Neuromuscular Junction Transmission Research Articles

Motor unit adaptation to disuse: crossing the threshold from firing rate suppression to neuromuscular junction transmission.

Neural conditioning to scenarios of muscle disuse is undoubtedly a cause of functional decrements that typically exceed losses of muscle size. Yet establishing the relative contribution of neural adaptation and the specific location in the motor pathway remains technically challenging. Several studies of healthy humans have targeted this system and have established that motor unit firing rate is suppressed following disuse, with a number of critical caveats. It is suppressed in the immobilized limb only, at relative and absolute force levels, and preferentially targets lower-threshold motor units. Concomitantly, electrophysiological investigation of neuromuscular junction transmission (NMJ) stability of lower-threshold motor units reveals minimal change following disuse. These findings contrast with numerous other methods, which show clear involvement of the NMJ but are unable to characterize the motor unit to which they belong. It is physiologically plausible that decrements observed following disuse are a result of suppressed firing rate of lower-threshold motor units and impairment of transmission of the NMJ of higher-threshold motor units. As such, motor units within the pool should be viewed in light of their varying susceptibility to disuse.

Neuromuscular junction dysfunction in Lafora disease.

Lafora disease (LD), a fatal neurodegenerative disorder, is caused by mutations in the EPM2A gene encoding laforin phosphatase or NHLRC1 gene encoding malin ubiquitin ligase. LD symptoms include epileptic seizures, ataxia, dementia and cognitive decline. Studies on LD have primarily concentrated on the pathophysiology in the brain. A few studies have reported motor symptoms, muscle weakness and muscle atrophy. Intriguingly, skeletal muscles are known to accumulate Lafora polyglucosan bodies. Using laforin-deficient mice, an established model for LD, we demonstrate that LD pathology correlated with structural and functional impairments in the neuromuscular junction (NMJ). Specifically, we found impairment in NMJ transmission, which coincided with altered expression of NMJ-associated genes and reduced motor endplate area, fragmented junctions and loss of fully innervated junctions at the NMJ. We also observed a reduction in alpha-motor neurons in the lumbar spinal cord, with significant presynaptic morphological alterations. Disorganised myofibrillar patterns, slight z-line streaming and muscle atrophy were also evident in LD animals. In summary, our study offers insight into the neuropathic and myopathic alterations leading to motor deficits in LD.

AAV-NRIP gene therapy ameliorates motor neuron degeneration and muscle atrophy in ALS model mice

BackgroundAmyotrophic lateral sclerosis (ALS) is characterized by progressive motor neuron (MN) degeneration, leading to neuromuscular junction (NMJ) dismantling and severe muscle atrophy. The nuclear receptor interaction protein (NRIP) functions as a multifunctional protein. It directly interacts with calmodulin or α-actinin 2, serving as a calcium sensor for muscle contraction and maintaining sarcomere integrity. Additionally, NRIP binds with the acetylcholine receptor (AChR) for NMJ stabilization. Loss of NRIP in muscles results in progressive motor neuron degeneration with abnormal NMJ architecture, resembling ALS phenotypes. Therefore, we hypothesize that NRIP could be a therapeutic factor for ALS.MethodsWe used SOD1 G93A mice, expressing human SOD1 with the ALS-linked G93A mutation, as an ALS model. An adeno-associated virus vector encoding the human NRIP gene (AAV-NRIP) was generated and injected into the muscles of SOD1 G93A mice at 60 days of age, before disease onset. Pathological and behavioral changes were measured to evaluate the therapeutic effects of AAV-NRIP on the disease progression of SOD1 G93A mice.ResultsSOD1 G93A mice exhibited lower NRIP expression than wild-type mice in both the spinal cord and skeletal muscle tissues. Forced NRIP expression through AAV-NRIP intramuscular injection was observed in skeletal muscles and retrogradely transduced into the spinal cord. AAV-NRIP gene therapy enhanced movement distance and rearing frequencies in SOD1 G93A mice. Moreover, AAV-NRIP increased myofiber size and slow myosin expression, ameliorated NMJ degeneration and axon terminal denervation at NMJ, and increased the number of α-motor neurons (α-MNs) and compound muscle action potential (CMAP) in SOD1 G93A mice.ConclusionsAAV-NRIP gene therapy ameliorates muscle atrophy, motor neuron degeneration, and axon terminal denervation at NMJ, leading to increased NMJ transmission and improved motor functions in SOD1 G93A mice. Collectively, AAV-NRIP could be a potential therapeutic drug for ALS.

