Mitochondrial dysfunction and oxidative stress are widely regarded as primary drivers of aging and are associated with several neurodegenerative diseases.The degeneration of motor neurons during aging is a critical pa...Mitochondrial dysfunction and oxidative stress are widely regarded as primary drivers of aging and are associated with several neurodegenerative diseases.The degeneration of motor neurons during aging is a critical pathological factor contributing to the progression of sarcopenia.However,the morphological and functional changes in mitochondria and their interplay in the degeneration of the neuromuscular junction during aging remain poorly understood.A defined systematic search of the Pub Med,Web of Science and Embase databases(last accessed on October 30,2024)was conducted with search terms including'mitochondria','aging'and'NMJ'.Clinical and preclinical studies of mitochondrial dysfunction and neuromuscular junction degeneration during aging.Twentyseven studies were included in this systematic review.This systematic review provides a summary of morphological,functional and biological changes in neuromuscular junction,mitochondrial morphology,biosynthesis,respiratory chain function,and mitophagy during aging.We focus on the interactions and mechanisms underlying the relationship between mitochondria and neuromuscular junctions during aging.Aging is characterized by significant reductions in mitochondrial fusion/fission cycles,biosynthesis,and mitochondrial quality control,which may lead to neuromuscular junction dysfunction,denervation and poor physical performance.Motor nerve terminals that exhibit redox sensitivity are among the first to exhibit abnormalities,ultimately leading to an early decline in muscle strength through impaired neuromuscular junction transmission function.Parg coactivator 1 alpha is a crucial molecule that regulates mitochondrial biogenesis and modulates various pathways,including the mitochondrial respiratory chain,energy deficiency,oxidative stress,and inflammation.Mitochondrial dysfunction is correlated with neuromuscular junction denervation and acetylcholine receptor fragmentation,resulting in muscle atrophy and a decrease in strength during aging.Physical therapy,pharmacotherapy,and gene therapy can alleviate the structural degeneration and functional deterioration of neuromuscular junction by restoring mitochondrial function.Therefore,mitochondria are considered potential targets for preserving neuromuscular junction morphology and function during aging to treat sarcopenia.展开更多
Objective To study the role of HLB-1 in regulating the organization and function of neuromuscular junctions in nematode Caenorhabditis elegans. Methods To evaluate the functions of HLB-1 in regulating the organization...Objective To study the role of HLB-1 in regulating the organization and function of neuromuscular junctions in nematode Caenorhabditis elegans. Methods To evaluate the functions of HLB-1 in regulating the organization and function of neuromuscular junctions, effects of hlb-1 mutation on the synaptic structures were revealed by uncovering the expression patterns of SNB-1 ：：GFP and UNC-49：GFP, and pharmacologic assays with aldicarb and levamisole were also used to test the synaptic functions. Further rescue and mosaic analysis confirmed HLB-1＇s role in regulating the organization and function of neuromuscular junctions. Results Loss of HLB-1 function did not result in defects in neuronal outgrowth or neuronal loss, but caused obvious defects of SNB-1：：GFP and UNC-49：：GFP puncta localization, suggesting the altered presynaptic and postsynaptic structures. The mutant animals exhibited severe defects in locomotion behaviors and altered responses to an inhibitor of acetylcholinesterase and a cholinergic agonist, indicating the altered presynaptic and postsynaptic functions. Rescue and mosaic analysis experiments suggested that HLB-1 regulated synaptic functions in a cell nonautonomously way. Moreover, HLB- 1 expression was not required for the presynaptic active zone morphology. Genetic evidence further demonstrated that hlb-1 acted in a parallel pathway with syd-2 to regulate the synaptic functions. Conclusion HLB-1 appeared as a new regulator for the organization and function of neuromuscular junctions in C. elegans.展开更多
Ethylene thiourea(ETU)converted from ethylene bisdithiocarbamate(EBDC)fungicides has aroused great concern because of its prevalence and harmful effects.Although ETU-induced neurotoxicity has been reported,the potenti...Ethylene thiourea(ETU)converted from ethylene bisdithiocarbamate(EBDC)fungicides has aroused great concern because of its prevalence and harmful effects.Although ETU-induced neurotoxicity has been reported,the potential mechanisms remain unclear.This study provided insights into its neurotoxic effects at environmentally relevant concentrations in zebrafish.Our findings showed that embryonic exposure to ETU decreased the hatch rate and delayed somite development.Furthermore,ETU treatment significantly reduced the dark velocity in the locomotion assay.The upregulated tendency of the mitogen-activated protein kinases(MAPK)pathway(mknk1,atf4,mapkapk3)screened by transcriptome analysis implied motor neuron degeneration,which was validated by subsequent morphological observation,as axon length and branches were truncated in the 62.5μg/L ETU group.However,although the rescue experiment with a p38 MAPK inhibitor(SB203580)successfully ameliorated axon degeneration,it failed to reverse the locomotion behaviors.Further exploration of transcriptome data revealed the varied expression of presynaptic scaffold protein-related genes(pcloa,pclob,bsna),whose downregulation might impair the neuromuscular junction(NMJ).Therefore,we reasonably suspected that ETU-induced neurobehavioral deficits might result from the combined effects of the MAPK pathway and presynaptic proteins.Considering this,we highlighted the necessity to take precautions and early interventions for susceptible ETU-exposed populations.展开更多
Ischemic stroke causes long-term disability and results in motor impairments.Such impairments are associated with structural changes in the neuromuscular junction(NMJ),including detailed morphology and three-dimension...Ischemic stroke causes long-term disability and results in motor impairments.Such impairments are associated with structural changes in the neuromuscular junction(NMJ),including detailed morphology and three-dimensional(3D)distribution.However,previous studies only explored morphological changes of individual NMJs after stroke,which limits the understanding of their role in post-stroke motor impairment.Here,we examine 3D distributions and detailed morphology of NMJs in entire mouse muscles after unilateral and bilateral strokes induced by photothrombosis.The results show that 3D distributions and numbers of NMJs do not change after stroke,and severe unilateral stroke causes similar levels of NMJ fragmentation and area enlargement to bilateral stroke.This research provides structural data,deepening the understanding of neuromuscular pathophysiology after stroke.展开更多
Skeletal muscles are essential for locomotion,posture,and metabolic regulation.To understand physiological processes,exercise adaptation,and muscle-related disorders,it is critical to understand the molecular pathways...Skeletal muscles are essential for locomotion,posture,and metabolic regulation.To understand physiological processes,exercise adaptation,and muscle-related disorders,it is critical to understand the molecular pathways that underlie skeletal muscle function.The process of muscle contra ction,orchestrated by a complex interplay of molecular events,is at the core of skeletal muscle function.Muscle contraction is initiated by an action potential and neuromuscular transmission requiring a neuromuscular junction.Within muscle fibers,calcium ions play a critical role in mediating the interaction between actin and myosin filaments that generate force.Regulation of calcium release from the sarcoplasmic reticulum plays a key role in excitation-contraction coupling.The development and growth of skeletal muscle are regulated by a network of molecular pathways collectively known as myogenesis.Myogenic regulators coordinate the diffe rentiation of myoblasts into mature muscle fibers.Signaling pathways regulate muscle protein synthesis and hypertrophy in response to mechanical stimuli and nutrient availability.Seve ral muscle-related diseases,including congenital myasthenic disorders,sarcopenia,muscular dystrophies,and metabolic myopathies,are underpinned by dys regulated molecular pathways in skeletal muscle.Therapeutic interventions aimed at preserving muscle mass and function,enhancing regeneration,and improving metabolic health hold promise by targeting specific molecular pathways.Other molecular signaling pathways in skeletal muscle include the canonical Wnt signaling pathway,a critical regulator of myogenesis,muscle regeneration,and metabolic function,and the Hippo signaling pathway.In recent years,more details have been uncovered about the role of these two pathways during myogenesis and in developing and adult skeletal muscle fibers,and at the neuromuscular junction.In fact,research in the last few years now suggests that these two signaling pathways are interconnected and that they jointly control physiological and pathophysiological processes in muscle fibers.In this review,we will summarize and discuss the data on these two pathways,focusing on their concerted action next to their contribution to skeletal muscle biology.However,an in-depth discussion of the noncanonical Wnt pathway,the fibro/a dipogenic precursors,or the mechanosensory aspects of these pathways is not the focus of this review.展开更多
