REVIEW | doi:10.20944/preprints201909.0276.v2
Subject: Life Sciences, Cell & Developmental Biology Keywords: synapse; agrin; MuSK; Lrp4; neuromuscular junction
Online: 29 September 2019 (05:04:45 CEST)
The vertebrate skeletal neuromuscular junction (NMJ) has long served as a model system for studying synapse structure, function and development. Over the last several decades a neuron-specific isoform of agrin, a heparan sulfate proteoglycan, has been identified as playing a central role in synapse formation at all vertebrate skeletal neuromuscular synapses. While agrin was initially postulated to be the inductive molecule that initiates synaptogenesis, this model has been modified in response to work showing that postsynaptic differentiation can develop in the absence of innervation, and that synapses can form in transgenic mice in which the agrin gene is ablated. In place of a unitary mechanism for neuromuscular synapse formation, studies in both mice and zebrafish have led to the proposal that two mechanisms mediate synaptogenesis, with some synapses being induced by nerve contact while others involve the incorporation of prepatterned postsynaptic structures. Moreover, the current model also proposes that agrin can serve two functions, to induce synaptogenesis and to stabilize new synapses, once these are formed. This review examines the evidence for these propositions, and concludes that it remains possible that a single molecular mechanism mediates synaptogenesis at all NMJs, and that agrin acts as a stabilizer, while its role as inducer is open to question. Moreover, if agrin does not act to initiate synaptogenesis, it follows that as yet uncharacterized molecular interactions are required to play this essential inductive role. Several alternatives to agrin for this function are suggested, including focal pericellular proteolysis and integrin signaling, but all require experimental validation.
ARTICLE | doi:10.20944/preprints202007.0384.v1
Subject: Medicine & Pharmacology, Other Keywords: neuromuscular disorders; dynamic arm support; activity monitoring; motor performance
Online: 17 July 2020 (14:17:28 CEST)
Neuromuscular disorders cause progressive muscular weakness, which limits upper extremity mobility and performance during activities of daily life. A dynamic arm support can improve mobility and quality of life. However, their use is often discontinued over time for unclear reasons. This study aimed to evaluate whether users of dynamic arm supports demonstrate and perceive quantifiable mobility benefits over a period of two months. Nine users of dynamic arm supports were included in this observational study. They had different neuromuscular disorders and collectively used four different arm supports. They were observed for three consecutive weeks during which they were equipped with a multi-sensor network of accelerometers to assess the actual use of the arm support and they were asked to provide self-reports on the perceived benefits of the devices. Benefits were experienced mainly during anti-gravity activities and the measured use did not change over time. The self-reports provided contextual information in domains such as participation to social life, in addition to the sensor system. However self-reports overestimated the actual use by up to three-fold compared to the accelerometer measures. A combination of objective and subjective methods is recommended for meaningful and quantifiable mobility benefits during activities of daily life.
ARTICLE | doi:10.20944/preprints202206.0007.v1
Subject: Medicine & Pharmacology, Sport Sciences & Therapy Keywords: neuromuscular fatigue; muscle bioelectrical activity; rating of perceived exertion; cycling exercise
Online: 1 June 2022 (06:23:30 CEST)
This study explored the development of neuromuscular fatigue responses during progressive cycling exercise. The sample comprised 32 participants aged 22.0 ± 0.54 years who were assigned into three groups: endurance-trained group (END, triathletes, n = 10), strength-trained group (STR, body-builders, n = 10), and control group (CON, recreationally active students, n = 12). The incremental cycling exercise was performed using a progressive protocol starting with a 3 min resting measurement and then 50 W workload with subsequent constant increments of 50 W every 3 minutes until 200 W. Surface electromyography (SEMG) of rectus femoris muscles was recorded during the final 30 s of each of the four workloads. During the final 15 s of each workload, participants rated their overall perception of effort using the 20-point RPE scale. Post-hoc Tukey’s HSD testing showed significant differences between END and STR groups in MF and MPF across all workloads (p < 0.001 and p < 0.01, respectively). Athletes from END group had significantly lower AEMG responses than those from STR (p = 0.0093) and CON group (p = 0.0006). Increasing RPE points from 50 to 200 W were significantly higher in STR than in END group (p < 0.001). In conclusion, there is a significant variation in neuromuscular fatigue profiles between athletes with different training backgrounds when a cycling exercise is applied. The approximately linear trend of the SEMG and RPE values of both groups of athletes with increasing workload support the increased skeletal muscle recruitment with perceived exertion or fatiguing effect.
