Cellular and molecular alterations to muscles and neuromuscular synapses in a mouse model of MEGF10-related myopathy.

Loss-of-function mutations in MEGF10 lead to a rare and understudied neuromuscular disorder known as MEGF10-related myopathy. There are no treatments for the progressive respiratory distress, motor impairment, and structural abnormalities in muscles caused by the loss of MEGF10 function. In this study, we deployed cellular and molecular assays to obtain additional insights about MEGF10-related myopathy in juvenile, young adult, and middle-aged Megf10 knockout (KO) mice. We found fewer muscle fibers in juvenile and adult Megf10 KO mice, supporting published studies that MEGF10 regulates myogenesis by affecting satellite cell differentiation. Interestingly, muscle fibers do not exhibit morphological hallmarks of atrophy in either young adult or middle-aged Megf10 KO mice. We next examined the neuromuscular junction (NMJ), in which MEGF10 has been shown to concentrate postnatally, using light and electron microscopy. We found early and progressive degenerative features at the NMJs of Megf10 KO mice that include increased postsynaptic fragmentation and presynaptic regions not apposed by postsynaptic nicotinic acetylcholine receptors. We also found perisynaptic Schwann cells intruding into the NMJ synaptic cleft. These findings strongly suggest that the NMJ is a site of postnatal pathology in MEGF10-related myopathy. In support of these cellular observations, RNA-seq analysis revealed genes and pathways associated with myogenesis, skeletal muscle health, and NMJ stability dysregulated in Megf10 KO mice compared to wild-type mice. Altogether, these data provide new and valuable cellular and molecular insights into MEGF10-related myopathy.

Extreme Tolerance of Extraocular Muscles to Diseases and Aging: Why and How?

The extraocular muscles (EOMs) possess unique characteristics that set them apart from other skeletal muscles. These muscles, responsible for eye movements, exhibit remarkable resistance to various muscular dystrophies and aging, presenting a significant contrast to the vulnerability of skeletal muscles to these conditions. In this review, we delve into the cellular and molecular underpinnings of the distinct properties of EOMs. We explore their structural complexity, highlighting differences in fiber types, innervation patterns, and developmental origins. Notably, EOM fibers express a diverse array of myosin heavy-chain isoforms, retaining embryonic forms into adulthood. Moreover, their motor innervation is characterized by a high ratio of nerve fibers to muscle fibers and the presence of unique neuromuscular junctions. These features contribute to the specialized functions of EOMs, including rapid and precise eye movements. Understanding the mechanisms behind the resilience of EOMs to disease and aging may offer insights into potential therapeutic strategies for treating muscular dystrophies and myopathies affecting other skeletal muscles.

Building, Breaking, and Repairing Neuromuscular Synapses.

A coordinated and complex interplay of signals between motor neurons, skeletal muscle cells, and Schwann cells controls the formation and maintenance of neuromuscular synapses. Deficits in the signaling pathway for building synapses, caused by mutations in critical genes or autoantibodies against key proteins, are responsible for several neuromuscular diseases, which cause muscle weakness and fatigue. Here, we describe the role that four key genes, Agrin, Lrp4, MuSK, and Dok7, play in this signaling pathway, how an understanding of their mechanisms of action has led to an understanding of several neuromuscular diseases, and how this knowledge has contributed to emerging therapies for treating neuromuscular diseases.

CaMKIIß deregulation contributes to neuromuscular junction destabilization in Myotonic Dystrophy type I.

