Neuromuscular Research Articles

P.058 Neuromuscular neurologists’ experience in recognizing, diagnosing, and treating Long-chain fatty acid disorders (LC-FAOD): a national survey

Background: LC-FAOD may be missed in neuromuscular (NM) clinics due to its rarity and absence from common NM genetic panels. The Canadian Neuromuscular Disease Registry (CNDR) collects real-world patient data and includes a network of clinician-investigators. Our objective was to inform future registry work by evaluating diagnosis pathways for LC-FAOD patients and estimating the number followed at Canadian NM clinics. Methods: A questionnaire was developed with an expert committee and circulated to 111 CNDR-affiliated NM neurologists. Results: 12 neurologists in 5 provinces, primarily adult-treating (n=8) completed the survey (10.8% response rate). Eleven (91.7%) practiced for >10 years. Agreement trends existed between definition of, and tests to evaluate, rhabdomyolysis. Four clinics routinely follow LC-FAOD patients. In the last 1-2 years, respondents diagnosed approximately 91 patients with LC-FAOD (mean=7.5 per clinic). 83.3% never received continuing education on LC-FAOD, though 75% indicated interest in expert-led webinars. Further data will be presented. Conclusions: Low sample size limits conclusions about LC-FAOD clinical trends. Results suggest LC-FAOD may be under-diagnosed or not routinely followed by NM specialists, limiting viability of an LC-FAOD registry. Practitioners may be interested in LC-FAOD-specific education. Future work could include collaboration with metabolic geneticists on education initiatives to raise awareness and improve care for these patients.

Exploring side effects of corticosteroids in myasthenia gravis: Unveiling alternatives for safer treatment

Myasthenia Gravis (MG) is a chronic organ-specific autoimmune disease that weakens voluntary muscles by affecting neuromuscular junctions. The formation of antibodies against acetylcholine receptors is the most prevalent cause. The incidence and prevalence rates of (MG) are increasing exponentially (1). In addition to symptomatic medication, corticosteroids continue to be the first-line treatment for MG due to their affordability, ease of access, and efficacy (2). Although corticosteroids are frequently prescribed, they are not without drawbacks. Long-term corticosteroid use can result in various side effects, including osteoporosis, weight gain, acne, elevated blood pressure, mood fluctuations, and a cushingoid appearance. It has also been linked to rare complications such as gastric and esophageal irritation, compressive fractures, and aseptic femoral head fracture (3). Given the hazards associated with long-term corticosteroid use in treating MG, researchers and healthcare professionals should investigate alternative MG treatments. By doing so, new and safer treatment options can be identified, which could contribute to improved treatment and substantially enhance the quality of life for MG-affected populations. Numerous nonsteroidal medications, including mycophenolate mofetil, methotrexate, and azathioprine, have demonstrated success in clinical trials for kidney transplantation, rheumatoid arthritis, and myasthenia gravis, respectively. To confirm the efficacy of these pharmaceuticals in the treatment of MG, urgent research and trials based on in vitro and animal models are required. Based on well-designed clinical trials, these also require human testing (4). The tapering of prednisone is an alternative option. Prednisone tapering is still a problem in the therapeutic management of patients with generalized MG because, although it is a useful treatment, it has a number of adverse effects that make it necessary to find the lowest possible effective dose as quickly as feasible. Rituximab and azathioprine enable quick tapering. It is necessary to evaluate and contrast the corticosteroid-sparing effect of novel treatments with that of azathioprine and rituximab. Given their impact on MG status, it's possible that these novel therapies will make it possible to drastically cut back on corticosteroids or possibly stop taking them entirely(5) The abnormal immune responses in MG can be managed and resolved with the new drugs that specifically target them. These agents include chimeric antigen receptor T [CART-T] cell therapy, autologous stem cell transplantation, B cell depleting agents (anti-CD 19 and 20, and B cell activating factor [BAFF] inhibitors), proteosome inhibitors, terminal complement C5 inhibitors, Fc receptor inhibitors, T cells, and cytokine-based therapies (subcutaneous immunoglobulin [SCIG]). ---Continue

Treating myasthenia gravis beyond the eye clinic.