Sex disparities of human neuromuscular decline in older humans

AbstractFemales typically live longer than males but, paradoxically, spend a greater number of later years in poorer health. The neuromuscular system is a critical component of the progression to frailty, and motor unit (MU) characteristics differ by sex in healthy young individuals and may adapt to ageing in a sex‐specific manner due to divergent hormonal profiles. The purpose of this study was to investigate sex differences in vastus lateralis (VL) MU structure and function in early to late elderly humans. Intramuscular electromyography signals from 50 healthy older adults (M/F: 26/24) were collected from VL during standardized submaximal contractions and decomposed to quantify MU characteristics. Muscle size and neuromuscular performance were also measured. Females had higher MU firing rate (FR) than males (P = 0.025), with no difference in MU structure or neuromuscular junction transmission (NMJ) instability. All MU characteristics increased from low‐ to mid‐level contractions (P < 0.05) without sex × level interactions. Females had smaller cross‐sectional area of VL, lower strength and poorer force steadiness (P < 0.05). From early to late elderly, both sexes showed decreased neuromuscular function (P < 0.05) without sex‐specific patterns. Higher VL MUFRs at normalized contraction levels previously observed in young are also apparent in old individuals, with no sex‐based difference of estimates of MU structure or NMJ transmission instability. From early to late elderly, the deterioration of neuromuscular function and MU characteristics did not differ between sexes, yet function was consistently greater in males. These parallel trajectories underscore the lower initial level for older females and may offer insights into identifying critical intervention periods. imageKey points Females generally exhibit an extended lifespan when compared to males, yet this is accompanied by a poorer healthspan and higher rates of frailty. In healthy young people, motor unit firing rate (MUFR) at normalized contraction intensities is widely reported to be higher in females than in age‐matched males. Here we show in 50 people that older females have higher MUFR than older males with little difference in other MU parameters. The trajectory of decline from early to late elderly does not differ between sexes, yet function is consistently lower in females. These findings highlight distinguishable sex disparities in some MU characteristics and neuromuscular function, and suggest early interventions are needed for females to prevent functional deterioration to reduce the ageing health–sex paradox.

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.

КЛИНИЧЕСКОЕ НАБЛЮДЕНИЕ РАЗВИТИЯ МИАСТЕНИЧЕСКОГО СИНДРОМА ЛАМБЕРТА–ИТОНА У ПАЦИЕНТКИ С ТЯЖЕЛЫМ ТЕЧЕНИЕМ ЯЗВЕННОГО КОЛИТА

Authors represent the Russia’s first clinical case description of a pediatric patient with ulcerative colitis whose diagnosis was combined with Lambert-Eaton myasthenic syndrome (LEMS), a rare autoimmune disorder of neuromuscular junction transmission. The observed case draws specialists’ attention to the complexity of diagnosis and the importance of a multidisciplinary approach in the diagnosis and management of such patients. Another purpose was to increase physicians’ awareness of LEMS thereby reducing the period needed to establishing of the diagnosis, which in its turn improves the prognosis of the course of the disease for patients.