BACKGROUND: Myotonic Dystrophy type I (DM1) is the most common muscular dystrophy in adults. Previous reports have highlighted that neuromuscular junctions (NMJs) deteriorate in skeletal muscle from DM1 patients and mouse models thereof. However, the underlying pathomechanisms and their contribution to muscle dysfunction remain unknown. METHODS: We compared changes in NMJs and activity-dependent signalling pathways in HSALR and Mbnl1ΔE3/ΔE3 mice, two established mouse models of DM1. RESULTS: Muscle from DM1 mouse models showed major deregulation of calcium/calmodulin-dependent protein kinases II (CaMKIIs), which are key activity sensors regulating synaptic gene expression and acetylcholine receptor (AChR) recycling at the NMJ. Both mouse models exhibited increased fragmentation of the endplate, which preceded muscle degeneration. Endplate fragmentation was not accompanied by changes in AChR turnover at the NMJ. However, the expression of synaptic genes was up-regulated in mutant innervated muscle, together with an abnormal accumulation of histone deacetylase 4 (HDAC4), a known target of CaMKII. Interestingly, denervation-induced increase in synaptic gene expression and AChR turnover was hampered in DM1 muscle. Importantly, CaMKIIß/ßM overexpression normalized endplate fragmentation and synaptic gene expression in innervated Mbnl1ΔE3/ΔE3 muscle, but it did not restore denervation-induced synaptic gene up-regulation. CONCLUSIONS: Our results indicate that CaMKIIß-dependent and -independent mechanisms perturb synaptic gene regulation and muscle response to denervation in DM1 mouse models. Changes in these signalling pathways may contribute to NMJ destabilization and muscle dysfunction in DM1 patients.

Meta-analysis towards FSHD reveals misregulation of neuromuscular junction, nuclear envelope, and spliceosome.

Facioscapulohumeral muscular dystrophy (FSHD) is one of the most common autosomal dominant muscle disorders, yet no cure or amelioration exists. The clinical presentation is diverse, making it difficult to identify the actual driving pathomechanism among many downstream events. To unravel this complexity, we performed a meta-analysis of 13 original omics datasets (in total 171 FSHD and 129 control samples). Our approach confirmed previous findings about the disease pathology and specified them further. We confirmed increased expression of former proposed DUX4 biomarkers, and furthermore impairment of the respiratory chain. Notably, the meta-analysis provides insights about so far not reported pathways, including misregulation of neuromuscular junction protein encoding genes, downregulation of the spliceosome, and extensive alterations of nuclear envelope protein expression. Finally, we developed a publicly available shiny app to provide a platform for researchers who want to search our analysis for genes of interest in the future.

Neuromuscular Junction Development Differs Between Extraocular and Skeletal Muscles and Between Different Extraocular Muscles.

Purpose: To determine whether development of neuromuscular junctions (NMJs) differs between extraocular muscles (EOMs) and other skeletal muscles. Methods: Mouse EOMs, diaphragm, and tibialis anterior (TA) were collected at postnatal day (P)0, P3, P7, P10, P14, and P21, and 12 weeks. Whole muscles were stained with α-bungarotoxin, anti-neurofilament antibody, and slow or fast myosin heavy chain antibody, and imaged with a confocal microscope. Images were quantified using Imaris software. Results: NMJs in the EOMs show a unique pattern of morphological development compared to diaphragm and TA. At P0, diaphragm and TA NMJs were oval plaques; EOM single NMJs were long, thin rods. NMJs in the three muscle types progress to mature morphology at different rates. At all ages, EOM single NMJs were larger, especially relative to myofiber size. The inferior oblique and inferior rectus muscles show delayed single NMJ development compared to other EOMs. NMJs on multiply-innervated fibers in the EOMs vary widely in size, and there were no consistent differences between muscles or over time. Incoming motor nerves formed complex branching patterns, dividing first into superficial and deep branches, each of which branched extensively over the full width of the muscle. Motor axons that innervate multiply-innervated fibers entered the muscle with the axons that innervate singly-innervated fibers, then extended both proximally and distally. EOM NMJs had more subsynaptic nuclei than skeletal muscle NMJs throughout development. Conclusions: EOMs show a unique pattern of NMJ development and have more subsynaptic nuclei than other muscles, which may contribute to the exquisite control of eye movements.

Neuronal Circuit Dysfunction in Amyotrophic Lateral Sclerosis.