BACKGROUND The previous studies have primarily focused on the influence of botulinum toxin A(BoNT-A)injection on emotions during the period of peak motor symptom improvement in blepharospasm patients,based on facial f...BACKGROUND The previous studies have primarily focused on the influence of botulinum toxin A(BoNT-A)injection on emotions during the period of peak motor symptom improvement in blepharospasm patients,based on facial feedback hypothesis.AIM To evaluate the sustained anxiolytic and antidepressant effects of BoNT-A in blepharospasm patients beyond motor symptom control.METHODS We recruited benign essential blepharospasm patients with BoNT-A treatment and collected their data to compare scale scores of Jankovic Rating Scale,Blepharospasm Disability Index,Self-rating Anxiety Scale(SAS),Self-rating Depression Scale(SDS),Hamilton Anxiety Scale and Hamilton Depression Scale between pretreatment(baseline)and pre-reinjection(treatment),to further assess the effects of repeated treatments with BoNT by using sub-group analyses in the certain special states.RESULTS A total of 21 eligible blepharospasm patients were with the mean age of 58.4 years and a male-to-female ratio of 1:6.Significantly decreases in the subscale scores of SDS and SAS,including SDS well-being index,decreased capacity and hard to decide,SAS inability to sit still and headache were showed at post-a single BoNT-A injection when scale scores of Jankovic Rating Scale and Blepharospasm Disability Index were matched between baseline and posttreatment.With each additional BoNT-A injection,the odds ratio of patients with the moderate depressive symptoms decreased by 92.6%.Moreover,BoNT treatment remained a decrease in the subscale scores of SDS and SAS in patients with repeated injections.CONCLUSION This study is to demonstrate that repeated BoNT-A injection have a long-lasting relief for anxiety and depressive symptoms in blepharospasm even after its motor symptom-modulating effects have diminished.展开更多
Skeletal muscle is a dynamic tissue in which homeostasis and function are guaranteed by a very defined three-dimensional organization of myofibers in respect to other nonmuscular components,including the extracellular...Skeletal muscle is a dynamic tissue in which homeostasis and function are guaranteed by a very defined three-dimensional organization of myofibers in respect to other nonmuscular components,including the extracellular matrix and the nervous network.In particular,communication between myofibers and the nervous system is essential for the overall correct development and function of the skeletal muscle.A wide range of chronic,acute and genetic-based human pathologies that lead to the alteration of muscle function are associated with modified preservation of the fine interaction between motor neurons and myofibers at the neuromuscular junction.Recent advancements in the development of in vitro models for human skeletal muscle have shown that three-dimensionality and integration of multiple cell types are both key parameters required to unveil pathophysiological relevant phenotypes.Here,we describe recent achievement reached in skeletal muscle modeling which used biomaterials for the generation of three-dimensional constructs of myotubes integrated with motor neurons.展开更多
Myasthenia gravis is an autoimmune disorder in which antibodies have been shown to form against the nicotinic acetylcholine nicotinic postsynaptic receptors located at the neuromuscular junction.＂Warming yang and inv...Myasthenia gravis is an autoimmune disorder in which antibodies have been shown to form against the nicotinic acetylcholine nicotinic postsynaptic receptors located at the neuromuscular junction.＂Warming yang and invigorating qi＂ acupuncture treatment has been shown to reduce serum inflammatory cytokine expression and increase transforming growth factor beta expression in rats with experimental autoimmune myasthenia gravis.However,few studies have addressed the effects of this type of acupuncture on the acetylcholine receptors at the neuromuscular junction.Here,we used confocal laser scanning microscopy to examine the area and density of immunoreactivity for an antibody to the nicotinic acetylcholine receptor at the neuromuscular junction in the phrenic nerve of rats with experimental autoimmune myasthenia gravis following ＂warming yang and invigorating qi＂ acupuncture therapy.Needles were inserted at acupressure points Shousanli（LI10）,Zusanli（ST36）,Pishu（BL20）,and Shenshu（BL23） once daily for 7 consecutive days.The treatment was repeated after 1 day of rest.We found that area and the integrated optical density of the immunoreactivity for the acetylcholine receptor at the neuromuscular junction of the phrenic nerve was significantly increased following acupuncture treatment.This outcome of the acupuncture therapy was similar to that of the cholinesterase inhibitor pyridostigmine bromide.These findings suggest that ＂warming yang and invigorating qi＂ acupuncture treatment increases acetylcholine receptor expression at the neuromuscular junction in a rat model of autoimmune myasthenia gravis.展开更多
Amyotrophic lateral sclerosis(ALS) is a devastating motoneuron disease,in which lower motoneurons lose control of skeletal muscles.Degeneration of neuromuscular junctions(NMJs) occurs at the initial stage of ALS.Dipep...Amyotrophic lateral sclerosis(ALS) is a devastating motoneuron disease,in which lower motoneurons lose control of skeletal muscles.Degeneration of neuromuscular junctions(NMJs) occurs at the initial stage of ALS.Dipeptide repeat proteins(DPRs) from G4C2repeat-associated non-ATG(RAN) translation are known to cause C9orf72-associated ALS(C9-ALS).However,DPR inclusion burdens are weakly correlated with neurodegenerative areas in C9-ALS patients,indicating that DPRs may exert cell non-autonomous effects,in addition to the known intracellular pathological mechanisms.Here,we report that poly-GA,the most abundant form of DPR in C9-ALS,is released from cells.Local administration of poly-GA proteins in peripheral synaptic regions causes muscle weakness and impaired neuromuscular transmission in vivo.The NMJ structure cannot be maintained,as evidenced by the fragmentation of postsynaptic acetylcholine receptor(AChR) clusters and distortion of presynaptic nerve terminals.Mechanistic study demonstrated that extracellular poly-GA sequesters soluble Agrin ligands and inhibits Agrin-MuSK signaling.Our findings provide a novel cell non-autonomous mechanism by which poly-GA impairs NMJs in C9-ALS.Thus,targeting NMJs could be an early therapeutic intervention for C9-ALS.展开更多