Effects of a ketogenic diet on motor function and motor unit number estimation in aged C57BL/6 mice

ObjectivePathological, age-related loss of muscle function, commonly referred to as sarcopenia, contributes to loss of mobility, impaired independence, as well as increased risk of adverse health events. Sarcopenia has been attributed to changes in both neural and muscular integrity during aging. Current treatment options are primarily limited to exercise and dietary protein fortification, but the therapeutic impact of these approaches are often inadequate. Prior work has suggested that a ketogenic diet (KD) might improve healthspan and lifespan in aging mice. Thus, we sought to investigate the effects of a KD on neuromuscular indices of sarcopenia in aged C57BL/6 mice. DesignA randomized, controlled pre-clinical experiment consisting of longitudinal assessments performed starting at 22-months of age (baseline) as well as 2, 6 and 10 weeks after the start of a KD vs. regular chow intervention. SettingPreclinical laboratory study. Sample sizeThirty-six 22-month-old mice were randomized into 2 dietary groups: KD [n = 22 (13 female and 9 male)], and regular chow [n = 15 (7 female and 8 male)]. MeasurementsMeasures included body mass, hindlimb and all limb grip strength, rotarod for motor performance, plantarflexion muscle contractility, motor unit number estimations (MUNE), and repetitive nerve stimulation (RNS) as an index of neuromuscular junction transmission efficacy recorded from the gastrocnemius muscle. At end point, muscle wet weight and blood samples were collected to assess blood beta-hydroxybutyrate levels. Statistical analysisPrimary analyses were two-way mixed effects ANOVA (diet and time × diet) to determine the effect of a KD on indices of motor function (grip, rotarod) and indices of motor unit (MUNE) and muscle (contractility) function. ResultsBeta-hydroxybutyrate (BHB) was significantly higher at 10 weeks in mice on a KD vs control group (0.83 ± 0.44 mmol/l versus 0.42 ± 0.21 mmol/l, η2 = 0.265, unpaired t-test, p = 0.0060). Mice on the KD intervention demonstrated significantly increased hindlimb grip strength (diet, p = 0.0001; time × diet, p = 0.0030), all limb grip strength (diet, p = 0.0005; time × diet, p = 0.0523), and rotarod latency to fall (diet, p = 0.0126; time × diet, p = 0.0021). Mice treated with the KD intervention also demonstrated increased MUNE (diet, p = 0.0465; time × diet, p = 0.0064), but no difference in muscle contractility (diet, p = 0.5248; time × diet, p = 0.5836) or RNS (diet, p = 0.3562; time × diet, p = 0.9871). ConclusionKD intervention improved neuromuscular and motor function in aged mice. This pre-clinical work suggests that further research is needed to assess the efficacy and physiological effects of a KD on indices of sarcopenia.

Stimulated Single Fiber Electromyography (SFEMG) for Assessing Neuromuscular Junction Transmission in Rodent Models

Stimulated Single Fiber Electromyography (SFEMG) for Assessing Neuromuscular Junction Transmission in Rodent Models

Neuromuscular dysfunction precedes muscle atrophy in C26 tumor-bearing mice

Background: Cancer patients frequently develop skeletal muscle wasting and weakness, which are hallmarks of cachexia, a wasting disease which worsens quality of life and is directly responsible for up to 30% of all cancer-related deaths. While advancements in detection and treatment have increased the population of cancer survivors, skeletal muscle dysfunction can persist for years following cancer remission. We previously demonstrated that late-stage cachexia is associated with impaired skeletal muscle innervation, linking loss of motor unit (MU) connectivity to cancer-induced wasting and weakness. In the present study, we investigated the onset of neuromuscular dysfunction in a preclinical model of cancer cachexia.
 Methods: CD2F1 male mice (8-week-old) were subcutaneously injected with C26 colorectal cancer cells (1.0x106) or saline and randomized into one the following timepoint groups: day 6, day 8, or day 10 (n=8-10). Animals were assessed for indices of MU connectivity and muscle function at each timepoint. Following functional assessment, skeletal muscles were harvested, weighed, and processed for molecular analyses.
 Results: 6 days post tumor injection, C26 hosts displayed reductions in neuromuscular junction (NMJ) transmission and motor unit connectivity, while muscle torque and mass were preserved. Specific torque was reduced in C26 hosts at day 8, while reductions in muscle mass or cross-sectional area did not occur until day 10. Molecular analysis revealed alterations of NMJ components as early as day 6 in C26 hosts, further suggesting that neuromuscular dysfunction precedes muscle atrophy.
 Conclusions: Altogether our data demonstrate that cancer-induced neuromuscular dysfunction precedes cancer-induced muscle atrophy, identifying impaired innervation as an early prognosticator of cachexia progression. Our work supports strategies to counteract impaired neuromuscular function in the treatment of cancer cachexia, in hopes of sustaining quality of life in cancer patients and the growing population of cancer survivors.