ARTICLE | doi:10.20944/preprints202208.0184.v1
Subject: Medicine & Pharmacology, Sport Sciences & Therapy Keywords: Exergames; Kinect; neuromuscular disesase; physical disability; rehabilitation; serious games; Virtual reality rehabilitation
Online: 10 August 2022 (03:24:24 CEST)
This paper presents a modular approach to generic exergame design that combines custom physical exercises in a meaningful and motivating story. This aims to provide a tool that can be individually tailored and adapted to people with different needs, making it applicable to different diseases and states of disease. The game is based on motion capturing and integrates four example exercises that can be configured via our therapeutic web platform "Blexer-med". To prove the feasibility for a wide range of different users, evaluation tests were performed on 14 patients with various types and degrees of neuromuscular disorders, classified into three groups based on strength and autonomy. Users were free to choose their schedule and frequency. Game scores and three surveys (before, during, and after the intervention) showed similar experiences for all groups, with the most vulnerable having the most fun and satisfaction. The players were motivated by the story and by achieving high scores. The average usage time was 2.5 times per week, 20 minutes per session. Pure exercise time was about half the game time. The concept has proven feasible and forms a reasonable basis for further developments. The full 3D exercise needs further fine-tuning to enhance fun and motivation.
ARTICLE | doi:10.20944/preprints202011.0064.v1
Subject: Medicine & Pharmacology, Allergology Keywords: manual muscle testing; neuromuscular diagnostics; force profiles; reproducibility; Adaptive Force; handheld device
Online: 2 November 2020 (16:36:04 CET)
The manual muscle test (MMT) is a flexible diagnostic tool, which is used in many disciplines, applied in several ways. The main problem is the subjectivity of the test. The MMT in the version of a “break test” depends on the tester’s force rise and the patient’s ability to resist the applied force. As a first step, the investigation of the reproducibility of the testers’ force profiles is required for valid application. The study examined the force profiles of n=29 testers (n=9 experiences (Exp), n=8 little experienced (LitExp), n =12 beginners (Beg)). The testers performed 10 MMTs according to the test of hip flexors, but against a fixed leg to exclude the patient’s reaction. A handheld device recorded the temporal course of the applied force. The results show significant differences between Exp and Beg concerning the starting force (padj=0.029), the ratio of starting to maximum force (padj=0.005) and the normalized mean Euclidean distances between the 10 trials (padj=0.015). The slope is significantly higher in Exp vs. LitExp (p=0.006) and Beg (p=0.005). The results also indicate that experienced testers show inter-tester differences and partly even a low intra-tester reproducibility. That highlights the necessity of an objective MMT-assessment. Furthermore, an agreement on a standardized force profile is required – a suggestion is given.
REVIEW | doi:10.20944/preprints202209.0227.v1
Subject: Life Sciences, Molecular Biology Keywords: Amyotrophic lateral sclerosis (ALS); neurodegeneration; neuroinflammation; neuromuscular disease; autoimmunity; the clonotypic immune system
Online: 15 September 2022 (08:51:54 CEST)
Amyotrophic lateral sclerosis (ALS) is a fatal neuromuscular disease, characterized by progressive degeneration of upper and lower motor neurons in the cortex and spinal cord. Although the pathogenesis of ALS remains unclear, evidence on the role of the clonotypic immune system is growing. Adaptive immunity cells often appear changed in number or activation profile peripherally and centrally. However, their role in ALS appears conflicting. Data, from human and animal model studies, currently reported in literature show that each subset of lymphocytes and their mediators may mediate a protective or toxic mechanism in ALS, affecting both its progression and risk of death. In the present review article and attempt is made to shed light on the actual role of the cellular clonotypic immunity in ALS by integrating recent clinical studies and experimental observations.