OBJECTⅣE: To investigate the protective role of Sijunzi decoction in neuromuscular junction(NMJ)and muscle cell mitochondria ultrastructure; as well as its effects on the amount of adenosine triphosphate(ATP) and the...OBJECTⅣE: To investigate the protective role of Sijunzi decoction in neuromuscular junction(NMJ)and muscle cell mitochondria ultrastructure; as well as its effects on the amount of adenosine triphosphate(ATP) and the activities of mitochondrial respiratory chain complexes I, Ⅱ, Ⅲ, and Ⅳ in autoimmune myasthenia gravis rats.METHODS: An experimental autoimmune myasthenia gravis(EAMG) rat model was established by inoculating rats with acetylcholine receptors extracted from Torpedo. Rats were divided into three groups: model, prednisone, and Sijunzi decoction, and were fed physiological saline, prednisone, or Sijunzi decoction, respectively. NMJ and muscle cell mitochondria ultrastructure were observed by transmission electron microscope. The amount of ATP was assessed by high performance liquid chromatography. The activities ofmitochondrial respiratory chain complexes I, Ⅱ, Ⅲ,and Ⅳ was determined using the Clark oxygen electrode method.RESULTS: In the model group, there were sparse muscle fibers, with decreased mitochondria, and sparse, diffluent, or absent NMJ folds. After intervention with Sijunzi decoction, the above pathology changes were improved: muscle fiber structure was clear and complete; the mitochondria count was higher; and the NMJ structure was close to normal. Gastrocnemius muscle mitochondria in the model group produced significantly less ATP than those in the prednisone group(P<0.01). Conversely, the ATP of Sijunzi decoction group was significantly higher than prednisone group(P<0.01). The activities of gastrocnemius muscle mitochondrial respiratory chain complexes I, Ⅱ, Ⅲ, and Ⅳ in both the prednisone and Sijunzi decoction groups was dramatically higher compared with the model group(P<0.05). The activities of complexes I and Ⅲ in the Sijunzi decoction group were significantly higher than those in the prednisone group(P<0.05), but there was no obvious difference in complex Ⅱ or Ⅳ activities between the two groups(P>0.05).CONCLUSION: Sijunzi decoction improved pathological changes in muscle mitochondria and NMJ,enhanced the amount of ATP in gastrocnemius muscle mitochondria, and improved the activities of respiratory chain complexes I, Ⅱ, Ⅲ, and Ⅳ(especially I and Ⅲ) of the EAMG rats.展开更多
The presynaptic active zone is a dynamic structure that orchestrates regulated release of neurotrans- mitters. Developmental and aging processes, and changes in neuronal network activity can all modulate the number, s...The presynaptic active zone is a dynamic structure that orchestrates regulated release of neurotrans- mitters. Developmental and aging processes, and changes in neuronal network activity can all modulate the number, size and composition of active zone and thereby synaptic efficacy. However, very little is known about the mechanism that controls the structural stability of active zone. By study- ing a model synapse, the Drosophila neuromuscular iunction, our recent work shed light on how two scaffolding proteins at the active zone regulate active zone stability by promoting a localized dephos- phorylation event at the nerve terminal. Here we discuss the major insights from our findings and their implications for future research.展开更多
Amyloid peptide（Aβ）oligomers are considered one of the primary causal factors for the synaptic loss characteristic of Alzheimer’s disease（AD）（Karran and De Strooper,2016）.However,Aβis generated in normal brai...Amyloid peptide（Aβ）oligomers are considered one of the primary causal factors for the synaptic loss characteristic of Alzheimer’s disease（AD）（Karran and De Strooper,2016）.However,Aβis generated in normal brains and accumulates at synaptic sites,which raises the question whether Aβplays a physiological role in synapses.展开更多
The effects of manganese on neuromuscular junction transmission were studied in the isolated rat phrenic nerve diaphragm preparation, chick biventer cervicis nerve-muscle preparation and toad rectus abdominis muscle p...The effects of manganese on neuromuscular junction transmission were studied in the isolated rat phrenic nerve diaphragm preparation, chick biventer cervicis nerve-muscle preparation and toad rectus abdominis muscle preparation. It wa found that manganese could adversely andconcentration-dependently inhibit muscular contraction response developed by indirect stimulation or direct stimulation. The IC50 of indirect and direct stimulation were 0.28 mmol/L and 10 mmol/Lrespectively. The time required to inhibit 50% of the contraction by indirect stimulation was 4.3±1. 0 min. The inhibitory action could be antagonized partially by high Ca2+. Manganese could reduce the seusitivity of the chick biventer cervicis muscle to acetylcholine, and shift the dose-respond curves foracetylcholine to the right in a nonparallel manner with a pD2' value of 2. 62. The result suggested that manganese acted on pre- and post-synaptic sites.展开更多
The anatomical plan of adult muscle innervation is relatively simple： a given muscle comprises several motor units, each constituted by one motor neuron and the muscle fibers that it innervates; moreover, every muscl...The anatomical plan of adult muscle innervation is relatively simple： a given muscle comprises several motor units, each constituted by one motor neuron and the muscle fibers that it innervates; moreover, every muscle fiber is innervated by only one axonal terminal. In other words, motor units have separate, although intermingled, territories of inner- vation （Figure 1D）. In striking contrast, the anatomical organization is different at birth, when every muscle fiber is innervated by several nerve terminals belonging to different motor neurons, a condition known as ＂polyneuronal inner- vation＂, with the consequence that motor units have larger and overlapped territories of innervation （Figure 1A） （Tapia and Lichtman, 2012）. Soon after birth, redundant nerve ter- minals are progressively eliminated in a couple of weeks in rodents, and muscle fibers acquire their mature mononeu- ronal innervation. The same process occurs again in the adult muscle during reinnervation after nerve damage, when a transient period of polyneuronal innervation involves a good fraction of the fibers （Rich and Lichtman, 1989;展开更多
Schwann cells are essential for the maintenance and function of motor neurons,axonal networks,and the neuromuscular junction.In amyotrophic lateral sclerosis,where motor neuron function is progressively lost,Schwann c...Schwann cells are essential for the maintenance and function of motor neurons,axonal networks,and the neuromuscular junction.In amyotrophic lateral sclerosis,where motor neuron function is progressively lost,Schwann cell function may also be impaired.Recently,important signaling and potential trophic activities of Schwann cell-derived exosomal vesicles have been reported.This case report describes the treatment of a patient with advanced amyotrophic lateral sclerosis using serial intravenous infusions of allogeneic Schwann cell-derived exosomal vesicles,marking,to our knowledge,the first instance of such treatment.An 81-year-old male patient presented with a 1.5-year history of rapidly progressive amyotrophic lateral sclerosis.After initial diagnosis,the patient underwent a combination of generic riluzole,sodium phenylbutyrate for the treatment of amyotrophic lateral sclerosis,and taurursodiol.The patient volunteered to participate in an FDA-approved single-patient expanded access treatment and received weekly intravenous infusions of allogeneic Schwann cell-derived exosomal vesicles to potentially restore impaired Schwann cell and motor neuron function.We confirmed that cultured Schwann cells obtained from the amyotrophic lateral sclerosis patient via sural nerve biopsy appeared impaired(senescent)and that exposure of the patient’s Schwann cells to allogeneic Schwann cell-derived exosomal vesicles,cultured expanded from a cadaver donor improved their growth capacity in vitro.After a period of observation lasting 10 weeks,during which amyotrophic lateral sclerosis Functional Rating Scale-Revised and pulmonary function were regularly monitored,the patient received weekly consecutive infusions of 1.54×1012(×2),and then consecutive infusions of 7.5×1012(×6)allogeneic Schwann cell-derived exosomal vesicles diluted in 40 mL of Dulbecco’s phosphate-buffered saline.None of the infusions were associated with adverse events such as infusion reactions(allergic or otherwise)or changes in vital signs.Clinical lab serum neurofilament and cytokine levels measured prior to each infusion varied somewhat without a clear trend.A more sensitive in-house assay suggested possible inflammasome activation during the disease course.A trend for clinical stabilization was observed during the infusion period.Our study provides a novel approach to address impaired Schwann cells and possibly motor neuron function in patients with amyotrophic lateral sclerosis using allogeneic Schwann cell-derived exosomal vesicles.Initial findings suggest that this approach is safe.展开更多