The primary neural circuit affected in Amyotrophic Lateral Sclerosis (ALS) patients is the corticospinal motor circuit, originating in upper motor neurons (UMNs) in the cerebral motor cortex which descend to synapse with the lower motor neurons (LMNs) in the spinal cord to ultimately innervate the skeletal muscle. Perturbation of these neural circuits and consequent loss of both UMNs and LMNs, leading to muscle wastage and impaired movement, is the key pathophysiology observed. Despite decades of research, we are still lacking in ALS disease-modifying treatments. In this review, we document the current research from patient studies, rodent models, and human stem cell models in understanding the mechanisms of corticomotor circuit dysfunction and its implication in ALS. We summarize the current knowledge about cortical UMN dysfunction and degeneration, altered excitability in LMNs, neuromuscular junction degeneration, and the non-cell autonomous role of glial cells in motor circuit dysfunction in relation to ALS. We further highlight the advances in human stem cell technology to model the complex neural circuitry and how these can aid in future studies to better understand the mechanisms of neural circuit dysfunction underpinning ALS.

Neuronal LRP4 directs the development, maturation and cytoskeletal organization of Drosophila peripheral synapses.

Synaptic development requires multiple signaling pathways to ensure successful connections. Transmembrane receptors are optimally positioned to connect the synapse and the rest of the neuron, often acting as synaptic organizers to synchronize downstream events. One such organizer, the LDL receptor-related protein LRP4, is a cell surface receptor that has been most well-studied postsynaptically at mammalian neuromuscular junctions. Recent work, however, identified emerging roles, but how LRP4 acts as a presynaptic organizer and the downstream mechanisms of LRP4 are not well understood. Here, we show that LRP4 functions presynaptically at Drosophila neuromuscular synapses, acting in motoneurons to instruct pre- and postsynaptic development. Loss of presynaptic LRP4 results in multiple defects, impairing active zone organization, synapse growth, physiological function, microtubule organization, synaptic ultrastructure and synapse maturation. We further demonstrate that LRP4 promotes most aspects of presynaptic development via a downstream SR-protein kinase, SRPK79D. These data demonstrate a function for presynaptic LRP4 as a peripheral synaptic organizer, highlight a downstream mechanism conserved with its CNS function in Drosophila, and underscore previously unappreciated but important developmental roles for LRP4 in cytoskeletal organization, synapse maturation and active zone organization.

Serial repetitive nerve stimulation studies in organophosphorus poisoning indicate two distinct pathophysiological processes occur at the neuromuscular junction in the intermediate syndrome.

INTRODUCTION: Intermediate syndrome is an important cause of respiratory failure following acute organophosphorus pesticide poisoning. The objective of this study was to examine the pathophysiology of this syndrome by analysis of sequential repetitive nerve stimulation studies in patients with acute organophosphorus pesticide poisoning. METHODS: Thirty-four consenting symptomatic patients with acute organophosphorus pesticide poisoning with intermediate syndrome (n = 10) or a milder forme fruste intermediate syndrome (n = 24) were assessed prospectively with daily physical examination and repetitive nerve stimulation done on the right and left median and ulnar nerves. The compound muscle action potential at 1, 3, 10, 15, 20 and 30 Hertz was measured with a train of ten stimuli. The amplitudes of the resulting stimuli were normalized to the first stimulus (100 per cent) and plotted against time. The decrease in the area under the curve of all the second stimulus compound muscle action potentials in the first 0.3 seconds was measured as a means of quantifying the refractory block. The decrease in the area under the curve under the 10, 15, 20 and 30 Hertz compound muscle action potentials relative to this pooled second stimulus compound muscle action potentials-area under the curve indicated the extent of additional rate-dependent block (decreasing compound muscle action potential-area under the curve over the first 0.3 seconds after the first stimulus with increasing Hertz). RESULTS: These new measurements strongly correlated with the severity of weakness. Refractory block was seen in most patients but was more severe in those with intermediate syndrome than those with forme fruste (partial) intermediate syndrome (median 55 per cent versus 16 per cent, P = 0.0001). Similar large differences were found for rate-dependent block (30 per cent versus 7 per cent, P = 0.001), which was uncommon in forme fruste intermediate syndrome but found in nine out of 10 patients with intermediate syndrome. Rate dependent block was generally only observed after 24 hours. The simplest strong predictor was total block at 30 Hertz repetitive nerve stimulation (89 per cent [interquartile range 73 to 94 per cent] versus 21 per cent [4 to 55 per cent]; P < 0.0001), which was very similar to total block calculated by summing other calculations. DISCUSSION: These findings likely represent depolarization and desensitization block from prolonged excessive cholinergic stimulation but it is not clear if these are from pre- or post-synaptic pathology. An animal model of intermediate syndrome with repetitive nerve stimulation studies might enable a better pathophysiological understanding of the two types of block. LIMITATIONS: The limited number of repetitive nerve stimulation studies performed were sufficient to demonstrate proof-of-concept, but further studies with more patients are needed to better define the correlates, clinical relevance and possible diagnostic/prognostic roles for the use of this technique. CONCLUSION: There are two easily distinguishable pathophysiological abnormalities in the neuromuscular block in intermediate syndrome. While they often coincide, both may be observed in isolation. The total and rate-dependent block at 30 Hertz are strongly associated with more severe weakness.

