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Cells
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Cellular and Molecular Mechanisms in Neuromuscular Diseases: From Basic Research...
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Cellular and Molecular Mechanisms in Neuromuscular Diseases: From Basic Research to Clinical Approach

A special issue of Cells (ISSN 2073-4409). This special issue belongs to the section "Cells of the Nervous System".

Deadline for manuscript submissions: closed (31 August 2022) | Viewed by 38524

Special Issue Editors

Dr. Anne Schänzer

E-Mail Website
Guest Editor
Institute of Neuropathology, Justus Liebig University Giessen, Giessen, Germany
Interests: neuromuscular disorder; myopathies; muscle haemostasis; autophagy; Pompe disease; electron microscopy; morphometry; cardio-skeletal myopathies
Prof. Dr. Tobias Ruck

E-Mail Website
Guest Editor
Department of Neurology, Heinrich-Heine University Düsseldorf, Düsseldorf, Germany
Interests: basic research; neuromuscular disorders; autoimmunity; myositis; myopathies; myasthenia gravis; immune cell activation; immune cell function; immune cell migration; immune cell maturation
Special Issues, Collections and Topics in MDPI journals
Prof. Dr. Andreas Hahn

E-Mail Website
Guest Editor
Department of of Child Neurology, Justus Liebig University Giessen, Giessen, Germany
Interests: treatment of pediatric metabolic and neuromuscular diseases; spinal muscular atrophy; Duchenne muscular dystrophy; Pompe disease
Dr. Corinna Preusse

E-Mail Website
Guest Editor
Department of Neuropathology, Charité – Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Charitéplatz 1, 10117 Berlin, Germany
Interests: basic research; neuromuscular disorders; myositis; immune regulations; immune cells; histology; gene analyses
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

Neuromuscular disorders (NMD) form a heterogeneous group of genetic and acquired disorders that occur from early childhood to older age. In recent years, the classification of NMD has substantially improved and novel genetic diseases have been identified. New treatment strategies have been implemented for genetic NMD, and several drugs have been recently approved for the treatment of specific NMDs. Despite these huge advances, many NMDs still remain without causative treatment, and therapy is imperfect in others. Therefore, deeper insights into the pathophysiologic cellular and molecular mechanisms are urgently needed to provide new treatment targets and to further improve existing therapies. Acquired NMDs are often associated with immunological dysregulation. Specific antibodies can predict prognosis and outcome to therapy. In addition, new therapies such as immune check point inhibitors can lead to novel phenotypes. However, there are still many unsolved questions concerning the aetiology and pathogenesis of acquired NMD, and new analysis strategies are needed.

This Special Issue of Cells aims to provide new insights into cellular and molecular mechanisms responsible for NMD and to outline novel therapeutic strategies. We aim to cover a wide range of aspects from basic science to clinical application.

Topics of interest regarding cellular and molecular mechanisms in NMD may include the following:

  • Advances in understanding the disease aetiology and pathogenesis
  • “Omics” analysis in healthy and diseased muscles to identify content and function
  • Generation of induced pluripotent stem cells (iPSC)-derived myocytes for understanding molecular mechanisms and new treatment strategies
  • Differences and similarities in skeletal and heart sarcomere maintenance
  • Immunological response in neuromuscular diseases and new therapeutic strategies
  • Autophagy processes in maintaining cellular homeostasis in striated muscles
  • Genetic therapeutic targets in neuromuscular diseases
  • Fibroblast transdifferentiation into myotubes
  • Organoids
  • Potential biomarkers/stratification markers
  • Clinical studies evaluating diagnostic, prognostic and therapeutic measures

We look forward to your contribution.

Dr. Anne Schänzer
Dr. Tobias Ruck
Prof. Dr. Andreas Hahn
Dr. Corinna Preusse
Guest Editors

Manuscript Submission Information

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Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. Cells is an international peer-reviewed open access semimonthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 2700 CHF (Swiss Francs). Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

  • neuromuscular disorder
  • myopathies
  • muscle haemostasis
  • gene therapy
  • cardio-skeletal myopathy
  • inflammatory disease
  • myositis
  • neuropathy
  • myasthenia gravis
  • autoimmunity
  • spinal muscular atrophy (SMA)
  • amyotrophic lateral sclerosis (ALS)
  • muscle dystrophy

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Published Papers (11 papers)