Substantial reductions in muscle motor unit numbers accompany ageing and occur in parallel the age-related changes in skeletal muscle mass and fibre number.These motor unit changes are reflected in reduced motor neuro...Substantial reductions in muscle motor unit numbers accompany ageing and occur in parallel the age-related changes in skeletal muscle mass and fibre number.These motor unit changes are reflected in reduced motor neuron numbers and size,axonal integrity and disrupted pre-and post-synaptic neuromuscular junctions(NMJ).Conversely,data indicate that the effects of ageing on neuromuscular transmission are relatively minor.Some authors have therefore argued that structural degeneration of motor axons and NMJ are unimportant in the pathogenesis of sarcopenia and for a non-neurogenic origin for ageing-induced muscle loss.Increased Reactive Oxygen Species(ROS)activities and changes in redox status are a feature of ageing and may play a key role in muscle loss through increased mitochondrial peroxide generation.This article will review the changes in motor units and NMJ seen during ageing and develop the argument that the changes in muscle mitochondrial peroxide generation and redox status may be caused by age-related changes in neuromuscular structure,but are not directly related to neuromuscular transmission.This provides an alternative explanation on how age-related changes in neural tissue might drive skeletal muscle fibre loss and weakness.Exercise interventions are known to reduce muscle loss and weakness in the elderly,but studies of such interventions on age-related changes in motor units,motor neurons or NMJ structure and function provide conflicting data.A further aim is therefore to identify areas where there is a need for novel research to understand whether,and how,targeted or long-term exercise might influence neuromuscular changes in ageing.展开更多
Inhibitor of DNA binding 2(Id2)can promote axonal regeneration after injury of the central nervous system.However,whether Id2 can promote axonal regeneration and functional recovery after peripheral nerve injury is cu...Inhibitor of DNA binding 2(Id2)can promote axonal regeneration after injury of the central nervous system.However,whether Id2 can promote axonal regeneration and functional recovery after peripheral nerve injury is currently unknown.In this study,we established a mouse model of bilateral sciatic nerve crush injury.Two weeks before injury,AAV9-Id2-3×Flag-GFP was injected stereotaxically into the bilateral ventral horn of lumbar spinal cord.Our results showed that Id2 was successfully delivered into spinal cord motor neurons projecting to the sciatic nerve,and the number of regenerated motor axons in the sciatic nerve distal to the crush site was increased at 2 weeks after injury,arriving at the tibial nerve and reinnervating a few endplates in the gastrocnemius muscle.By 1 month after injury,extensive neuromuscular reinnervation occurred.In addition,the amplitude of compound muscle action potentials of the gastrocnemius muscle was markedly recovered,and their latency was shortened.These findings suggest that Id2 can accelerate axonal regeneration,promote neuromuscular reinnervation,and enhance functional improvement following sciatic nerve injury.Therefore,elevating the level of Id2 in adult neurons may present a promising strategy for peripheral nerve repair following injury.The study was approved by the Experimental Animal Ethics Committee of Jinan University(approval No.20160302003)on March 2,2016.展开更多
In this study, we developed a novel artificial nerve graft termed self-assembling peptide nanofiber scaffold （SAPNS）-containing poly（lactic-co-glycolic acid） （PLGA） conduit （SPC） and used it to bridge a 10-mm-...In this study, we developed a novel artificial nerve graft termed self-assembling peptide nanofiber scaffold （SAPNS）-containing poly（lactic-co-glycolic acid） （PLGA） conduit （SPC） and used it to bridge a 10-mm-long sciatic nerve defect in the rat. Retrograde tracing, behavioral testing and histomorphometric analyses showed that compared with the empty PLGA conduit implantation group, the SPC implantation group had a larger number of growing and extending axons, a markedly increased diameter of regenerated axons and a greater thickness of the myelin sheath in the conduit. Furthermore, there was an increase in the size of the neuromuscular junction and myofiber diameter in the target muscle. These findings suggest that the novel artificial SPC nerve graft can promote axonal regeneration and remyelination in the transected peripheral nerve and can be used for repairing peripheral nerve injury.展开更多
Myasthenia gravis is a rare and invalidating disease affecting the neuromuscular junction of voluntary muscles.The classical form of this autoimmune disease is characterized by the presence of antibodies against the m...Myasthenia gravis is a rare and invalidating disease affecting the neuromuscular junction of voluntary muscles.The classical form of this autoimmune disease is characterized by the presence of antibodies against the most abundant protein in the neuromuscular junction,the nicotinic acetylcholine receptor.Other variants of the disease involve autoimmune attack of non-receptor scaffolding proteins or enzymes essential for building or maintaining the integrity of this peripheral synapse.This review summarizes the participation of the above proteins in building the neuromuscular junction and the destruction of this cholinergic synapse by autoimmune aggression in myasthenia gravis.The review also covers the application of a powerful biophysical technique,superresolution optical microscopy,to image the nicotinic receptor in live cells and follow its motional dynamics.The hypothesis is entertained that anomalous nanocluster formation by antibody crosslinking may lead to accelerated endocytic internalization and elevated turnover of the receptor,as observed in myasthenia gravis.展开更多
OBJECTIVE: To investigate the effect of Jianpiyiqi granule, prepared according to a Traditional Chinese Medicine(TCM) formula, on the ocular type of myasthenia gravis(MG) caused by a defect in synaptic transmission at...OBJECTIVE: To investigate the effect of Jianpiyiqi granule, prepared according to a Traditional Chinese Medicine(TCM) formula, on the ocular type of myasthenia gravis(MG) caused by a defect in synaptic transmission at the neuromuscular junction.METHODS: A total of 155 children with ocular MG were recruited from January 2008 to January 2015.All individuals received ineffective glucocorticoid treatment prior to admission, and were given Jianpiyiqi granules(two doses per day) for 12 months.Plasma levels of acetylcholine receptor autoantibodies(ACh R-Ab), cytokines, immune parameters and clinical score were analyzed.RESULTS: After intervention with Jianpiyiqi granule for 12 months, the levels of cytokines [including interleukin(IL)-6, IL-12, IL-17], immune parameters[including immunoglobulin G(Ig G), Ig M, free triiodothyronine, free thyroxine] and ACh R-Ab were sig-nificantly decreased(P = 0.042, P = 0.049, P = 0.011,P = 0.02, P = 0.04, P = 0.03, P = 0.01; F = 21.60, P =0.000). In contrast, IL-4 levels were significantly increased(P = 0.049). The absolute clinical score after treatment declined significantly compared with before treatment(F = 33.24, P = 0.000). The effective cure rate and the total effective rate gradually increased to a maximum of 149(96.2%) and 151(97.4%) in MG patients after 12 months of treatment, respectively.CONCLUSION: The Jianpiyiqi granule treatment lowered ACh R-Ab levels and improved cytokine and other immune parameter levels, which suggests that the granule could be an ancillary treatment for ocular MG in children caused by a defect in synaptic transmission at the neuromuscular junction.展开更多
基金supported by grants from Collaborative Research Fund(Ref:C4032-21GF)General Research Grant(Ref:14114822)+1 种基金Group Research Scheme(Ref:3110146)Area of Excellence(Ref:Ao E/M-402/20)。