Unraveling the causes of sarcopenia: Roles of neuromuscular junction impairment and mitochondrial dysfunction.

Sarcopenia is a systemic skeletal muscle disease characterized by a decline in skeletal muscle mass and function. Originally defined as an age-associated condition, sarcopenia presently also encompasses muscular atrophy due to various pathological factors, such as intensive care unit-acquired weakness, inactivity, and malnutrition. The exact pathogenesis of sarcopenia is still unknown; herein, we review the pathological roles of the neuromuscular junction and mitochondria in this condition. Sarcopenia is caused by complex and interdependent pathophysiological mechanisms, including aging, neuromuscular junction impairment, mitochondrial dysfunction, insulin resistance, lipotoxicity, endocrine factors, oxidative stress, and inflammation. Among these, neuromuscular junction instability and mitochondrial dysfunction are particularly significant. Dysfunction in neuromuscular junction can lead to muscle weakness or paralysis. Mitochondria, which are plentiful in neurons and muscle fibers, play an important role in neuromuscular junction transmission. Therefore, impairments in both mitochondria and neuromuscular junction may be one of the key pathophysiological mechanisms leading to sarcopenia. Moreover, this article explores the structural and functional alterations in the neuromuscular junction and mitochondria in sarcopenia, suggesting that a deeper understanding of these changes could provide valuable insights for the prevention or treatment of sarcopenia.

Antibody Response to HERV-K and HERV-W Envelope Epitopes in Patients with Myasthenia Gravis.

Myasthenia gravis is an antibody-mediated autoimmune neurological disorder characterized by impaired neuromuscular junction transmission, resulting in muscle weakness. Recently, the involvement of Human Endogenous Retroviruses (HERVs) in the pathophysiology of different immune-mediated and neurodegenerative diseases, such as multiple sclerosis, has been demonstrated. We aimed to investigate potential immune system involvement related to humoral responses targeting specific epitopes of HERV-K and HERV-W envelope proteins in myasthenia gravis. Myasthenia gravis patients were recruited in the Neurology Unit, while healthy controls were selected from the Blood Transfusion Center, both affiliated with AOU Sassari. Highly immunogenic antigens of HERV-K and HERV-W envelope proteins were identified using the Immune Epitope Database (IEDB) online tool. These epitopes were utilized in enzyme-linked immunosorbent assays (ELISA) to detect autoantibodies in serum directed against these sequences. The study involved 39 Healthy Donors and 47 MG patients, further categorized into subgroups based on the presence of autoantibodies: MG-AchR Ab+ (n = 17), MG-MuSK Ab+ (n = 7), double seronegative patients (MG-DSN, n = 18), MG-LRP4 Ab + (n = 4), and one patient with no antibodies data (n = 1). Our findings revealed high levels of autoantibodies in myasthenia gravis patients directed against the HERV-K-env-su(19-37), HERV-K-env-su(109-126), HERV-K-env-su(164-186), HERV-W-env(93-108), HERV-W-env(129-14), and HERV-W-env(248-262) epitopes. Notably, these results remained highly significant even when patients were subdivided into MG-AchR Ab+ and MG-DSN subgroups. Correlation analysis further revealed significant positive associations between the antibody levels against HERV-K and HERV-W families in patients, suggesting a synergistic action of the two HERVs in the pathology context since this correlation is absent in the control group. This study marks the first identification of a specific humoral response directed against defined epitopes of HERV-K and HERV-W envelope proteins in myasthenia gravis patients. These findings lay the foundation for future investigations aimed at elucidating the molecular mechanisms driving this immune response. The detection of these autoantibodies suggests the potential for novel biomarkers, especially within the MG-DSN patient subgroup, addressing the need for new biomarkers in this population.

Serum Pentaxin 3 (PTX3) Promotes NLRP3 Inflammasome and Pyroptosis in Patients with Up-Regulated Myasthenia Gravis.

