◽  
Thin Sections ◽  
Axon Terminals ◽  
Ultrastructural Studies

The aim of our research was to examine whether there are differences in the morphology of neuromuscular junctions of different types of muscle fibers in rodents, and after their adaptation to six weeks endurance exercise training. After 5-day acclimation, Wistar rats were subjected to run with the speed 35 m/min during 6 week, 5 days per week and the training volume reached 60 min per day. Muscle samples for ultrastructural studies were fixed, dehydrated and embedded in Epon-812. Ultra-thin sections were cut from longitudinally and transversely oriented blocs, using 4 blocks from each animal. The area of axon terminals on fast- twitch fibers is 1.5 time large (p&lt;0.001) and the perimeter of terminals is 1.7 time large in comparison with slow- twitch oxidative fibers (p&lt;0.001) in control group. There are correlation between cross-sectional area of different muscle fibers and length of axon terminals (r=0.72), between cross-sectional area and with of axon terminal (r=-0.62), and between turnover rate of contractile proteins and length of axon terminal (r=0.75). Fast remodeling of synapse on oxidative and oxidative-glycolytic muscle fibers during endurance training seems to guarantees the intensive renewal of the structures of muscle fibers with higher oxidative capacity.

Interplay of CXCR4 and FLT3-ITD in the Regulation of Stem Cell Migration and Proliferation.

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 1818-1818 ◽  
Author(s):  
Angela Jacobi ◽  
Martin F. Ryser ◽  
Sina Koch ◽  
Romy Lehmann ◽  
Martin Bornhaeuser ◽  
...  
Keyword(s):  
Stem Cell ◽  
Cord Blood ◽  
Stone Formation ◽  
Cytokine Signaling ◽  
Published Data ◽  
Cxcr4 Antagonist ◽  
Cxcr4 Signaling ◽  
Stem Cell Migration ◽  
Stromal Cell Line ◽  
Genetic Aberration

Abstract Activating mutations of the FLT3-receptor tyrosine kinase such as the short internal tandem duplication (ITD) represent the single most common genetic aberration in patients with acute myeloid leukemia (AML). FLT3-ITD mutations are present in about 25% of AML patients and are associated with high blast counts and a higher rate of relapse after conventional chemotherapy. CXCR4 and its ligand SDF-1 are of central importance for stem cell homing to the bone marrow. In FLT3-ITD positive AML, CXCR4 expression on stem cells is negatively correlated to overall survival. Using retroviral vector transduction we achieved overexpression of the human FLT-ITD transgene, the FLT3-wt or the GFP control gene in greater than 70% of cord blood hematopoietic progenitors (HP). In contrast to previously published data in murine cell lines, we found that FLT3-ITD positive human cells display strongly reduced migration towards the CXCR4 ligand SDF-1. Analysis of SOCS3 (suppressor of cytokine signaling 3) expression revealed strongly increased mRNA expression in FLT3-ITD overexpressing CD34+HP and FLT3-ITD positive AML blasts. Since SOCS3 is a known antagonist of CXCR4 signaling, increased SOCS3 levels might cause the observed inhibition of SDF-1 dependent migration. For individually tested CD34+HP from 6 cord blood donors, co-cultivation of FLT3-ITD overexpressing HP on the irradiated mouse stromal cell line M210-B4 or on primary mesenchymal stromal cells resulted in an increased formation of early cobble stones and a dramatic proliferation advantage for suspended cells compared to naïve, FLT3-wt or GFP-transduced HP. Addition of the CXCR4 chemokine inhibitor AMD3100 to the co-culture decreased the cobble stone formation and growth advantage of FLT3-ITD transduced cord blood HP. Similar results were obtained using FLT3-ITD positive AML cells from 3 patients. Using CFSE to track cell proliferation and PI/Annexin staining to analyze apoptosis, we demonstrate that the addition of AMD3100 had no effect on apoptosis but decreased the proliferation rate of FLT3-ITD positive blast cells. Using primary AML blasts and FLT3-ITD transgene overexpressing cord blood HP, we demonstrate that the robust FLT3-ITD mediated proliferation advantage can be partly inhibited by the CXCR4 antagonist AMD3100.

Ultrastructure of intraocular muscles of diving and nondiving ducks

1982 ◽  
Vol 60 (7) ◽  
pp. 1588-1606 ◽  
Author(s):  
J. G. Sivak ◽  
O. E. Vrablic
Keyword(s):  
Neuromuscular Junctions ◽  
Muscle Fibres ◽  
Dark Cell ◽  
Domestic Ducks ◽  
Diving Ducks ◽  
Light Cell ◽  
Axon Terminals ◽  
End Plate ◽  
Transmission Electron ◽  
Skeletal Muscle Fibres

The fine structure of ciliary muscle (CM), iris sphincter (IS), and neuromuscular junctions (NMJ) were studied by light and transmission electron microscopy in domestic ducks (Anas platyrhynchos) and diving ducks (Mergus merganser). Previous work has shown that the iris produces exaggerated acommodative ability in the diver. Both muscles are striated in the two species. While both muscles of domestic ducks and the CM of the diving ducks consist of one cell type, the IS of the latter is made up of two types of cells referred to as "light" and "dark." The "light" cell has long, thin, uniformly distributed mitochondria, while in the "dark" cells they are large, unevenly dispersed and often aggregated subsarcolemmally. The sarcoplasmic reticulum is more abundant in both IS and CM of domestic ducks, while well developed T tubules are seen more regularly in the intraocular muscles of diving ducks.The NMJ's do not show the complexity seen in singly innervated skeletal muscle fibres. All the nerve axon terminals end in a flat shallow trough and postjunctional folds are either nonexistent or very shallow. The NMJ's of the IS of domestic ducks and of the "dark" cell of the IS of diving ducks consist of a large single end plate. That of the CM of domestic ducks consists of a diffuse single end plate while the NMJ of the CM of diving ducks consists of diffuse multiple endings. Nerve endings of similar size and structure but occurring only singly were found on the "light" cell of the IS of domestic ducks.

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