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Research

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17 pages, 4994 KiB  
Article
High-Dimensional Cytometry Dissects Immunological Fingerprints of Idiopathic Inflammatory Myopathies
by Christopher Nelke, Marc Pawlitzki, Christina B. Schroeter, Niklas Huntemann, Saskia Räuber, Vera Dobelmann, Corinna Preusse, Andreas Roos, Yves Allenbach, Olivier Benveniste, Heinz Wiendl, Ingrid E. Lundberg, Werner Stenzel, Sven G. Meuth and Tobias Ruck
Cells 2022, 11(20), 3330; https://doi.org/10.3390/cells11203330 - 21 Oct 2022
Cited by 3 | Viewed by 2883
Abstract
Chronic inflammation of skeletal muscle is the common feature of idiopathic inflammatory myopathies (IIM). Given the rarity of the disease and potential difficulty of routinely obtaining target tissue, i.e., standardized skeletal muscle, our understanding of immune signatures of the IIM spectrum remains incomplete. [...] Read more.
Chronic inflammation of skeletal muscle is the common feature of idiopathic inflammatory myopathies (IIM). Given the rarity of the disease and potential difficulty of routinely obtaining target tissue, i.e., standardized skeletal muscle, our understanding of immune signatures of the IIM spectrum remains incomplete. Further insight into the immune topography of IIM is needed to determine specific treatment targets according to clinical and immunological phenotypes. Thus, we used high-dimensional flow cytometry to investigate the immune phenotypes of anti-synthetase syndrome (ASyS), dermatomyositis (DM) and inclusion-body myositis (IBM) patients as representative entities of the IIM spectrum and compared them to healthy controls. We studied the CD8, CD4 and B cell compartments in the blood aiming to provide a contemporary overview of the immune topography of the IIM spectrum. ASyS was characterized by altered CD4 composition and expanded T follicular helper cells supporting B cell-mediated autoimmunity. For DM, unsupervised clustering identified expansion of distinct B cell subtypes highly expressing immunoglobulin G4 (IgG4) and CD38. Lastly, terminally differentiated, cytotoxic CD8 T cells distinguish IBM from other IIM. Interestingly, these terminally differentiated CD8 T cells highly expressed the integrin CD18 mediating cellular adhesion and infiltration. The distinct immune cell topography of IIM might provide the framework for targeted treatment approaches potentially improving therapeutic outcomes. Full article
(This article belongs to the Special Issue Cellular and Molecular Mechanisms in Neuromuscular Diseases: From Basic Research to Clinical Approach)
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23 pages, 18769 KiB  
Article
Unraveling the Molecular Basis of the Dystrophic Process in Limb-Girdle Muscular Dystrophy LGMD-R12 by Differential Gene Expression Profiles in Diseased and Healthy Muscles
by Christophe E. Depuydt, Veerle Goosens, Rekin’s Janky, Ann D’Hondt, Jan L. De Bleecker, Nathalie Noppe, Stefaan Derveaux, Dietmar R. Thal and Kristl G. Claeys
Cells 2022, 11(9), 1508; https://doi.org/10.3390/cells11091508 - 30 Apr 2022
Cited by 6 | Viewed by 3059
Abstract
Limb-girdle muscular dystrophy R12 (LGMD-R12) is caused by two mutations in anoctamin-5 (ANO5). Our aim was to identify genes and pathways that underlie LGMD-R12 and explain differences in the molecular predisposition and susceptibility between three thigh muscles that are severely (semimembranosus), [...] Read more.