Myasthenia gravis (MG) is an autoantibodies-mediated autoimmune disease with the complications of neuromuscular junction transmission. In this study, we aimed to investigate the molecular regulatory roles of pentaxin 3 (PTX3) in patients and in animal model with MG and to explore its underlying mechanism. Patients with MG were identified and enrolled at our designated hospital and animal model was utilized for the proposed study. Enzyme-linked immunosorbent assay (ELISA) kit were used to quantify the IL-1β, IL-6, INF-γ, IL-17, TNF-α, anti-TAChR IgG/IgG1/IgG2b/IgG2c levels. Serum PTX3 expression level in patients with MG was up-regulated as compared to normal. Furthermore, we found increased expression level of mRNA and protein product of PTX3 in the mice with MG. PTX3 promoted inflammation, pyroptosis in patients as well as in the MG mouse model. In addition, PTX3 induced the STAT3/NLRP3 inflammasome and promoted gene synthesis of STAT3. We found that METTL3-mediated m6A modification decreases PTX3 stability. Our study suggests that the PTX3 is associated with the enhancement of inflammation and pyroptosis through regulating the STAT3/NLRP3 inflammasome signaling pathway at the early stage of the disease. The pro-inflammatory PTX3 facilitates the development of MG and it can be used as a potantial MG-associated diagnostic biomarker for MG.

Menstrual Cycle Associated Alteration of Vastus Lateralis Motor Unit Function

BackgroundEstrogen and progesterone are the primary female sex hormones and have net excitatory and inhibitory effects, respectively, on neuronal function. Fluctuating concentrations across the menstrual cycle has led to several lines of research in relation to neuromuscular function and performance; however evidence from animal and cell culture models has yet to be demonstrated in human motor units coupled with quantification of circulating hormones. Intramuscular electromyography was used to record motor unit potentials and corresponding motor unit potential trains from the vastus lateralis of nine eumenorrheic females during the early follicular, ovulation and mid luteal phases of the menstrual cycle, alongside assessments of neuromuscular performance. Multi-level regression models were applied to explore effects of time and of contraction level. Statistical significance was accepted as p < 0.05.ResultsKnee extensor maximum voluntary contraction, jump power, force steadiness, and balance did not differ across the menstrual phases (all p > 0.4). Firing rate of low threshold motor units (10% maximum voluntary contraction) was lower during the ovulation and mid luteal phases (β = − 0.82 Hz, p < 0.001), with no difference in motor unit potentials analysed from 25% maximum voluntary contraction contractions. Motor unit potentials were more complex during ovulation and mid luteal phase (p < 0.03), with no change in neuromuscular junction transmission instability (p > 0.3).ConclusionsAssessments of neuromuscular performance did not differ across the menstrual cycle. The suppression of low threshold motor unit firing rate during periods of increased progesterone may suggest a potential inhibitory effect and an alteration of recruitment strategy; however this had no discernible effect on performance. These findings highlight contraction level-dependent modulation of vastus lateralis motor unit function over the eumenorrheic cycle, occurring independently of measures of performance.

Neuromuscular junction transmission failure in aging and sarcopenia: The nexus of the neurological and muscular systems.