Distinct transcriptomic profile of satellite cells contributes to preservation of neuromuscular junctions in extraocular muscles of ALS mice.

Amyotrophic lateral sclerosis (ALS) is a fatal neuromuscular disorder characterized by progressive weakness of almost all skeletal muscles, whereas extraocular muscles (EOMs) are comparatively spared. While hindlimb and diaphragm muscles of end-stage SOD1G93A (G93A) mice (a familial ALS mouse model) exhibit severe denervation and depletion of Pax7+satellite cells (SCs), we found that the pool of SCs and the integrity of neuromuscular junctions (NMJs) are maintained in EOMs. In cell sorting profiles, SCs derived from hindlimb and diaphragm muscles of G93A mice exhibit denervation-related activation, whereas SCs from EOMs of G93A mice display spontaneous (non-denervation-related) activation, similar to SCs from wild-type mice. Specifically, cultured EOM SCs contain more abundant transcripts of axon guidance molecules, including Cxcl12, along with more sustainable renewability than the diaphragm and hindlimb counterparts under differentiation pressure. In neuromuscular co-culture assays, AAV-delivery of Cxcl12 to G93A-hindlimb SC-derived myotubes enhances motor neuron axon extension and innervation, recapitulating the innervation capacity of EOM SC-derived myotubes. G93A mice fed with sodium butyrate (NaBu) supplementation exhibited less NMJ loss in hindlimb and diaphragm muscles. Additionally, SCs derived from G93A hindlimb and diaphragm muscles displayed elevated expression of Cxcl12 and improved renewability following NaBu treatment in vitro. Thus, the NaBu-induced transcriptomic changes resembling the patterns of EOM SCs may contribute to the beneficial effects observed in G93A mice. More broadly, the distinct transcriptomic profile of EOM SCs may offer novel therapeutic targets to slow progressive neuromuscular functional decay in ALS and provide possible 'response biomarkers' in pre-clinical and clinical studies.

The intricate dance of non-coding RNAs in myasthenia gravis pathogenesis and treatment.