Myasthenia gravis (MG) is one of the most well characterised autoimmune disorders affecting the neuromuscular junction with autoantibodies targeting the acetylcholine receptor (AChR) complex. The vast majority of patients present with ocular symptoms including double vision and ptosis, but may progress on to develop generalised fatiguable muscle weakness. Severe involvement of the bulbar muscles can lead to dysphagia, dysarthria and breathing difficulties which can progress to myasthenic crisis needing ventilatory support. Given the predominant ocular onset of the disease, it is important that ophthalmologists are aware of the differential diagnosis, investigations and management including evolving therapies. When the disease remains localised to the extraocular muscles (ocular MG) IgG1 and IgG3 antibodies against the AChR (including clustered AChR) are present in nearly 50% of patients. In generalised MG this is seen in nearly 90% patients. Other antibodies include those against muscle specific tyrosine kinase (MuSK) and lipoprotein receptor related protein 4 (LRP4). Even though decremental response on repetitive nerve stimulation is the most well recognised neurophysiological abnormality, single fibre electromyogram (SFEMG) in experienced hands is the most sensitive test which helps in the diagnosis. Initial treatment should be using cholinesterase inhibitors and then proceeding to immunosuppression using corticosteroids and steroid sparing drugs. Patients requiring bulbar muscle support may need rescue therapies including plasma exchange and intravenous immunoglobulin (IVIg). Newer therapeutic targets include those against the B lymphocytes, complement system, neonatal Fc receptors (FcRn) and various other elements of the immune system.

Zilucoplan: a novel therapeutic approach to treat generalized myasthenia gravis

Myasthenia gravis (MG) is an autoimmune neuromuscular disease characterized by muscle weakness due to autoantibodies targeting the neuromuscular junction (NMJ). Zilucoplan, a novel complement inhibitor, has shown promise in managing generalized MG (gMG) by blocking the terminal complement cascade. This article provides an overview of Zilucoplan's pharmacological properties, including its mechanism of action, pharmacokinetics, and pharmacodynamics. Clinical trials, including a phase 3 trial (RAISE), have demonstrated Zilucoplan's efficacy in improving muscle strength and function, as measured by the MG-ADL (MG-activities of daily life) score, compared to placebo. The safety profile of Zilucoplan is favorable, with injection-site reactions being the most common adverse event. Notably, Zilucoplan effectively inhibits both wild-type and clinical C5 variants, expanding its potential utility for patients who do not respond well to existing treatments. While further research is needed to assess its long-term safety and efficacy, Zilucoplan represents a valuable addition to the therapeutic armamentarium for managing gMG.

Quantitative evaluation of factors influencing the 3 Hz repetitive nerve stimulation test in patients with amyotrophic lateral sclerosis.

Previous studies have suggested that treatments targeting the neuromuscular junction (NMJ) may play a role in the treatment of amyotrophic lateral sclerosis (ALS). However, factors impacting repetitive nerve stimulation (RNS), a technique to evaluate NMJ function, have yet to be fully elucidated. We aimed to identify independent factors contributing to the decremental response of the accessory nerve and evaluated its value in ALS clinical practice. A total of 626 patients who were diagnosed with ALS and underwent 3 Hz RNS tests on the accessory nerve were enrolled. Data on their clinical and electrophysiological indicators were divided into a training set (collected from June 2016 to December 2022) and a test set (collected from January to August 2023). Stepwise regression was used in independent variable selection and model building. Forty-two percent of patients had a decrement larger than 10% and 24% had a decrement larger than 15%. Onset age, sex, onset site, forced vital capacity (FVC) and motor unit potential (MUP) duration were independent factors contributing to the results of the RNS test. MUP duration had the greatest impact on decremental response, followed by FVC and onset age. The decremental response in females was larger than in males. Upper limb onset was found to contribute more to the decrement than lower limb or bulbar onset. In patients with ALS, NMJ safety factor is reduced during re-innervation. Decremental response is affected by multiple factors, which needs to be considered in clinical trials targeting the NMJ in these patients.