Limb-girdle muscular dystrophy R12 (LGMD-R12) is caused by two mutations in anoctamin-5 (ANO5). Our aim was to identify genes and pathways that underlie LGMD-R12 and explain differences in the molecular predisposition and susceptibility between three thigh muscles that are severely (semimembranosus), moderately (vastus lateralis) or mildly (rectus femoris) affected in this disease. We performed transcriptomics on these three muscles in 16 male LGMD-R12 patients and 15 age-matched male controls. Our results showed that LGMD-R12 dystrophic muscle is associated with the expression of genes indicative of fibroblast and adipocyte replacement, such as fibroadipogenic progenitors and immune cell infiltration, while muscle protein synthesis and metabolism were downregulated. Muscle degeneration was associated with an increase in genes involved in muscle injury and inflammation, and muscle repair/regeneration. Baseline differences between muscles in healthy individuals indicated that muscles that are the most affected by LGMD-R12 have the lowest expression of transcription factor networks involved in muscle (re)generation and satellite stem cell activation. Instead, they show relative high levels of fetal/embryonic myosins, all together indicating that muscles differ in their baseline regenerative potential. To conclude, we profiled the gene expression landscape in LGMD-R12, identified baseline differences in expression levels between differently affected muscles and characterized disease-associated changes. Full article
(This article belongs to the Special Issue Cellular and Molecular Mechanisms in Neuromuscular Diseases: From Basic Research to Clinical Approach)
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14 pages, 12871 KiB  
Article
Non-Invasive Optical Motion Tracking Allows Monitoring of Respiratory Dynamics in Dystrophin-Deficient Mice
by Angelika Svetlove, Jonas Albers, Swen Hülsmann, Marietta Andrea Markus, Jana Zschüntzsch, Frauke Alves and Christian Dullin
Cells 2022, 11(5), 918; https://doi.org/10.3390/cells11050918 - 7 Mar 2022
Cited by 3 | Viewed by 2469
Abstract
Duchenne muscular dystrophy (DMD) is the most common x-chromosomal inherited dystrophinopathy which leads to progressive muscle weakness and a premature death due to cardiorespiratory dysfunction. The mdx mouse lacks functional dystrophin protein and has a comparatively human-like diaphragm phenotype. To date, diaphragm function [...] Read more.
Duchenne muscular dystrophy (DMD) is the most common x-chromosomal inherited dystrophinopathy which leads to progressive muscle weakness and a premature death due to cardiorespiratory dysfunction. The mdx mouse lacks functional dystrophin protein and has a comparatively human-like diaphragm phenotype. To date, diaphragm function can only be inadequately mapped in preclinical studies and a simple reliable translatable method of tracking the severity of the disease still lacks. We aimed to establish a sensitive, reliable, harmless and easy way to assess the effects of respiratory muscle weakness and subsequent irregularity in breathing pattern. Optical respiratory dynamics tracking (ORDT) was developed utilising a camera to track the movement of paper markers placed on the thoracic-abdominal region of the mouse. ORDT successfully distinguished diseased mdx phenotype from healthy controls by measuring significantly higher expiration constants (k) in mdx mice compared to wildtype (wt), which were also observed in the established X-ray based lung function (XLF). In contrast to XLF, with ORDT we were able to distinguish distinct fast and slow expiratory phases. In mdx mice, a larger part of the expiratory marker displacement was achieved in this initial fast phase as compared to wt mice. This phenomenon could not be observed in the XLF measurements. We further validated the simplicity and reliability of our approach by demonstrating that it can be performed using free-hand smartphone acquisition. We conclude that ORDT has a great preclinical potential to monitor DMD and other neuromuscular diseases based on changes in the breathing patterns with the future possibility to track therapy response. Full article
(This article belongs to the Special Issue Cellular and Molecular Mechanisms in Neuromuscular Diseases: From Basic Research to Clinical Approach)
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17 pages, 31951 KiB  
Article
Induction of Survival of Motor Neuron (SMN) Protein Deficiency in Spinal Astrocytes by Small Interfering RNA as an In Vitro Model of Spinal Muscular Atrophy
by Markus Leo, Linda-Isabell Schmitt, Michael Fleischer, Rebecca Steffen, Cora Osswald, Christoph Kleinschnitz and Tim Hagenacker