Sarcopenia, or age-related decline in muscle form and function, exerts high personal, societal, and economic burdens when untreated. Integrity and function of the neuromuscular junction (NMJ), as the nexus between the nervous and muscular systems, is critical for input and dependable neural control of muscle force generation. As such, the NMJ has long been a site of keen interest in the context of skeletal muscle function deficits during aging and in the context of sarcopenia. Historically, changes of NMJ morphology during aging have been investigated extensively but primarily in aged rodent models. Aged rodents have consistently shown features of NMJ endplate fragmentation and denervation. Yet, the presence of NMJ changes in older humans remains controversial, and conflicting findings have been reported. This review article describes the physiological processes involved in NMJ transmission, discusses the evidence that supports NMJ transmission failure as a possible contributor to sarcopenia, and speculates on the potential of targeting these defects for therapeutic development. The technical approaches that are available for assessment of NMJ transmission, whether each approach has been applied in the context of aging and sarcopenia, and the associated findings are summarized. Like morphological studies, age-related NMJ transmission deficits have primarily been studied in rodents. In preclinical studies, isolated synaptic electrophysiology recordings of endplate currentsor potentials have been mostly used, and paradoxically, have shown enhancement, rather than failure, with aging. Yet, in vivo assessment of single muscle fiber action potential generation using single fiber electromyography and nerve-stimulated muscle force measurements show evidence of NMJ failure in aged mice and rats. Together these findings suggest that endplate response enhancement may be a compensatory response to post-synaptic mechanisms of NMJ transmission failure in aged rodents. Possible, but underexplored, mechanisms of this failure are discussed including the simplification of post-synaptic folding and altered voltage-gated sodium channel clustering or function. In humans, there is limited clinical data that has selectively investigated single synaptic function in the context of aging. If sarcopenic older adults turn out to exhibit notable impairments in NMJ transmission (this has yet to be examined but based on available evidence appears to be plausible) then these NMJ transmission defects present a well-defined biological mechanism and offer a well-defined pathway for clinical implementation. Investigation of small molecules that are currently available clinically or being testing clinically in other disorders may provide a rapid route for development of interventions for older adults impacted by sarcopenia.

A systematic review of how cannabinoids affect motoneuron output.

Spinal motoneurons contain many ion channels and receptors upon which various cannabinoids are known to act. This scoping review involved the synthesis of evidence from literature published before August 2022 about the effects of cannabinoids on quantifiable measures of motoneuron output. Four databases (MEDLINE, Embase, PsycINFO, and Web of Science CoreCollection) were queried and 4,237 unique articles were retrieved. Twenty-three studies met the inclusion criteria, and the findings from these studies were grouped according to four emergent themes: rhythmic motoneuron output, afferent feedback integration, membrane excitability, and neuromuscular junction transmission. This synthesis of evidence suggests that CB1 agonists can increase the frequency of cyclical patterns of motoneuron output (i.e., fictive locomotion). Furthermore, a majority of the evidence indicates that activating CB1 receptors at motoneuron synapses promotes excitation of motoneurons by enhancing excitatory synaptic transmission and depressing inhibitory synaptic transmission. The collated study results reveal variable effects of cannabinoids on acetylcholine release at the neuromuscular junction, and the influence of cannabinoids in this area requires more work to ensure precision of findings for CB1 agonist and antagonist impact. Altogether, these reports indicate that the endocannabinoid system is integral within the final common pathway and can impact motor output. This review contributes to understanding the effects of endocannabinoids on synaptic integration at the motoneuron and modulation of motor output.

Age-related alterations in human motor units properties and in muscle innervation profile