Strength Simulator Codes for Different Age Groups Considering Physiological Processes of Adaptation in Conditions of Strength Fitness

Topicality. Determination of optimal load parameters in fitness, based on age-related physiological features and adaptive changes of the neuromuscular system, is one of the most debated issues among leading scientists in this field. The research purpose was to develop models of code combinations for strength training of different age groups, considering physiological processes of human body adaptation to a stressful physical stimulus in the conditions of strength fitness. Methods. A comparative analysis of the research results on the effectiveness of using the optimal combination between the parameters of an external physical stimulus and the physiological features of the human body adaptive reactions has been used over the research. The results. It was established that in the process of developing code combinations for different age groups` strength training, the nature of the physiological reactions of their neuromuscular system to a stressful stimulus depend on the features of the load regime and the structure of the exercise program. For adolescence, considering the peculiarities of the physiological process of adaptation, it is used of moderate-intensity activity in combination with a complex of isolation exercises that promotes the processes of intra-muscular and inter-muscular coordination. For youth, in the process of developing code combinations aimed at the development of the main types of strength, the entire range of load modes is actively used. Particular attention is paid to stimuli that contribute to increasing the number of active (FF) motor units. In adulthood, especially in the second period, the content of code combinations to increase strength capabilities changes significantly. In the vast majority, this applies to the parameters of the intensity of load modes, the use of which will selectively affect the hypertrophy of a certain type of muscle fibers within intermuscular coordination. For the elderly, in the process of developing code combinations for strength training, priority is given to the selective activity of agonists during moderate-intensity isolated exercises. Findings. Strength Simulator codes considering physiological processes of the neuromuscular system adaptation to a stressful physical stimulus, is one of the innovative mechanisms for improving the training program of different age groups in the conditions of strength fitness.

CaMKIIβ deregulation contributes to neuromuscular junction destabilization in Myotonic Dystrophy type I

BackgroundMyotonic 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.MethodsWe compared changes in NMJs and activity-dependent signalling pathways in HSALR and Mbnl1ΔE3/ΔE3 mice, two established mouse models of DM1.ResultsMuscle 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, CaMKIIβ/βM overexpression normalized endplate fragmentation and synaptic gene expression in innervated Mbnl1ΔE3/ΔE3 muscle, but it did not restore denervation-induced synaptic gene up-regulation.ConclusionsOur results indicate that CaMKIIβ-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.

Protein networking: nicotinic acetylcholine receptors and their protein-protein-associations.

Nicotinic acetylcholine receptors (nAChR) are complex transmembrane proteins involved in neurotransmission in the nervous system and at the neuromuscular junction. nAChR disorders may lead to severe, potentially fatal pathophysiological states. To date, the receptor has been the focus of basic and applied research to provide novel therapeutic interventions. Since most studies have investigated only the nAChR itself, it is necessary to consider the receptor as part of its protein network to understand or elucidate-specific pathways. On its way through the secretory pathway, the receptor interacts with several chaperones and proteins. This review takes a closer look at these molecular interactions and focuses especially on endoplasmic reticulum biogenesis, secretory pathway sorting, Golgi maturation, plasma membrane presentation, retrograde internalization, and recycling. Additional knowledge regarding the nAChR protein network may lead to a more detailed comprehension of the fundamental pathomechanisms of diseases or may lead to the discovery of novel therapeutic drug targets.

Respiratory characterization of a humanized Duchenne muscular dystrophy mouse model

Duchenne muscular dystrophy (DMD) is the most common X-linked disease. DMD is caused by a lack of dystrophin, a critical structural protein in striated muscle. Dystrophin deficiency leads to inflammation, fibrosis, and muscle atrophy. Boys with DMD have progressive muscle weakness within the diaphragm that results in respiratory failure in the 2nd or 3rd decade of life. The most common DMD mouse model – the mdx mouse – is not sufficient for evaluating genetic medicines that specifically target the human DMD (hDMD) gene sequence. Therefore, a novel transgenic mouse carrying the hDMD gene with an exon 52 deletion was created (hDMDΔ52;mdx). We characterized the respiratory function and pathology in this model using whole body plethysmography, histology, and immunohistochemistry. At 6-months-old, hDMDΔ52;mdx mice have reduced maximal respiration, neuromuscular junction pathology, and fibrosis throughout the diaphragm, which worsens at 12-months-old. In conclusion, the hDMDΔ52;mdx exhibits moderate respiratory pathology, and serves as a relevant animal model to study the impact of novel genetic therapies, including gene editing, on respiratory function.