Cells 2022, 11(3), 558; https://doi.org/10.3390/cells11030558 - 5 Feb 2022
Cited by 5 | Viewed by 3291
Abstract
Spinal muscular atrophy (SMA) is a motor neuron disorder leading to progressive loss of ventral horn neurons resulting in muscle wasting. Here we investigate the contribution of spinal astrocytes to the pathogenesis of late-onset SMA forms using a mouse model. Furthermore, we generated [...] Read more.
Spinal muscular atrophy (SMA) is a motor neuron disorder leading to progressive loss of ventral horn neurons resulting in muscle wasting. Here we investigate the contribution of spinal astrocytes to the pathogenesis of late-onset SMA forms using a mouse model. Furthermore, we generated SMA-like astrocytes using survival of motor neuron (SMN) siRNA transfection techniques. In the SMA mouse model, the activation of spinal astrocytes and the reduction of the inward rectifier potassium channel Kir4.1 and excitatory amino acid transporter 1 (EAAT1) were observed at postnatal day (P) 28, preceding the loss of spinal motor neurons appearing earliest at P42. Using SMA-like astrocytes, we could mimic the modulation of spinal astrocytes of the mouse model in a dish and perform electrophysiological assessments and functional assays. In SMA-like astrocytes, glutamate uptake was diminished due to a reduction in EAAT1. Furthermore, patch-clamp measurements revealed reduced potassium uptake into astrocytes with membrane depolarization. Additionally, exposure of healthy spinal motor neurons to a conditioned medium of SMA-like astrocytes resulted in increased firing frequency. These data demonstrate spinal astrocytes’ crucial role in the late-onset SMA forms’ pathogenesis. Full article
(This article belongs to the Special Issue Cellular and Molecular Mechanisms in Neuromuscular Diseases: From Basic Research to Clinical Approach)
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14 pages, 641 KiB  
Article
Six-Minute Walk Distance Is a Useful Outcome Measure to Detect Motor Decline in Treated Late-Onset Pompe Disease Patients
by Kristl G. Claeys, Ann D’Hondt, Lucas Fache, Koen Peers and Christophe E. Depuydt
Cells 2022, 11(3), 334; https://doi.org/10.3390/cells11030334 - 20 Jan 2022
Cited by 5 | Viewed by 2756
Abstract
Late-onset Pompe disease (LOPD) is a rare, progressive disorder characterized by limb–girdle muscle weakness and/or respiratory insufficiency, caused by acid alpha-glucosidase (GAA) gene mutations and treated with enzyme replacement therapy. We studied isometric muscle strength in eight muscle groups bilaterally using [...] Read more.
Late-onset Pompe disease (LOPD) is a rare, progressive disorder characterized by limb–girdle muscle weakness and/or respiratory insufficiency, caused by acid alpha-glucosidase (GAA) gene mutations and treated with enzyme replacement therapy. We studied isometric muscle strength in eight muscle groups bilaterally using a Biodex® dynamometer, as well as the Medical Research Council sum score (MRC-SS), hand grip strength, 6 min walk distance (6MWD), 10 m walk test (10MWT) and timed up-and-go test (TUG) in 12 adult, ambulatory, treated LOPD patients and 12 age-/gender-matched healthy controls, every 6 months for 2 years. The mean isometric muscle strength showed a significant decline in right and left knee extensors at 12 months in controls (p < 0.014; p < 0.016), at 18 months in patients (p < 0.010; p < 0.007) and controls (only right side, p < 0.030) and at 24 months in both groups (p < 0.035). The mean 6MWD in patients significantly decreased after 24 months, from 451.9 m to 368.1 m (p < 0.003), whereas in controls, the mean 6MWD significantly increased after 6 months (p < 0.045) and 18 months (p < 0.020) (at 24 months p = 0.054). In patients and controls, the MRC-SS, hand grip test, 10MWT and TUG did not show significant changes (p > 0.05). We conclude that the 6MWD is a useful outcome measure to detect motor decline in treated LOPD patients. Full article
(This article belongs to the Special Issue Cellular and Molecular Mechanisms in Neuromuscular Diseases: From Basic Research to Clinical Approach)