ARTICLE | doi:10.20944/preprints202203.0178.v1
Subject: Mathematics & Computer Science, Computational Mathematics Keywords: artificial intelligence; data mining; diagnostic decision support; rare diseases; questionnaire anamnesis; neuromuscular diseases; high latencies
Online: 14 March 2022 (08:58:29 CET)
During the COVID-19 pandemic, individuals with symptoms other than cough or fever have refrained from seeking medical advice. However, a delay in treatment might lead to serious consequences. At the same time, digital health initiatives have emerged to overcome this bottleneck of healthcare. Herein, we report the results of a multi-center initiative using a combination of patient history and artificial intelligence (AI) to identify individuals with rare neuromuscular diseases. First, a questionnaire with 46 items was developed by interviewing patients with muscular dystrophies, amyotrophic lateral sclerosis, Morbus Pompe, neuropathies, and myasthenia gravis. Second, patients with proven neurological diseases answered the questionnaire. Third, a combination of classifiers (artificial neural network, support vector, and random forest) was trained and, finally, the system was challenged with new questionnaires. Users with an abnormal questionnaire pattern received a unique code for data privacy and contact details for a neurologist for further advice. The neurologists confirmed or refuted the AI-based diagnosis. The questionnaire was accessed 3122 times, leading to 853 unique codes. Only for a few patients the computer-based diagnoses and the confirmed final diagnoses were reported to us. However, for these few patients, the genetic testing and high CK levels finally ended their long-lasting diagnostic odyssey.
REVIEW | doi:10.20944/preprints202202.0013.v1
Subject: Medicine & Pharmacology, Clinical Neurology Keywords: ALS; motor neuron disease (MND); metabolism; muscle; TP53; TDP43; immunomodulatory therapies; neuromuscular junction; mitochondria; epigenetic regulation
Online: 1 February 2022 (12:49:48 CET)
Amyotrophic lateral sclerosis (ALS) is also called "motor neuron disease”. In this review, we propose that ALS is not just a neuromotor disorder, but begins as a disorder of P53-modulated skeletal muscle metabolism, leading to failures at the energy state of the cells, incorrect redox states, motor denervation, and a loss of muscle fibers. Motoneurons die as a consequence of the lack of muscular feedback, and the oligomeric TDP43 aggregates progressively and relentlessly lead to mistakes in peripheral immune self-tolerance sustained over time. An effective treatment has not been found for this devastating pathology, as for 152 years the target has not been accurately defined. Scientists and doctors should consider new knowledge regarding ALS and consider immunomodulatory therapies that, based on genetic analysis and symptoms, can be combined with compounds that regulate metabolism and promote the elimination of useless organelles and cells. What if ALS could be cured as a result of seeing motor neuron disease differently? This review aims to develop that goal and change the paradigm of our understanding of ALS.
ARTICLE | doi:10.20944/preprints201810.0540.v1
Subject: Medicine & Pharmacology, Sport Sciences & Therapy Keywords: maximal voluntary contraction; peripheral fatigue; neuromuscular activation; femoral nerve electrical stimulation; critical peripheral fatigue threshold; electromyography
Online: 23 October 2018 (15:12:43 CEST)
We asked whether the level of peripheral fatigue would differ when three consecutive exercise trials were completed to task failure, and whether there would be delayed recovery in maximal voluntary contraction (MVC) force, neuromuscular activation and peripheral fatigue following task failure. Ten trained sport students performed three consecutive knee extension isometric trials (T1, T2, T3) to task failure without breaks between trials. T1 and T2 consisted of repeated 5-s contractions followed by 5-s rest. In T1, contractions were performed at a target force at 60% pre-exercise MVC. In T2, all contractions were MVCs, and task failure occurred at 50% MVC. T3 was a sustained MVC performed until force fell below 15% MVC. Evoked force responses to supramaximal electrical femoral nerve stimulation were recorded to assess peripheral fatigue. Electromyography signals were normalized to M-wave amplitude to assess neuromuscular activation. Lower levels of evoked peak forces were observed at T3 compared to T2 and T1. Within 5 s of task failure in T3, MVC force and neuromuscular activation recovered substantially without any recovery in evoked peak force. Neuromuscular activation 5-10 s after T3 was unchanged from pre-exercise values, but evoked peak forces were substantially reduced. These results challenge the existence of a critical peripheral fatigue threshold that reduces neuromuscular activation. Since neuromuscular activation changed independently of any change in evoked peak force, immediate recovery in force production after exercise is due to increased central recruitment and not to peripheral mechanisms.