Synthesis and characterization of nitrogen-doped-MWCNT@cobalt oxide for nerve agent simulant detection

Organophosphorus nerve agents are toxic compounds that disrupt neuromuscular transmission by inhibiting the neurotransmitter enzyme, acetylcholinesterase, leading to rapid death. A hybrid composite was synthesized using a hydrothermal process for the early detection of dimethyl methyl phosphonate (DMMP), a simulant of the G-series nerve agent, sarin. Quartz crystal microbalance (QCM) and surface acoustic wave (SAW) sensors were used as detectors. Nitrogen-doped multiwalled carbon nanotubes (N-MWCNTs), cobalt oxide (Co3O4), and N-MWCNT@Co3O4 were compared to detect DMMP concentrations of 25–150 ppm. At 25 ppm, the differential frequencies (Δf) of the N-MWCNT, Co3O4, and N-MWCNT@Co3O4 sensors were 5.8, 2.3, and 99.5 Hz, respectively. The selectivity results revealed a preference for the DMMP rather than potential interference. The coefficients of determination (R2) of the N-MWCNT, Co3O4, and N-MWCNT@Co3O4 sensors for detecting 25–150 ppm DMMP were 0.983, 0.986, and 0.999, respectively. The response times of the N-MWCNT, Co3O4, and N-MWCNT@Co3O4 sensors for detecting 100 ppm DMMP were 25, 27, and 34 s, respectively, while the corresponding recovery times were 85, 105, and 181 s. The repeatability results revealed the reversible adsorption and desorption phenomena for the fixed DMMP concentration of 100 ppm. These unique findings show that synthesized materials can be used to detect organophosphorus nerve agents.

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

To determine whether development of neuromuscular junctions (NMJs) differs between extraocular muscles (EOMs) and other skeletal muscles. 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. 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. 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.

Transcriptomics reveals transient and dynamic muscle fibrosis and atrophy differences following spinal cord injury in rats.

The rate and magnitude of skeletal muscle wasting after severe spinal cord injury (SCI) exceeds most other disuse conditions. Assessing the time course of molecular changes can provide insight into the progression of muscle wasting post-SCI. The goals of this study were (1) to identify potential targets that may prevent the pathologic features of SCI in soleus muscles and (2) to establish therapeutic windows for treating these pathologic changes. Four-month-old Sprague-Dawley male rats received T9 laminectomy (SHAM surgery) or severe contusion SCI. Hindlimb locomotor function was assessed weekly, with soleus muscles obtained 1week, 2weeks, 1month and 3months post-surgery (n=6-7 per group per timepoint). RNA was extracted from muscles for bulk RNA-sequencing analysis (n=3-5 per group per timepoint). Differentially expressed genes (DEGs) were evaluated between age-matched SHAM and SCI animals. Myofiber size, muscle fibre type and fibrosis were assessed on contralateral muscles. SCI produced immediate and persistent hindlimb paralysis, with Basso-Beattie-Bresnahan locomotor scores remaining below 7 throughout the study, contributing to a progressive 25-50% lower soleus mass and myofiber atrophy versus SHAM (P<0.05 at all timepoints). Transcriptional comparisons of SCI versus SHAM resulted in 184 DEGs (1week), 436 DEGs (2weeks), 133 DEGs (1month) and 1200 DEGs (3months). Upregulated atrophy-related genes included those associated with cell senescence, nuclear factor kappa B, ubiquitin proteasome and unfolded protein response pathways, along with upregulated genes that negatively influence muscle growth through the transforming growth factor beta pathway and inhibition of insulin-like growth factor-I/Akt/mechanistic target of rapamycin and p38/mitogen-activated protein kinase signalling. Genes associated with extracellular matrix (ECM), including collagens, collagen crosslinkers, proteoglycans and those regulating ECM integrity, were enriched within upregulated DEGs at 1week but subsequently downregulated at 2weeks and 3months and were accompanied by >50% higher ECM areas and hydroxyproline levels in SCI muscles (P<0.05). Myofiber remodelling genes were enriched in upregulated DEGs at 2weeks and 1month and were downregulated at 3months. Genes that regulate neuromuscular junction remodelling were evident in muscles post-SCI, along with slow-to-fast fibre-type shifts: 1 week and 2 weeks SCI muscles were composed of 90% myosin heavy chain (MHC) type I fibres, which decreased to only 16% at 3months and were accompanied by 50% fibres containing MHC IIX (P<0.05). Metabolism genes were enriched in upregulated DEGs at 1month and were further enriched at 3months. Our results substantiate many known pathologic features of SCI-induced wasting in rat skeletal muscle and identify a progressive and dynamic transcriptional landscape within the post-SCI soleus. Future studies are warranted to consider these therapeutic treatment windows when countering SCI muscle pathology.