文摘Mitochondrial dysfunction and oxidative stress are widely regarded as primary drivers of aging and are associated with several neurodegenerative diseases.The degeneration of motor neurons during aging is a critical pathological factor contributing to the progression of sarcopenia.However,the morphological and functional changes in mitochondria and their interplay in the degeneration of the neuromuscular junction during aging remain poorly understood.A defined systematic search of the Pub Med,Web of Science and Embase databases(last accessed on October 30,2024)was conducted with search terms including'mitochondria','aging'and'NMJ'.Clinical and preclinical studies of mitochondrial dysfunction and neuromuscular junction degeneration during aging.Twentyseven studies were included in this systematic review.This systematic review provides a summary of morphological,functional and biological changes in neuromuscular junction,mitochondrial morphology,biosynthesis,respiratory chain function,and mitophagy during aging.We focus on the interactions and mechanisms underlying the relationship between mitochondria and neuromuscular junctions during aging.Aging is characterized by significant reductions in mitochondrial fusion/fission cycles,biosynthesis,and mitochondrial quality control,which may lead to neuromuscular junction dysfunction,denervation and poor physical performance.Motor nerve terminals that exhibit redox sensitivity are among the first to exhibit abnormalities,ultimately leading to an early decline in muscle strength through impaired neuromuscular junction transmission function.Parg coactivator 1 alpha is a crucial molecule that regulates mitochondrial biogenesis and modulates various pathways,including the mitochondrial respiratory chain,energy deficiency,oxidative stress,and inflammation.Mitochondrial dysfunction is correlated with neuromuscular junction denervation and acetylcholine receptor fragmentation,resulting in muscle atrophy and a decrease in strength during aging.Physical therapy,pharmacotherapy,and gene therapy can alleviate the structural degeneration and functional deterioration of neuromuscular junction by restoring mitochondrial function.Therefore,mitochondria are considered potential targets for preserving neuromuscular junction morphology and function during aging to treat sarcopenia.
基金the National Natural Science Foundation of China (No. 30771113, 30870810)the Program for New Century Excellent Talents in University, Ministry of Education, China
文摘Objective To study the role of HLB-1 in regulating the organization and function of neuromuscular junctions in nematode Caenorhabditis elegans. Methods To evaluate the functions of HLB-1 in regulating the organization and function of neuromuscular junctions, effects of hlb-1 mutation on the synaptic structures were revealed by uncovering the expression patterns of SNB-1 ：：GFP and UNC-49：GFP, and pharmacologic assays with aldicarb and levamisole were also used to test the synaptic functions. Further rescue and mosaic analysis confirmed HLB-1＇s role in regulating the organization and function of neuromuscular junctions. Results Loss of HLB-1 function did not result in defects in neuronal outgrowth or neuronal loss, but caused obvious defects of SNB-1：：GFP and UNC-49：：GFP puncta localization, suggesting the altered presynaptic and postsynaptic structures. The mutant animals exhibited severe defects in locomotion behaviors and altered responses to an inhibitor of acetylcholinesterase and a cholinergic agonist, indicating the altered presynaptic and postsynaptic functions. Rescue and mosaic analysis experiments suggested that HLB-1 regulated synaptic functions in a cell nonautonomously way. Moreover, HLB- 1 expression was not required for the presynaptic active zone morphology. Genetic evidence further demonstrated that hlb-1 acted in a parallel pathway with syd-2 to regulate the synaptic functions. Conclusion HLB-1 appeared as a new regulator for the organization and function of neuromuscular junctions in C. elegans.
基金supported by the National Key R&D Program of China (Nos.2018YFC1004300 and 2018YFC1004304)。
文摘Ethylene thiourea(ETU)converted from ethylene bisdithiocarbamate(EBDC)fungicides has aroused great concern because of its prevalence and harmful effects.Although ETU-induced neurotoxicity has been reported,the potential mechanisms remain unclear.This study provided insights into its neurotoxic effects at environmentally relevant concentrations in zebrafish.Our findings showed that embryonic exposure to ETU decreased the hatch rate and delayed somite development.Furthermore,ETU treatment significantly reduced the dark velocity in the locomotion assay.The upregulated tendency of the mitogen-activated protein kinases(MAPK)pathway(mknk1,atf4,mapkapk3)screened by transcriptome analysis implied motor neuron degeneration,which was validated by subsequent morphological observation,as axon length and branches were truncated in the 62.5μg/L ETU group.However,although the rescue experiment with a p38 MAPK inhibitor(SB203580)successfully ameliorated axon degeneration,it failed to reverse the locomotion behaviors.Further exploration of transcriptome data revealed the varied expression of presynaptic scaffold protein-related genes(pcloa,pclob,bsna),whose downregulation might impair the neuromuscular junction(NMJ).Therefore,we reasonably suspected that ETU-induced neurobehavioral deficits might result from the combined effects of the MAPK pathway and presynaptic proteins.Considering this,we highlighted the necessity to take precautions and early interventions for susceptible ETU-exposed populations.
基金supported by the National Natural Science Foundation of China(No.61860206009)the Key Research and Development Project of Hubei Province(No.2022BCA023)the Innovation Fund of WNLO.
文摘Ischemic stroke causes long-term disability and results in motor impairments.Such impairments are associated with structural changes in the neuromuscular junction(NMJ),including detailed morphology and three-dimensional(3D)distribution.However,previous studies only explored morphological changes of individual NMJs after stroke,which limits the understanding of their role in post-stroke motor impairment.Here,we examine 3D distributions and detailed morphology of NMJs in entire mouse muscles after unilateral and bilateral strokes induced by photothrombosis.The results show that 3D distributions and numbers of NMJs do not change after stroke,and severe unilateral stroke causes similar levels of NMJ fragmentation and area enlargement to bilateral stroke.This research provides structural data,deepening the understanding of neuromuscular pathophysiology after stroke.
基金supported by the German Research Council(Deutsche Forschungsgemeinschaft,HA3309/3-1/2,HA3309/6-1,HA3309/7-1)。
文摘Skeletal muscles are essential for locomotion,posture,and metabolic regulation.To understand physiological processes,exercise adaptation,and muscle-related disorders,it is critical to understand the molecular pathways that underlie skeletal muscle function.The process of muscle contra ction,orchestrated by a complex interplay of molecular events,is at the core of skeletal muscle function.Muscle contraction is initiated by an action potential and neuromuscular transmission requiring a neuromuscular junction.Within muscle fibers,calcium ions play a critical role in mediating the interaction between actin and myosin filaments that generate force.Regulation of calcium release from the sarcoplasmic reticulum plays a key role in excitation-contraction coupling.The development and growth of skeletal muscle are regulated by a network of molecular pathways collectively known as myogenesis.Myogenic regulators coordinate the diffe rentiation of myoblasts into mature muscle fibers.Signaling pathways regulate muscle protein synthesis and hypertrophy in response to mechanical stimuli and nutrient availability.Seve ral muscle-related diseases,including congenital myasthenic disorders,sarcopenia,muscular dystrophies,and metabolic myopathies,are underpinned by dys regulated molecular pathways in skeletal muscle.Therapeutic interventions aimed at preserving muscle mass and function,enhancing regeneration,and improving metabolic health hold promise by targeting specific molecular pathways.Other molecular signaling pathways in skeletal muscle include the canonical Wnt signaling pathway,a critical regulator of myogenesis,muscle regeneration,and metabolic function,and the Hippo signaling pathway.In recent years,more details have been uncovered about the role of these two pathways during myogenesis and in developing and adult skeletal muscle fibers,and at the neuromuscular junction.In fact,research in the last few years now suggests that these two signaling pathways are interconnected and that they jointly control physiological and pathophysiological processes in muscle fibers.In this review,we will summarize and discuss the data on these two pathways,focusing on their concerted action next to their contribution to skeletal muscle biology.However,an in-depth discussion of the noncanonical Wnt pathway,the fibro/a dipogenic precursors,or the mechanosensory aspects of these pathways is not the focus of this review.