Myasthenia gravis (MG) stands as a perplexing autoimmune disorder affecting the neuromuscular junction, driven by a multitude of antibodies targeting postsynaptic elements. However, the mystery of MG pathogenesis has yet to be completely uncovered, and its heterogeneity also challenges diagnosis and treatment. Growing evidence shows the differential expression of non-coding RNAs (ncRNAs) in MG has played an essential role in the development of MG in recent years. Remarkably, these aberrantly expressed ncRNAs exhibit distinct profiles within diverse clinical subgroups and among patients harboring various antibody types. Furthermore, they have been implicated in orchestrating the production of inflammatory cytokines, perturbing the equilibrium of T helper 1 cells (Th1), T helper 17 cells (Th17), and regulatory T cells (Tregs), and inciting B cells to generate antibodies. Studies have elucidated that certain ncRNAs mirror the clinical severity of MG, while others may hold therapeutic significance, showcasing a propensity to return to normal levels following appropriate treatments or potentially foretelling the responsiveness to immunosuppressive therapies. Notably, the intricate interplay among these ncRNAs does not follow a linear trajectory but rather assembles into a complex network, with competing endogenous RNA (ceRNA) emerging as a prominent hub in some cases. This comprehensive review consolidates the landscape of dysregulated ncRNAs in MG, briefly delineating their pivotal role in MG pathogenesis. Furthermore, it explores their promise as prospective biomarkers, aiding in the elucidation of disease subtypes, assessment of disease severity, monitoring therapeutic responses, and as novel therapeutic targets.

Identification of secretory autophagy as a mechanism modulating activity-induced synaptic remodeling.

The ability of neurons to rapidly remodel their synaptic structure and strength in response to neuronal activity is highly conserved across species and crucial for complex brain functions. However, mechanisms required to elicit and coordinate the acute, activity-dependent structural changes across synapses are not well understood, as neurodevelopment and structural plasticity are tightly linked. Here, using an RNAi screen in Drosophila against genes affecting nervous system functions in humans, we uncouple cellular processes important for synaptic plasticity and synapse development. We find mutations associated with neurodegenerative and mental health disorders are 2-times more likely to affect activity-induced synaptic remodeling than synapse development. We report that while both synapse development and activity-induced synaptic remodeling at the fly NMJ require macroautophagy (hereafter referred to as autophagy), bifurcation in the autophagy pathway differentially impacts development and synaptic plasticity. We demonstrate that neuronal activity enhances autophagy activation but diminishes degradative autophagy, thereby driving the pathway towards autophagy-based secretion. Presynaptic knockdown of Snap29, Sec22, or Rab8, proteins implicated in the secretory autophagy pathway, is sufficient to abolish activity-induced synaptic remodeling. This study uncovers secretory autophagy as a transsynaptic signaling mechanism modulating synaptic plasticity.

Human skeletal muscle aging atlas.

Skeletal muscle aging is a key contributor to age-related frailty and sarcopenia with substantial implications for global health. Here we profiled 90,902 single cells and 92,259 single nuclei from 17 donors to map the aging process in the adult human intercostal muscle, identifying cellular changes in each muscle compartment. We found that distinct subsets of muscle stem cells exhibit decreased ribosome biogenesis genes and increased CCL2 expression, causing different aging phenotypes. Our atlas also highlights an expansion of nuclei associated with the neuromuscular junction, which may reflect re-innervation, and outlines how the loss of fast-twitch myofibers is mitigated through regeneration and upregulation of fast-type markers in slow-twitch myofibers with age. Furthermore, we document the function of aging muscle microenvironment in immune cell attraction. Overall, we present a comprehensive human skeletal muscle aging resource ( https://www.muscleageingcellatlas.org/ ) together with an in-house mouse muscle atlas to study common features of muscle aging across species.

scRNA-seq data from the larval Drosophila ventral cord provides a resource for studying motor systems function and development.

The Drosophila larval ventral nerve cord (VNC) shares many similarities with the spinal cord of vertebrates and has emerged as a major model for understanding the development and function of motor systems. Here, we use high-quality scRNA-seq, validated by anatomical identification, to create a comprehensive census of larval VNC cell types. We show that the neural lineages that comprise the adult VNC are already defined, but quiescent, at the larval stage. Using fluorescence-activated cell sorting (FACS)-enriched populations, we separate all motor neuron bundles and link individual neuron clusters to morphologically characterized known subtypes. We discovered a glutamate receptor subunit required for basal neurotransmission and homeostasis at the larval neuromuscular junction. We describe larval glia and endorse the general view that glia perform consistent activities throughout development. This census represents an extensive resource and a powerful platform for future discoveries of cellular and molecular mechanisms in repair, regeneration, plasticity, homeostasis, and behavioral coordination.

hkb is required for DIP-α expression and target recognition in the Drosophila neuromuscular circuit.