Introduction: Mounting evidence suggests that motoneuron and neuromuscular junction (NMJ) degeneration, muscle fiber denervation and loss of motor units contribute to muscle wasting and weakness in old age. However, these aspects are still poorly investigated in humans. This study aimed at comparing the neuromuscular system integrity and function of young and older adults, with particular focus on NMJ and motor unit potential (MUP) characteristics. We hypothesized that older individuals would present altered electrophysiological properties and innervation profile. Methods: We recruited 55 healthy young individuals (YI) (aged 26.1±4.5 yr; 50% females) and 88 older individuals (OI) (aged 75.9±4.7 yr; 55% females). Muscle force was evaluated by isometric dynamometry, muscle morphology by ultrasound and neuromuscular excitability by compound motor unit action potential (CMAP). MUP properties and motor unit number estimate (iMUNE) were obtained by intramuscular electromyography (iEMG). In a sub-cohort of individuals (n=16 YI and n=34 OI), vastus lateralis (VL) muscle biopsies were obtained. We assessed denervation status by scoring neural cell adhesion molecule (NCAM) positive fibers. Generalized linear mixed models were carried out for iEMG data, while unpaired t-tests were carried out for all the other parameters. Results: OI showed alterations in muscle morphology when compared to YI, evident as smaller whole quadriceps cross-sectional area (p&lt;0.001) and VL fiber diameter (p&lt;0.01), together with smaller VL pennation angles (p&lt;0.001) and fascicle lengths (p&lt;0.05), resulting in an increased ultrasound sarcopenia index (p=0.001). Muscle force (p&lt;0.001) and CMAP (p&lt;0.001) were also largely impaired in OI, suggesting that muscle function and neuromuscular excitability are considerably affected by aging. iEMG analysis revealed changes in MUP turns (p&lt;0.001), near fiber (NF) MUP duration (p&lt;0.001) and NF count (p&lt;0.001) in OI, pointing towards an increased MUP complexity, in absence of sex differences. The iMUNE was reduced (p&lt;0.001) and the NMJ transmission stability was significantly altered in OI, as suggested by elevated NF jiggle (p&lt;0.001) and segmented jitter (p&lt;0.05). These electrophysiological alterations seem likely due to altered muscle innervation profile, as highlighted by an increased percentage of NCAM-positive fiber (p&lt;0.001). Conclusions: This study showed that changes in muscle morphology and function, MUP properties, motor units loss and denervation status occur in older humans; these may be serve as useful markers of human neuromuscular aging. The present work was funded by PRIN project NeuAge (2017CBF8NJ_001) to MVN and the Milky Way Foundation, the Baxter Foundation, and the Li Ka Shing Foundation to HMB. This is the full abstract presented at the American Physiology Summit 2023 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.

Acute adaptation of central and peripheral motor unit features to exercise-induced fatigue differs with concentric and eccentric loading.

What is the central question of this study? Conflicting evidence exists on motor unit (MU) firing rate in response to exercise-induced fatigue, possibly due to the contraction modality used: Do MU properties adapt similarly following concentric and eccentric loading? What is the main finding and its importance? MU firing rate increased following eccentric loading only despite a decline in absolute force. Force steadiness deteriorated following both loading methods. Central and peripheral MU features are altered in a contraction type-dependant manner, which is an important consideration for training interventions. Force output of muscle is partly mediated by the adjustment of motor unit (MU) firing rate (FR). Disparities in MU features in response to fatigue may be influenced by contraction type, as concentric (CON) and eccentric (ECC) contractions demand variable amounts of neural input, which alters the response to fatigue. This study aimed to determine the effects of fatigue following CON and ECC loading on MU features of the vastus lateralis (VL). High-density surface (HD-sEMG) and intramuscular (iEMG) electromyography were used to record MU potentials (MUPs) from bilateral VLs of 12 young volunteers (six females) during sustained isometric contractions at 25% and 40% of the maximum voluntary contraction (MVC), before and after completing CON and ECC weighted stepping exercise. Multi-level mixed effects linear regression models were performed with significance assumed as P<0.05. MVC decreased in both CON and ECC legs post-exercise (P<0.0001), as did force steadiness at both 25% and 40% MVC (P<0.004). MU FR increased in ECC at both contraction levels (P<0.001) but did not change in CON. FR variability increased in both legs at 25% and 40% MVC following fatigue (P<0.01). From iEMG measures at 25% MVC, MUP shape did not change (P>0.1) but neuromuscular junction transmission instability increased in both legs (P<0.04), and markers of fibre membrane excitability increased following CON only (P=0.018). These data demonstrate that central and peripheral MU features are altered following exercise-induced fatigue and differ according to exercise modality. This is important when considering interventional strategies targeting MU function.

Knowledge mapping of global trends for myasthenia gravis development: A bibliometrics analysis.