基金Supported by the Special Funds of Jiangsu Provincial Key Research and Development Projects,No.BE2019612Scientific Research Project Cooperated by Lanzhou Biotechnology Development Co.,Ltd.+3 种基金the Key R&D Program of Jiangsu Science and Technology Project,No.BE2022049 and No.BE2022049-1National Natural Science Foundation of China,No.82171249Nanjing Rehabilitation Medicine Center ProjectJiangsu Provincial Health Commission Special Fund for Aging and Health.
文摘BACKGROUND The previous studies have primarily focused on the influence of botulinum toxin A(BoNT-A)injection on emotions during the period of peak motor symptom improvement in blepharospasm patients,based on facial feedback hypothesis.AIM To evaluate the sustained anxiolytic and antidepressant effects of BoNT-A in blepharospasm patients beyond motor symptom control.METHODS We recruited benign essential blepharospasm patients with BoNT-A treatment and collected their data to compare scale scores of Jankovic Rating Scale,Blepharospasm Disability Index,Self-rating Anxiety Scale(SAS),Self-rating Depression Scale(SDS),Hamilton Anxiety Scale and Hamilton Depression Scale between pretreatment(baseline)and pre-reinjection(treatment),to further assess the effects of repeated treatments with BoNT by using sub-group analyses in the certain special states.RESULTS A total of 21 eligible blepharospasm patients were with the mean age of 58.4 years and a male-to-female ratio of 1:6.Significantly decreases in the subscale scores of SDS and SAS,including SDS well-being index,decreased capacity and hard to decide,SAS inability to sit still and headache were showed at post-a single BoNT-A injection when scale scores of Jankovic Rating Scale and Blepharospasm Disability Index were matched between baseline and posttreatment.With each additional BoNT-A injection,the odds ratio of patients with the moderate depressive symptoms decreased by 92.6%.Moreover,BoNT treatment remained a decrease in the subscale scores of SDS and SAS in patients with repeated injections.CONCLUSION This study is to demonstrate that repeated BoNT-A injection have a long-lasting relief for anxiety and depressive symptoms in blepharospasm even after its motor symptom-modulating effects have diminished.
基金supported by IRP Consolidator Grant 2021(Grant Code:21/05 Irp),Fondazione Cittàdella Speranza,Italy(to AU)。
文摘Skeletal muscle is a dynamic tissue in which homeostasis and function are guaranteed by a very defined three-dimensional organization of myofibers in respect to other nonmuscular components,including the extracellular matrix and the nervous network.In particular,communication between myofibers and the nervous system is essential for the overall correct development and function of the skeletal muscle.A wide range of chronic,acute and genetic-based human pathologies that lead to the alteration of muscle function are associated with modified preservation of the fine interaction between motor neurons and myofibers at the neuromuscular junction.Recent advancements in the development of in vitro models for human skeletal muscle have shown that three-dimensionality and integration of multiple cell types are both key parameters required to unveil pathophysiological relevant phenotypes.Here,we describe recent achievement reached in skeletal muscle modeling which used biomaterials for the generation of three-dimensional constructs of myotubes integrated with motor neurons.
基金supported by the National Natural Science Foundation of China,No.81173344
文摘Myasthenia gravis is an autoimmune disorder in which antibodies have been shown to form against the nicotinic acetylcholine nicotinic postsynaptic receptors located at the neuromuscular junction.＂Warming yang and invigorating qi＂ acupuncture treatment has been shown to reduce serum inflammatory cytokine expression and increase transforming growth factor beta expression in rats with experimental autoimmune myasthenia gravis.However,few studies have addressed the effects of this type of acupuncture on the acetylcholine receptors at the neuromuscular junction.Here,we used confocal laser scanning microscopy to examine the area and density of immunoreactivity for an antibody to the nicotinic acetylcholine receptor at the neuromuscular junction in the phrenic nerve of rats with experimental autoimmune myasthenia gravis following ＂warming yang and invigorating qi＂ acupuncture therapy.Needles were inserted at acupressure points Shousanli（LI10）,Zusanli（ST36）,Pishu（BL20）,and Shenshu（BL23） once daily for 7 consecutive days.The treatment was repeated after 1 day of rest.We found that area and the integrated optical density of the immunoreactivity for the acetylcholine receptor at the neuromuscular junction of the phrenic nerve was significantly increased following acupuncture treatment.This outcome of the acupuncture therapy was similar to that of the cholinesterase inhibitor pyridostigmine bromide.These findings suggest that ＂warming yang and invigorating qi＂ acupuncture treatment increases acetylcholine receptor expression at the neuromuscular junction in a rat model of autoimmune myasthenia gravis.
基金supported by the National Key Research and Development Program of China (2022YFF1000500 to K.Z. and2021YFA1101100 to C.S.)Zhejiang Provincial Natural Science Foundation(LZ22C110002 to C.S.)National Natural Science Foundation of China(32271031 to K.Z. and 82230038, 31871203, and 32071032 to C.S.)。
文摘Amyotrophic lateral sclerosis(ALS) is a devastating motoneuron disease,in which lower motoneurons lose control of skeletal muscles.Degeneration of neuromuscular junctions(NMJs) occurs at the initial stage of ALS.Dipeptide repeat proteins(DPRs) from G4C2repeat-associated non-ATG(RAN) translation are known to cause C9orf72-associated ALS(C9-ALS).However,DPR inclusion burdens are weakly correlated with neurodegenerative areas in C9-ALS patients,indicating that DPRs may exert cell non-autonomous effects,in addition to the known intracellular pathological mechanisms.Here,we report that poly-GA,the most abundant form of DPR in C9-ALS,is released from cells.Local administration of poly-GA proteins in peripheral synaptic regions causes muscle weakness and impaired neuromuscular transmission in vivo.The NMJ structure cannot be maintained,as evidenced by the fragmentation of postsynaptic acetylcholine receptor(AChR) clusters and distortion of presynaptic nerve terminals.Mechanistic study demonstrated that extracellular poly-GA sequesters soluble Agrin ligands and inhibits Agrin-MuSK signaling.Our findings provide a novel cell non-autonomous mechanism by which poly-GA impairs NMJs in C9-ALS.Thus,targeting NMJs could be an early therapeutic intervention for C9-ALS.