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25 pages, 19167 KiB  
Article
Morphological Characteristics of Idiopathic Inflammatory Myopathies in Juvenile Patients
by Anne Schänzer, Leonie Rager, Iris Dahlhaus, Carsten Dittmayer, Corinna Preusse, Adela Della Marina, Hans-Hilmar Goebel, Andreas Hahn and Werner Stenzel
Cells 2022, 11(1), 109; https://doi.org/10.3390/cells11010109 - 30 Dec 2021
Cited by 7 | Viewed by 3246
Abstract
Background: In juvenile idiopathic inflammatory myopathies (IIMs), morphological characteristic features of distinct subgroups are not well defined. New treatment strategies require a precise diagnosis of the subgroups in IIM, and, therefore, knowledge about the pathomorphology of juvenile IIMs is warranted. Methods: Muscle biopsies [...] Read more.
Background: In juvenile idiopathic inflammatory myopathies (IIMs), morphological characteristic features of distinct subgroups are not well defined. New treatment strategies require a precise diagnosis of the subgroups in IIM, and, therefore, knowledge about the pathomorphology of juvenile IIMs is warranted. Methods: Muscle biopsies from 15 patients (median age 8 (range 3–17) years, 73% female) with IIM and seven controls were analyzed by standard methods, immunohistochemistry, and transmission electron microscopy (TEM). Detailed clinical and laboratory data were accessed retrospectively. Results: Proximal muscle weakness and skin symptoms were the main clinical symptoms. Dermatomyositis (DM) was diagnosed in 9/15, antisynthetase syndrome (ASyS) in 4/15, and overlap myositis (OM) in 2/15. Analysis of skeletal muscle tissues showed inflammatory cells and diffuse upregulation of MHC class I in all subtypes. Morphological key findings were COX-deficient fibers as a striking pathology in DM and perimysial alkaline phosphatase positivity in anti-Jo-1-ASyS. Vascular staining of the type 1 IFN-surrogate marker, MxA, correlated with endothelial tubuloreticular inclusions in both groups. None of these specific morphological findings were present in anti-PL7-ASyS or OM patients. Conclusions: Morphological characteristics discriminate IIM subtypes in juvenile patients, emphasizing differences in aetiopathogenesis and supporting the notion of individual and targeted therapeutic strategies. Full article
(This article belongs to the Special Issue Cellular and Molecular Mechanisms in Neuromuscular Diseases: From Basic Research to Clinical Approach)
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18 pages, 6194 KiB  
Article
Phenotypical and Myopathological Consequences of Compound Heterozygous Missense and Nonsense Variants in SLC18A3
by Adela Della Marina, Annabelle Arlt, Ulrike Schara-Schmidt, Christel Depienne, Andrea Gangfuß, Heike Kölbel, Albert Sickmann, Erik Freier, Nicolai Kohlschmidt, Andreas Hentschel, Joachim Weis, Artur Czech, Anika Grüneboom and Andreas Roos
Cells 2021, 10(12), 3481; https://doi.org/10.3390/cells10123481 - 9 Dec 2021
Cited by 2 | Viewed by 3256
Abstract
Background: Presynaptic forms of congenital myasthenic syndromes (CMS) due to pathogenic variants in SLC18A3 impairing the synthesis and recycling of acetylcholine (ACh) have recently been described. SLC18A3 encodes the vesicular ACh transporter (VAChT), modulating the active transport of ACh at the neuromuscular junction, [...] Read more.
Background: Presynaptic forms of congenital myasthenic syndromes (CMS) due to pathogenic variants in SLC18A3 impairing the synthesis and recycling of acetylcholine (ACh) have recently been described. SLC18A3 encodes the vesicular ACh transporter (VAChT), modulating the active transport of ACh at the neuromuscular junction, and homozygous loss of VAChT leads to lethality. Methods: Exome sequencing (ES) was carried out to identify the molecular genetic cause of the disease in a 5-year-old male patient and histological, immunofluorescence as well as electron- and CARS-microscopic studies were performed to delineate the muscle pathology, which has so far only been studied