Our nervous system contains billions of neurons that form precise connections with each other through interactions between cell surface proteins. In Drosophila, the Dpr and DIP immunoglobulin protein subfamilies form homophilic or heterophilic interactions to instruct synaptic connectivity, synaptic growth, and cell survival. However, the upstream regulatory mechanisms of Dprs and DIPs are not clear. On the other hand, while transcription factors have been implicated in target recognition, their downstream cell surface proteins remain mostly unknown. We conduct an F1 dominant modifier genetic screen to identify regulators of Dprs and DIPs. We identify huckebein (hkb), a transcription factor previously implicated in target recognition of the dorsal Is motor neuron. We show that hkb genetically interacts with DIP-α and loss of hkb leads to complete removal of DIP-α expression specifically in dorsal Is motor neurons. We then confirm that this specificity is through the dorsal Is motor neuron specific transcription factor, even-skipped (eve), which acts downstream of hkb. Analysis of the genetic interaction between hkb and eve reveals that they act in the same pathway to regulate dorsal Is motor neuron connectivity. Our study provides insight into the transcriptional regulation of DIP-α and suggests that distinct regulatory mechanisms exist for the same CSP in different neurons.

The CHD Protein Kismet Restricts the Synaptic Localization of Cell Adhesion Molecules at the Drosophila Neuromuscular Junction.

The appropriate expression and localization of cell surface cell adhesion molecules must be tightly regulated for optimal synaptic growth and function. How neuronal plasma membrane proteins, including cell adhesion molecules, cycle between early endosomes and the plasma membrane is poorly understood. Here we show that the Drosophila homolog of the chromatin remodeling enzymes CHD7 and CHD8, Kismet, represses the synaptic levels of several cell adhesion molecules. Neuroligins 1 and 3 and the integrins αPS2 and ßPS are increased at kismet mutant synapses but Kismet only directly regulates transcription of neuroligin 2. Kismet may therefore regulate synaptic CAMs indirectly by activating transcription of gene products that promote intracellular vesicle trafficking including endophilin B (endoB) and/or rab11. Knock down of EndoB in all tissues or neurons increases synaptic FasII while knock down of EndoB in kis mutants does not produce an additive increase in FasII. In contrast, neuronal expression of Rab11, which is deficient in kis mutants, leads to a further increase in synaptic FasII in kis mutants. These data support the hypothesis that Kis influences the synaptic localization of FasII by promoting intracellular vesicle trafficking through the early endosome.

Postsynaptic ß1 spectrin maintains Na+ channels at the neuromuscular junction.

Spectrins function together with actin as obligatory subunits of the submembranous cytoskeleton. Spectrins maintain cell shape, resist mechanical forces, and stabilize ion channel and transporter protein complexes through binding to scaffolding proteins. Recently, pathogenic variants of SPTBN4 (ß4 spectrin) were reported to cause both neuropathy and myopathy. Although the role of ß4 spectrin in neurons is mostly understood, its function in skeletal muscle, another excitable tissue subject to large forces, is unknown. Here, using a muscle specific ß4 spectrin conditional knockout mouse, we show that ß4 spectrin does not contribute to muscle function. In addition, we show ß4 spectrin is not present in muscle, indicating the previously reported myopathy associated with pathogenic SPTBN4 variants is neurogenic in origin. More broadly, we show that α2, ß1 and ß2 spectrins are found in skeletal muscle, with α2 and ß1 spectrins being enriched at the postsynaptic neuromuscular junction (NMJ). Surprisingly, using muscle specific conditional knockout mice, we show that loss of α2 and ß2 spectrins had no effect on muscle health, function or the enrichment of ß1 spectrin at the NMJ. Muscle specific deletion of ß1 spectrin also had no effect on muscle health, but, with increasing age, resulted in the loss of clustered NMJ Na+ channels. Together, our results suggest that muscle ß1 spectrin functions independently of an associated α spectrin to maintain Na+ channel clustering at the postsynaptic NMJ. Furthermore, despite repeated exposure to strong forces and in contrast to neurons, muscles do not require spectrin cytoskeletons to maintain cell shape or integrity. KEY POINTS: The myopathy found in pathogenic human SPTBN4 variants (where SPTBN4 is the gene encoding ß4 spectrin) is neurogenic in origin. ß1 spectrin plays essential roles in maintaining the density of neuromuscular junction Nav1.4 Na+ channels. By contrast to the canonical view of spectrin organization and function, we show that ß1 spectrin can function independently of an associated α spectrin. Despite the large mechanical forces experienced by muscle, we show that spectrins are not required for muscle cell integrity. This is in stark contrast to red blood cells and the axons of neurons.