基金Supported by the National Natural Science Foundation of China(No.30873244) in Guangzhou University of Traditional Chinese Medicine
文摘OBJECTⅣE: To investigate the protective role of Sijunzi decoction in neuromuscular junction(NMJ)and muscle cell mitochondria ultrastructure; as well as its effects on the amount of adenosine triphosphate(ATP) and the activities of mitochondrial respiratory chain complexes I, Ⅱ, Ⅲ, and Ⅳ in autoimmune myasthenia gravis rats.METHODS: An experimental autoimmune myasthenia gravis(EAMG) rat model was established by inoculating rats with acetylcholine receptors extracted from Torpedo. Rats were divided into three groups: model, prednisone, and Sijunzi decoction, and were fed physiological saline, prednisone, or Sijunzi decoction, respectively. NMJ and muscle cell mitochondria ultrastructure were observed by transmission electron microscope. The amount of ATP was assessed by high performance liquid chromatography. The activities ofmitochondrial respiratory chain complexes I, Ⅱ, Ⅲ,and Ⅳ was determined using the Clark oxygen electrode method.RESULTS: In the model group, there were sparse muscle fibers, with decreased mitochondria, and sparse, diffluent, or absent NMJ folds. After intervention with Sijunzi decoction, the above pathology changes were improved: muscle fiber structure was clear and complete; the mitochondria count was higher; and the NMJ structure was close to normal. Gastrocnemius muscle mitochondria in the model group produced significantly less ATP than those in the prednisone group(P<0.01). Conversely, the ATP of Sijunzi decoction group was significantly higher than prednisone group(P<0.01). The activities of gastrocnemius muscle mitochondrial respiratory chain complexes I, Ⅱ, Ⅲ, and Ⅳ in both the prednisone and Sijunzi decoction groups was dramatically higher compared with the model group(P<0.05). The activities of complexes I and Ⅲ in the Sijunzi decoction group were significantly higher than those in the prednisone group(P<0.05), but there was no obvious difference in complex Ⅱ or Ⅳ activities between the two groups(P>0.05).CONCLUSION: Sijunzi decoction improved pathological changes in muscle mitochondria and NMJ,enhanced the amount of ATP in gastrocnemius muscle mitochondria, and improved the activities of respiratory chain complexes I, Ⅱ, Ⅲ, and Ⅳ(especially I and Ⅲ) of the EAMG rats.
文摘The presynaptic active zone is a dynamic structure that orchestrates regulated release of neurotrans- mitters. Developmental and aging processes, and changes in neuronal network activity can all modulate the number, size and composition of active zone and thereby synaptic efficacy. However, very little is known about the mechanism that controls the structural stability of active zone. By study- ing a model synapse, the Drosophila neuromuscular iunction, our recent work shed light on how two scaffolding proteins at the active zone regulate active zone stability by promoting a localized dephos- phorylation event at the nerve terminal. Here we discuss the major insights from our findings and their implications for future research.
基金supported Fundación Reina Sofía Grant PI0006-08 to LTby Ministerio de Ciencia y Tecnología(ES)grant BFU2008-04683-C02-02 to LT
文摘Amyloid peptide（Aβ）oligomers are considered one of the primary causal factors for the synaptic loss characteristic of Alzheimer’s disease（AD）（Karran and De Strooper,2016）.However,Aβis generated in normal brains and accumulates at synaptic sites,which raises the question whether Aβplays a physiological role in synapses.
文摘The effects of manganese on neuromuscular junction transmission were studied in the isolated rat phrenic nerve diaphragm preparation, chick biventer cervicis nerve-muscle preparation and toad rectus abdominis muscle preparation. It wa found that manganese could adversely andconcentration-dependently inhibit muscular contraction response developed by indirect stimulation or direct stimulation. The IC50 of indirect and direct stimulation were 0.28 mmol/L and 10 mmol/Lrespectively. The time required to inhibit 50% of the contraction by indirect stimulation was 4.3±1. 0 min. The inhibitory action could be antagonized partially by high Ca2+. Manganese could reduce the seusitivity of the chick biventer cervicis muscle to acetylcholine, and shift the dose-respond curves foracetylcholine to the right in a nonparallel manner with a pD2' value of 2. 62. The result suggested that manganese acted on pre- and post-synaptic sites.
文摘The anatomical plan of adult muscle innervation is relatively simple： a given muscle comprises several motor units, each constituted by one motor neuron and the muscle fibers that it innervates; moreover, every muscle fiber is innervated by only one axonal terminal. In other words, motor units have separate, although intermingled, territories of inner- vation （Figure 1D）. In striking contrast, the anatomical organization is different at birth, when every muscle fiber is innervated by several nerve terminals belonging to different motor neurons, a condition known as ＂polyneuronal inner- vation＂, with the consequence that motor units have larger and overlapped territories of innervation （Figure 1A） （Tapia and Lichtman, 2012）. Soon after birth, redundant nerve ter- minals are progressively eliminated in a couple of weeks in rodents, and muscle fibers acquire their mature mononeu- ronal innervation. The same process occurs again in the adult muscle during reinnervation after nerve damage, when a transient period of polyneuronal innervation involves a good fraction of the fibers （Rich and Lichtman, 1989;
基金support from the Miami Project to Cure Paralysis,the Buoniconti Fund,and the Interdisciplinary Stem Cell Institute(to AK,WDD,JDG,and ADL)the unconditional support of Dean Henri Ford of the Leonard M.Miller School of Medicine at the University of Miami.
文摘Schwann cells are essential for the maintenance and function of motor neurons,axonal networks,and the neuromuscular junction.In amyotrophic lateral sclerosis,where motor neuron function is progressively lost,Schwann cell function may also be impaired.Recently,important signaling and potential trophic activities of Schwann cell-derived exosomal vesicles have been reported.This case report describes the treatment of a patient with advanced amyotrophic lateral sclerosis using serial intravenous infusions of allogeneic Schwann cell-derived exosomal vesicles,marking,to our knowledge,the first instance of such treatment.An 81-year-old male patient presented with a 1.5-year history of rapidly progressive amyotrophic lateral sclerosis.After initial diagnosis,the patient underwent a combination of generic riluzole,sodium phenylbutyrate for the treatment of amyotrophic lateral sclerosis,and taurursodiol.The patient volunteered to participate in an FDA-approved single-patient expanded access treatment and received weekly intravenous infusions of allogeneic Schwann cell-derived exosomal vesicles to potentially restore impaired Schwann cell and motor neuron function.We confirmed that cultured Schwann cells obtained from the amyotrophic lateral sclerosis patient via sural nerve biopsy appeared impaired(senescent)and that exposure of the patient’s Schwann cells to allogeneic Schwann cell-derived exosomal vesicles,cultured expanded from a cadaver donor improved their growth capacity in vitro.After a period of observation lasting 10 weeks,during which amyotrophic lateral sclerosis Functional Rating Scale-Revised and pulmonary function were regularly monitored,the patient received weekly consecutive infusions of 1.54×1012(×2),and then consecutive infusions of 7.5×1012(×6)allogeneic Schwann cell-derived exosomal vesicles diluted in 40 mL of Dulbecco’s phosphate-buffered saline.None of the infusions were associated with adverse events such as infusion reactions(allergic or otherwise)or changes in vital signs.Clinical lab serum neurofilament and cytokine levels measured prior to each infusion varied somewhat without a clear trend.A more sensitive in-house assay suggested possible inflammasome activation during the disease course.A trend for clinical stabilization was observed during the infusion period.Our study provides a novel approach to address impaired Schwann cells and possibly motor neuron function in patients with amyotrophic lateral sclerosis using allogeneic Schwann cell-derived exosomal vesicles.Initial findings suggest that this approach is safe.