in VAChT-deficient animal models. Results: ES unraveled compound heterozygous missense and nonsense variants (c.315G>A, p.Trp105* and c.1192G>C, p.Asp398His) in SLC18A3. Comparison with already-published cases suggests a more severe phenotype including impaired motor and cognitive development, possibly related to a more severe effect of the nonsense variant. Therapy with pyridostigmine was only partially effective while 3,4 diaminopyridine showed no effect. Microscopic investigation of the muscle biopsy revealed reduced fibre size and a significant accumulation of lipid droplets. Conclusions: We suggest that nonsense variants have a more detrimental impact on the clinical manifestation of SLC18A3-associated CMS. The impact of pathogenic SLC18A3 variants on muscle fibre integrity beyond the effect of denervation is suggested by the build-up of lipid aggregates. This in turn implicates the importance of proper VAChT-mediated synthesis and recycling of ACh for lipid homeostasis in muscle cells. This hypothesis is further supported by the pathological observations obtained in previously published VAChT-animal models. Full article
(This article belongs to the Special Issue Cellular and Molecular Mechanisms in Neuromuscular Diseases: From Basic Research to Clinical Approach)
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13 pages, 1828 KiB  
Article
NK Cell Patterns in Idiopathic Inflammatory Myopathies with Pulmonary Affection
by Marc Pawlitzki, Christopher Nelke, Leoni Rolfes, Rebecca Hasseli, Stylianos Tomaras, Eugen Feist, Anne Schänzer, Saskia Räuber, Liesa Regner, Corinna Preuße, Yves Allenbach, Olivier Benveniste, Heinz Wiendl, Werner Stenzel, Sven G. Meuth and Tobias Ruck
Cells 2021, 10(10), 2551; https://doi.org/10.3390/cells10102551 - 27 Sep 2021
Cited by 10 | Viewed by 2777
Abstract
Background: Pulmonary affection (PA) is associated with a substantial increase in morbidity and mortality in patients with idiopathic inflammatory myopathies (IIM). However, the underlying immune mechanisms of PA remain enigmatic and prompt deeper immunological analyses. Importantly, the Janus-faced role of natural killer (NK) [...] Read more.
Background: Pulmonary affection (PA) is associated with a substantial increase in morbidity and mortality in patients with idiopathic inflammatory myopathies (IIM). However, the underlying immune mechanisms of PA remain enigmatic and prompt deeper immunological analyses. Importantly, the Janus-faced role of natural killer (NK) cells, capable of pro-inflammatory as well as regulatory effects, might be of interest for the pathophysiologic understanding of PA in IIM. Methods: To extend our understanding of immunological alterations in IIM patients with PA, we compared the signatures of NK cells in peripheral blood using multi-color flow cytometry in IIM patients with (n = 12, of which anti-synthetase syndrome = 8 and dermatomyositis = 4) or without PA (n = 12). Results: We did not observe any significant differences for B cells, CD4, and CD8 T cells, while total NK cell numbers in IIM patients with PA were reduced compared to non-PA patients. NK cell alterations were driven by a particular decrease of CD56dim NK cells, while CD56bright NK cells remained unchanged. Comparisons of the cell surface expression of a large panel of NK receptors revealed an increased mean fluorescence intensity of NKG2D+ on NK cells from patients with PA compared with non-PA patients, especially on the CD56dim subset. NKG2D+ and NKp46+ cell surface levels were associated with reduced vital capacity, serving as a surrogate marker for clinical severity of PA. Conclusion: Our data illustrate that PA in IIM is associated with alterations of the NK cell repertoire, suggesting a relevant contribution of NK cells in certain IIMs, which might pave the way for NK cell-targeted therapeutic approaches. Full article
(This article belongs to the Special Issue Cellular and Molecular Mechanisms in Neuromuscular Diseases: From Basic Research to Clinical Approach)
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Review