Female magnesium deficiency and its management: review of current knowledge

Magnesium is an important cofactor for metabolic reactions involving more than 300 enzymes, regulating a series of fundamental processes, such as myocardial contraction and blood pressure control, glucose regulation, participation in neuromuscular transmission. The prevalence of magnesium deficiency in various cohorts of fertile age women comprises up to 73.8 %. In clinical studies it was demonstrated that magnesium deficiency is associated with diseases and states such as dysmenorrhea, premenstrual syndrome (PMS), polycystic ovary syndrome (POS), climacteric syndrome, osteoporosis, use of combined oral contraceptives (COCs) and menopausal hormone therapy (MHT). Magnesium supplementation in combination with basic therapy can positively affect course and outcome of such pathologies. Magnesium organic salts could be used for countering magnesium deficiency. Among such agents, magnesium citrate has some advantage used in combination with pyridoxine (vitamin B6) providing additional effects. Health care professionals should be guided by the criteria for Mg-containing preparation selection, defined by the Russian Society of Obstetricians and Gynecologists (RSOG).

Muscular and neuronal control of voice production – forgotten findings, current concepts, and new developments

Voice production has been an area of interest in science since ancient times, and although advancing research has improved our understanding of the anatomy and function of the larynx, there is still little general consensus on these two topics. This review aims to outline the main developments in this field and highlight the areas where further research is needed. The most important hypotheses are presented and discussed highlighting the four main lines of research in the anatomy of the human larynx and their most important findings: (1) the arrangement of the muscle fibers of the thyroarytenoid muscle is not parallel to the vocal folds in the internal part (vocalis muscle), leading to altered properties during contraction; (2) the histological structure of the human vocal cords differs from other striated muscles; (3) there is a specialized type of heavy myosin chains in the larynx; and (4) the neuromuscular system of the larynx has specific structures that form the basis of an intrinsic laryngeal nervous system. These approaches are discussed in the context of current physiological models of vocal fold vibration, and new avenues of investigation are proposed.

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.

Функциональные резервы адаптации двигательной системы спортсменов с позиций физиолого-биомеханического подхода

Human adaptation to physical activity is manifested through mobilization of functional reserves. The purpose of this study was to provide a scientific and experimental substantiation of the adaptation of functional reserves of the motor system in athletes to specific sports activities from the standpoint of the physiological and biomechanical approach. Materials and methods. The study involved 704 elite athletes doing various sports. Reaction time was determined using the hardware and software package “Sports Psychophysiologist”. Stabilometric parameters were analysed using stabilometric platforms with the Smart BTS Motion System (BTS Bioengineering, Italy); the static analysis test protocol was applied. Electromyographic and biomechanical (kinematic and dynamic) movement control was performed using the Smart BTS Motion System as well. Functional reserves of the motor system were studied in line with the existing ideas about the components of the human body’s physiological reserves activated when doing sports. The following were evaluated: sensory systems (sensorimotor reactions, vestibular stability), movement control (stabilography, kinematics, dynamics), regulation of homeostasis, and implementation of activity (neuromuscular system). Results. We found that both single (in respect of urgent adaptation: an increase in voltage, optimization of kinematics and dynamics during a weightlifting snatch) and systematic (as regards long-term adaptation: improvement in reaction time and vestibular stability in athletes of various sports) training sessions involving maximum strength, power and speed contribute to the activation of the relevant sensory systems, central nervous system and muscular system, which form the basis of the motor system and increase its functionality as a whole.

Synaptic defects in a drosophila model of muscular dystrophy.