Myasthenia gravis (MG) is an autoimmune disease with acquired neuromuscular junction transmission disorders. In the last two decades, various pathogenesis, application of immunosuppressive agents, and targeted immunotherapy have been significant events. However, extracting the most critical information from complex events is very difficult to guide clinical work. Therefore, we used bibliometrics to summarize and look forward. Science Citation Index Expanded (SCI-E) from the Web of Science Core Collection (WoSCC) database was identified as a source of material for obtaining MG-related articles. Scimago Graphica, CiteSpace, VOSviewer, and bibliometrix were utilized for bibliometric analysis. Knowledge network graphs were constructed and visualized; countries, institutions, authors, journals, references, and keywords were evaluated. In addition, GraphPad Prism and Microsoft Excel 365 were applied for statistical analysis. As of October 25, 2022, 9,970 original MG-related articles were used for the bibliometric analysis; the cumulative number of citations to these articles was 236,987, with an H-index of 201. The United States ranked first in terms of the number of publications (2,877) and H-index (134). Oxford has the highest H-index (67), and Udice French Research University has the highest number of publications (319). The author with the highest average number of citations (66.19), publications (151), and H-index (53) was Vincent A. 28 articles have remained in an explosive period of citations. The final screening yielded predictive keywords related to clinical trials and COVID-19. We conducted a bibliometric analysis of 9,970 original MG-related articles published between 1966 and 2022. Ultimately, we found that future MG research hotspots include two major parts: (1) studies directly related to MG disease itself: clinical trials of various targeted biological agents; the relationship between biomarkers and therapeutic decisions, pathogenesis and outcome events, ultimately serving individualized management or precision therapy; (2) studies related to MG and COVID-19: different variants of COVID-19 (e.g., Omicron) on MG adverse outcome events; assessment of the safety of different COVID-19 vaccines for different subtypes of MG.

Myasthenia gravis: Frequently asked questions

Myasthenia gravis is a disorder of neuromuscular junction transmission, the result of antibodies against the post-synaptic aspect of the neuromuscular junction. Its clinical hallmark is fatigable weakness of skeletal muscles, which tends to vary in location and severity among patients. It is treated with pyridostigmine, immunotherapy, and thymectomy. Treatment is often individualized according to disease severity, antibody status, comorbidities, and other factors. This review uses a question-and-answer format to provide up-to-date, high-yield, clinically relevant information on myasthenia gravis.

Testing for N-type Voltage Gated Calcium Channel Antibody has Limited Utility in Evaluating Patients With Suspected Lambert-Eaton Myasthenic Syndrome

Objective To determine if testing for N-type voltage-gated calcium channel antibody improves diagnostic performance of serological testing for Lambert-Eaton Myasthenic Syndrome. Background Patients with suspected autoimmune neuromuscular junction transmission disorders are commonly tested for both P/Q-type (VGCC-P/Q) and N-type (VGCC-N) voltage-gated calcium channel antibodies to aid the diagnosis of Lambert-Eaton Myasthenic Syndrome (LEMS). Design/Methods This retrospective cross-sectional study included 93 patients diagnosed at Mayo Clinic with LEMS based on electrodiagnostic findings, clinical presentation and positive serology for VGCC-P/Q and/or VGCC-N. Results Forty-five patients (48.4%) were female, of median age 61 years (range 11- 99). Twenty-five (26.9%) were positive for both VGCC antibody types (reference interval &lt;0.04 nmol/L [VGCC-N] and &lt;0.03 nmol/L [VGCC-P/Q]); 67 (72.0%) were positive for VGCC-P/Q only and one (1.1%) was positive for VGCC-N only. The single VGCC-N positive only result [VGCC-N = 0.10 nmol/L; VGCC-PQ = 0.02 nmol/L] was from a patient with classic LEMS presentation and no evidence of malignancy by Chest CT. The prevalence of VGCC-N only positivity was lower than in the healthy population or other disease control populations. VGCC-P/Q antibody titers were higher in patients who had detectable co-existing VGCC-N antibody (median titer 1.58 versus 0.39 nmol/L, P = 0.02) and there was a positive correlation (r = 0.762, P &lt; 0.001) between VGCC-N and VGCC-P/Q titers in double positive cases. Dual positivity did not significantly increase the likelihood of an underlying cancer (40.9% versus 30.1%, P = 0.33). Conclusions Testing for VGCC-P/Q antibodies alone is sufficient in the serological evaluation of suspected LEMS cases. Inclusion of VGCC-N antibody testing does not improve diagnostic performance. A positive VGCC-N antibody did not significantly increase the risk of paraneoplastic LEMS.