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23 pages, 1696 KiB  
Review
Update on the Molecular Aspects and Methods Underlying the Complex Architecture of FSHD
by Valerio Caputo, Domenica Megalizzi, Carlo Fabrizio, Andrea Termine, Luca Colantoni, Carlo Caltagirone, Emiliano Giardina, Raffaella Cascella and Claudia Strafella
Cells 2022, 11(17), 2687; https://doi.org/10.3390/cells11172687 - 29 Aug 2022
Cited by 10 | Viewed by 3515
Abstract
Despite the knowledge of the main mechanisms involved in facioscapulohumeral muscular dystrophy (FSHD), the high heterogeneity and variable penetrance of the disease complicate the diagnosis, characterization and genotype–phenotype correlation of patients and families, raising the need for further research and data. Thus, the [...] Read more.
Despite the knowledge of the main mechanisms involved in facioscapulohumeral muscular dystrophy (FSHD), the high heterogeneity and variable penetrance of the disease complicate the diagnosis, characterization and genotype–phenotype correlation of patients and families, raising the need for further research and data. Thus, the present review provides an update of the main molecular aspects underlying the complex architecture of FSHD, including the genetic factors (related to D4Z4 repeated units and FSHD-associated genes), epigenetic elements (D4Z4 methylation status, non-coding RNAs and high-order chromatin interactions) and gene expression profiles (FSHD transcriptome signatures both at bulk tissue and single-cell level). In addition, the review will also describe the methods currently available for investigating the above-mentioned features and how the resulting data may be combined with artificial-intelligence-based pipelines, with the purpose of developing a multifunctional tool tailored to enhancing the knowledge of disease pathophysiology and progression and fostering the research for novel treatment strategies, as well as clinically useful biomarkers. In conclusion, the present review highlights how FSHD should be regarded as a disease characterized by a molecular spectrum of genetic and epigenetic factors, whose alteration plays a differential role in DUX4 repression and, subsequently, contributes to determining the FSHD phenotype. Full article
(This article belongs to the Special Issue Cellular and Molecular Mechanisms in Neuromuscular Diseases: From Basic Research to Clinical Approach)
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31 pages, 950 KiB  
Review
The Evolution of Complex Muscle Cell In Vitro Models to Study Pathomechanisms and Drug Development of Neuromuscular Disease
by Jana Zschüntzsch, Stefanie Meyer, Mina Shahriyari, Karsten Kummer, Matthias Schmidt, Susann Kummer and Malte Tiburcy
Cells 2022, 11(7), 1233; https://doi.org/10.3390/cells11071233 - 5 Apr 2022
Cited by 8 | Viewed by 4454
Abstract
Many neuromuscular disease entities possess a significant disease burden and therapeutic options remain limited. Innovative human preclinical models may help to uncover relevant disease mechanisms and enhance the translation of therapeutic findings to strengthen neuromuscular disease precision medicine. By concentrating on idiopathic inflammatory [...] Read more.
Many neuromuscular disease entities possess a significant disease burden and therapeutic options remain limited. Innovative human preclinical models may help to uncover relevant disease mechanisms and enhance the translation of therapeutic findings to strengthen neuromuscular disease precision medicine. By concentrating on idiopathic inflammatory muscle disorders, we summarize the recent evolution of the novel in vitro models to study disease mechanisms and therapeutic strategies. A particular focus is laid on the integration and simulation of multicellular interactions of muscle tissue in disease phenotypes in vitro. Finally, the requirements of a neuromuscular disease drug development workflow are discussed with a particular emphasis on cell sources, co-culture systems (including organoids), functionality, and throughput. Full article
(This article belongs to the Special Issue Cellular and Molecular Mechanisms in Neuromuscular Diseases: From Basic Research to Clinical Approach)
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17 pages, 2487 KiB  
Systematic Review
Muscle Sonography in Inclusion Body Myositis: A Systematic Review and Meta-Analysis of 944 Measurements
by Ramy Abdelnaby, Khaled Ashraf Mohamed, Anas Elgenidy, Yousef Tarek Sonbol, Mahmoud Mostafa Bedewy, Aya Moustafa Aboutaleb, Mohamed Ayman Ebrahim, Imene Maallem, Khaled Tarek Dardeer, Hamed Amr Heikal, Hazem Maher Gawish and Jana Zschüntzsch
Cells 2022, 11(4), 600; https://doi.org/10.3390/cells11040600 - 9 Feb 2022
Cited by 12 | Viewed by 4724
Abstract
Inclusion body myositis (IBM) is a slowly progressive muscle weakness of distal and proximal muscles, which is diagnosed by clinical and histopathological criteria. Imaging biomarkers are inconsistently used and do not follow international standardized criteria. We conducted a systematic review and meta-analysis to [...] Read more.
Inclusion body myositis (IBM) is a slowly progressive muscle weakness of distal and proximal muscles, which is diagnosed by clinical and histopathological criteria. Imaging biomarkers are inconsistently used and do not follow international standardized criteria. We conducted a systematic review and meta-analysis to investigate the diagnostic value of muscle ultrasound (US) in IBM compared to healthy controls. A systematic search of PubMed/MEDLINE, Scopus and Web of Science was performed. Articles reporting the use of muscle ultrasound in IBM, and published in peer-reviewed journals until 11 September 2021, were included in our study. Seven studies were included, with a total of 108 IBM and 171 healthy controls. Echogenicity between IBM and healthy controls, which was assessed by three studies, demonstrated a significant mean difference in the flexor digitorum profundus (FDP) muscle, which had a grey scale value (GSV) of 36.55 (95% CI, 28.65–44.45, p < 0.001), and in the gastrocnemius (GC), which had a GSV of 27.90 (95% CI 16.32–39.48, p < 0.001). Muscle thickness in the FDP showed no significant difference between the groups. The pooled sensitivity and specificity of US in the differentiation between IBM and the controls were 82% and 98%, respectively, and the area under the curve was 0.612. IBM is a rare disease, which is reflected in the low numbers of patients included in each of the studies and thus there was high heterogeneity in the results. Nevertheless, the selected studies conclusively demonstrated significant differences in echogenicity of the FDP and GC in IBM, compared to controls. Further high-quality studies, using standardized operating procedures, are needed to implement muscle ultrasound in the diagnostic criteria. Full article
(This article belongs to the Special Issue Cellular and Molecular Mechanisms in Neuromuscular Diseases: From Basic Research to Clinical Approach)
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