Recombinant Acetylcholine Receptor Immunization Induces a Robust Model of Experimental Autoimmune Myasthenia Gravis in Mice.

Myasthenia gravis (MG) is a prototypical autoimmune disease of the neuromuscular junction (NMJ). The study of the underlying pathophysiology has provided novel insights into the interplay of autoantibodies and complement-mediated tissue damage. Experimental autoimmune myasthenia gravis (EAMG) emerged as a valuable animal model, designed to gain further insight and to test novel therapeutic approaches for MG. However, the availability of native acetylcholine receptor (AChR) protein is limited favouring the use of recombinant proteins. To provide a simplified platform for the study of MG, we established a model of EAMG using a recombinant protein containing the immunogenic sequence of AChR in mice. This model recapitulates key features of EAMG, including fatigable muscle weakness, the presence of anti-AChR-antibodies, and engagement of the NMJ by complement and a reduced NMJ density. Further characterization of this model demonstrated a prominent B cell immunopathology supported by T follicular helper cells. Taken together, the herein-presented EAMG model may be a valuable tool for the study of MG pathophysiology and the pre-clinical testing of therapeutic applications.

MuSK Myasthenia Gravis-Potential Pathomechanisms and Treatment Directed against Specific Targets.

Myasthenia gravis (MG) is an autoimmune disease in which autoantibodies target structures within the neuromuscular junction, affecting neuromuscular transmission. Muscle-specific tyrosine kinase receptor-associated MG (MuSK-MG) is a rare, often more severe, subtype of the disease with different pathogenesis and specific clinical features. It is characterized by a more severe clinical course, more frequent complications, and often inadequate response to treatment. Here, we review the current state of knowledge about potential pathomechanisms of the MuSK-MG and their therapeutic implications as well as ongoing research in this field, with reference to key points of immune-mediated processes involved in the background of myasthenia gravis.

Disruption of Neuromuscular Junction Following Spinal Cord Injury and Motor Neuron Diseases.

The neuromuscular junction (NMJ) is a crucial structure that connects the cholinergic motor neurons to the muscle fibers and allows for muscle contraction and movement. Despite the interruption of the supraspinal pathways that occurs in spinal cord injury (SCI), the NMJ, innervated by motor neurons below the injury site, has been found to remain intact. This highlights the importance of studying the NMJ in rodent models of various nervous system disorders, such as amyotrophic lateral sclerosis (ALS), Charcot-Marie-Tooth disease (CMT), spinal muscular atrophy (SMA), and spinal and bulbar muscular atrophy (SBMA). The NMJ is also involved in myasthenic disorders, such as myasthenia gravis (MG), and is vulnerable to neurotoxin damage. Thus, it is important to analyze the integrity of the NMJ in rodent models during the early stages of the disease, as this may allow for a better understanding of the condition and potential treatment options. The spinal cord also plays a crucial role in the functioning of the NMJ, as the junction relays information from the spinal cord to the muscle fibers, and the integrity of the NMJ could be disrupted by SCI. Therefore, it is vital to study SCI and muscle function when studying NMJ disorders. This review discusses the formation and function of the NMJ after SCI and potential interventions that may reverse or improve NMJ dysfunction, such as exercise, nutrition, and trophic factors.