文摘Substantial reductions in muscle motor unit numbers accompany ageing and occur in parallel the age-related changes in skeletal muscle mass and fibre number.These motor unit changes are reflected in reduced motor neuron numbers and size,axonal integrity and disrupted pre-and post-synaptic neuromuscular junctions(NMJ).Conversely,data indicate that the effects of ageing on neuromuscular transmission are relatively minor.Some authors have therefore argued that structural degeneration of motor axons and NMJ are unimportant in the pathogenesis of sarcopenia and for a non-neurogenic origin for ageing-induced muscle loss.Increased Reactive Oxygen Species(ROS)activities and changes in redox status are a feature of ageing and may play a key role in muscle loss through increased mitochondrial peroxide generation.This article will review the changes in motor units and NMJ seen during ageing and develop the argument that the changes in muscle mitochondrial peroxide generation and redox status may be caused by age-related changes in neuromuscular structure,but are not directly related to neuromuscular transmission.This provides an alternative explanation on how age-related changes in neural tissue might drive skeletal muscle fibre loss and weakness.Exercise interventions are known to reduce muscle loss and weakness in the elderly,but studies of such interventions on age-related changes in motor units,motor neurons or NMJ structure and function provide conflicting data.A further aim is therefore to identify areas where there is a need for novel research to understand whether,and how,targeted or long-term exercise might influence neuromuscular changes in ageing.
基金This work was supported by the National Natural Science Foundation of China,Nos.82071369(to PY)and 81971198(to BZ)Guangdong grant‘Key Technologies for Treatment of Brain Disorders’of China,No.2018B030332001(to LZ and PY)+2 种基金Guangzhou Key Projects of Brain Science and Brain-Like Intelligence Technology,China,No.20200730090(to LZ)the Natural Science Foundation of Beijing of China,No.7192103(to BZ)the Clinical Innovation Research Program of Guangzhou Regenerative Medicine and Health Guangdong Laboratory of China,No.2018GZR0201006(to PY).
文摘Inhibitor of DNA binding 2(Id2)can promote axonal regeneration after injury of the central nervous system.However,whether Id2 can promote axonal regeneration and functional recovery after peripheral nerve injury is currently unknown.In this study,we established a mouse model of bilateral sciatic nerve crush injury.Two weeks before injury,AAV9-Id2-3×Flag-GFP was injected stereotaxically into the bilateral ventral horn of lumbar spinal cord.Our results showed that Id2 was successfully delivered into spinal cord motor neurons projecting to the sciatic nerve,and the number of regenerated motor axons in the sciatic nerve distal to the crush site was increased at 2 weeks after injury,arriving at the tibial nerve and reinnervating a few endplates in the gastrocnemius muscle.By 1 month after injury,extensive neuromuscular reinnervation occurred.In addition,the amplitude of compound muscle action potentials of the gastrocnemius muscle was markedly recovered,and their latency was shortened.These findings suggest that Id2 can accelerate axonal regeneration,promote neuromuscular reinnervation,and enhance functional improvement following sciatic nerve injury.Therefore,elevating the level of Id2 in adult neurons may present a promising strategy for peripheral nerve repair following injury.The study was approved by the Experimental Animal Ethics Committee of Jinan University(approval No.20160302003)on March 2,2016.
基金supported by a grant from the National Key Basic Research Program of China,No.2014CB542202 and 2014CB542205the National Natural Science Foundation of China,No.30973095&81371354+2 种基金a grant from Science and Technology Project of Guangzhou,in China,No.12C32121609the Natural Science Foundation of Guangdong Province of China,No.S2013010014697 to Guo JSHong Kong SCI Fund to Wu WT
文摘In this study, we developed a novel artificial nerve graft termed self-assembling peptide nanofiber scaffold （SAPNS）-containing poly（lactic-co-glycolic acid） （PLGA） conduit （SPC） and used it to bridge a 10-mm-long sciatic nerve defect in the rat. Retrograde tracing, behavioral testing and histomorphometric analyses showed that compared with the empty PLGA conduit implantation group, the SPC implantation group had a larger number of growing and extending axons, a markedly increased diameter of regenerated axons and a greater thickness of the myelin sheath in the conduit. Furthermore, there was an increase in the size of the neuromuscular junction and myofiber diameter in the target muscle. These findings suggest that the novel artificial SPC nerve graft can promote axonal regeneration and remyelination in the transected peripheral nerve and can be used for repairing peripheral nerve injury.
文摘Myasthenia gravis is a rare and invalidating disease affecting the neuromuscular junction of voluntary muscles.The classical form of this autoimmune disease is characterized by the presence of antibodies against the most abundant protein in the neuromuscular junction,the nicotinic acetylcholine receptor.Other variants of the disease involve autoimmune attack of non-receptor scaffolding proteins or enzymes essential for building or maintaining the integrity of this peripheral synapse.This review summarizes the participation of the above proteins in building the neuromuscular junction and the destruction of this cholinergic synapse by autoimmune aggression in myasthenia gravis.The review also covers the application of a powerful biophysical technique,superresolution optical microscopy,to image the nicotinic receptor in live cells and follow its motional dynamics.The hypothesis is entertained that anomalous nanocluster formation by antibody crosslinking may lead to accelerated endocytic internalization and elevated turnover of the receptor,as observed in myasthenia gravis.
基金Supported by Shijiazhuang Science and Technology Bureau Foundation(No.131460613)Science and Technology Agency Foundation of Hebei Province(grant no.14277758D)+1 种基金Natural Science Foundation of Hebei Province(No.H2015106020)Key Project of Hebei Provincial Administration of Traditional Chinese Medicine(No.2014221)
文摘OBJECTIVE: To investigate the effect of Jianpiyiqi granule, prepared according to a Traditional Chinese Medicine(TCM) formula, on the ocular type of myasthenia gravis(MG) caused by a defect in synaptic transmission at the neuromuscular junction.METHODS: A total of 155 children with ocular MG were recruited from January 2008 to January 2015.All individuals received ineffective glucocorticoid treatment prior to admission, and were given Jianpiyiqi granules(two doses per day) for 12 months.Plasma levels of acetylcholine receptor autoantibodies(ACh R-Ab), cytokines, immune parameters and clinical score were analyzed.RESULTS: After intervention with Jianpiyiqi granule for 12 months, the levels of cytokines [including interleukin(IL)-6, IL-12, IL-17], immune parameters[including immunoglobulin G(Ig G), Ig M, free triiodothyronine, free thyroxine] and ACh R-Ab were sig-nificantly decreased(P = 0.042, P = 0.049, P = 0.011,P = 0.02, P = 0.04, P = 0.03, P = 0.01; F = 21.60, P =0.000). In contrast, IL-4 levels were significantly increased(P = 0.049). The absolute clinical score after treatment declined significantly compared with before treatment(F = 33.24, P = 0.000). The effective cure rate and the total effective rate gradually increased to a maximum of 149(96.2%) and 151(97.4%) in MG patients after 12 months of treatment, respectively.CONCLUSION: The Jianpiyiqi granule treatment lowered ACh R-Ab levels and improved cytokine and other immune parameter levels, which suggests that the granule could be an ancillary treatment for ocular MG in children caused by a defect in synaptic transmission at the neuromuscular junction.