Muscular dystrophies are a devastating class of diseases that result in a progressive loss of muscle integrity. Duchenne Muscular Dystrophy, the most prevalent form of Muscular Dystrophy, is due to the loss of functional Dystrophin. While much is known regarding destruction of muscle tissue in these diseases, much less is known regarding the synaptic defects that also occur in these diseases. Synaptic defects are also among the earliest hallmarks of neurodegenerative diseases, including the neuromuscular disease Amyotrophic Lateral Sclerosis (ALS). Our current study investigates synaptic defects within adult muscle tissues as well as presynaptic motor neurons in Drosophila dystrophin mutants. Here we demonstrate that the progressive, age-dependent loss of flight ability in dystrophin mutants is accompanied by disorganization of Neuromuscular Junctions (NMJs), including impaired localization of both presynaptic and postsynaptic markers. We show that these synaptic defects, including presynaptic defects within motor neurons, are due to the loss of Dystrophin specifically within muscles. These results should help to better understand the early synaptic defects preceding cell loss in neuromuscular disorders.

Effective treatment with oral Salbutamol on late onset respiratory impairment in a DOK7 Congenital Myasthenia Syndrome: a case report.

DOK7 gene deficiency is a neuromuscular disease with an alteration in post-synaptic neuromuscular junction, leading to progressive respiratory impairment. Although, the therapy is not standardized, adrenergic agonists are suggested as first-line treatment. Case presentation: Our patient had an ambiguous late childhood-onset and had a generalized muscle weakness free of respiratory symptoms during the early phase of the disease. Subsequently, when the respiratory muscle and the diaphragm involvement was impaired, a substantial loss of respiratory function with hypopneas and severe desaturation was detected. It was noteworthy the striking respiratory beneficial impact of oral salbutamol in the resolution of symptoms and functional impairments, leading to a remarkable respiratory improvement and a better quality of life. Conclusion: Oral salbutamol treatment combined to a timely clinical recognition led to an outstanding respiratory improvement.

The MuSK agonist antibody protects the neuromuscular junction and extends the lifespan in C9orf72-ALS mice

The disassembly of the neuromuscular junction (NMJ) is an early event in amyotrophic lateral sclerosis (ALS), ultimately leading to motor dysfunction and lethal respiratory paralysis. The hexanucleotide GGGGCC repeat expansion in the C9orf72 gene is the most common genetic mutation, and the dipeptide repeat (DPR) proteins have been shown to cause neurodegeneration. While no drugs can treat ALS patients efficiently, new treatment strategies are urgently needed. Here, we report that a MuSK agonist antibody alleviates poly-PR-induced NMJ deficits in C9orf72-ALS mice. The HB9-PRF/F mice, which express poly-PR proteins in motor neurons, exhibited impaired motor behavior and NMJ deficits. Mechanistically, poly-PR proteins interacted with Agrin to disrupt the interaction between Agrin and Lrp4, leading to attenuated activation of MuSK. Treatment with a MuSK agonist antibody rescued NMJ deficits, and extended the lifespan of C9orf72-ALS mice. Moreover, impaired NMJ transmission was observed in C9orf72-ALS patients. These findings identify the mechanism by which poly-PR proteins attenuate MuSK activation and NMJ transmission, highlighting the potential of promoting MuSK activation with an agonist antibody as a therapeutic strategy to protect NMJ function and prolong the lifespan of ALS patients.

Nanodrug Delivery Systems for Myasthenia Gravis: Advances and Perspectives.

Myasthenia gravis (MG) is a rare chronic autoimmune disease caused by the production of autoantibodies against the postsynaptic membrane receptors present at the neuromuscular junction. This condition is characterized by fatigue and muscle weakness, including diplopia, ptosis, and systemic impairment. Emerging evidence suggests that in addition to immune dysregulation, the pathogenesis of MG may involve mitochondrial damage and ferroptosis. Mitochondria are the primary site of energy production, and the reactive oxygen species (ROS) generated due to mitochondrial dysfunction can induce ferroptosis. Nanomedicines have been extensively employed to treat various disorders due to their modifiability and good biocompatibility, but their application in MG management has been rather limited. Nevertheless, nanodrug delivery systems that carry immunomodulatory agents, anti-oxidants, or ferroptosis inhibitors could be effective for the treatment of MG. Therefore, this review focuses on various nanoplatforms aimed at attenuating immune dysregulation, restoring mitochondrial function, and inhibiting ferroptosis that could potentially serve as promising agents for targeted MG therapy.