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Biomolecules
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Molecular Basis of Neuromuscular Diseases
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Molecular Basis of Neuromuscular Diseases

A special issue of Biomolecules (ISSN 2218-273X). This special issue belongs to the section "Molecular Biology".

Deadline for manuscript submissions: closed (14 April 2022) | Viewed by 19781

Special Issue Editor

Dr. Pasquale Scarcia

E-Mail Website
Guest Editor
Department of Biosciences, Biotechnologies and Biopharmaceutics, Università degli Studi di Bari, Bari, Italy
Interests: mitochondrial carriers, bioenergetics, mitochondrial metabolism; rare diseases; gene expression; Saccharomyces cerevisiae
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

Neuromuscular diseases (NMDs) are caused by impairment of the functioning of the muscles, with many different forms that vary in onset, severity, and prognosis. NMDs can be classified into hereditary or acquired disorders with sensory impairment, motor impairment, or both.

Muscular impairment, generally manifested as muscle weakness and fatigue, can be linked to motor neuron disease (such as amyotrophic lateral sclerosis), peripheral neuropathy, neuromuscular junction disorders (like myasthenia gravis), and myopathy. These alterations can be determined by pathologies of the muscle or by alterations of the nerves or of the neuro-muscular junctions. Furthermore, NMDs can be also age-related neurodegenerative disorders. To date, many neuromuscular diseases have no cure, and their pathogeneses are not well known.

The alterations of many cellular processes and metabolic pathways underlie the onset of NMDs. The development of omics techniques (i.e., metabolomics, transcriptomics, and lipidomics) shed new light on various factors and disease-causing mechanisms that contribute to NMDs.

The Special Issue will focus on understanding the molecular basis and metabolic alterations underlie neuromuscular pathologies. Original manuscripts and reviews concerning with special attention of pathophysiology of muscular diseases, the prognostic and diagnostic biomarkers of NMDs, or the development of new synthetic or naturally originating molecules for the treatment of neuromuscular pathologies are very welcome.

You may choose our Joint Special Issue in NeuroSci.

Dr. Pasquale Scarcia
Guest Editor

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All submissions that pass pre-check are peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

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. Biomolecules is an international peer-reviewed open access monthly 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

  • biomarkers
  • neuromuscular junctions
  • bioenergetics
  • neuromuscular diseases
  • disease mechanisms
  • skeletal muscle
  • therapies
  • molecular diagnosis
  • omics techniques
  • myopathy amyotrophic lateral sclerosis
  • myasthenia gravis
  • muscular dystrophies
  • myalgia

Published Papers (6 papers)

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Research

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24 pages, 6246 KiB  
Article
Alteration of the Neuromuscular Junction and Modifications of Muscle Metabolism in Response to Neuron-Restricted Expression of the CHMP2Bintron5 Mutant in a Mouse Model of ALS-FTD Syndrome
by Robin Waegaert, Sylvie Dirrig-Grosch, Haoyi Liu, Marion Boutry, Ping Luan, Jean-Philippe Loeffler and Frédérique René
Biomolecules 2022, 12(4), 497; https://doi.org/10.3390/biom12040497 - 24 Mar 2022
Cited by 1 | Viewed by 2538
Abstract
CHMP2B is a protein that coordinates membrane scission events as a core component of the ESCRT machinery. Mutations in CHMP2B are an uncommon cause of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD), two neurodegenerative diseases with clinical, genetic, and pathological overlap. Different [...] Read more.
CHMP2B is a protein that coordinates membrane scission events as a core component of the ESCRT machinery. Mutations in CHMP2B are an uncommon cause of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD), two neurodegenerative diseases with clinical, genetic, and pathological overlap. Different mutations have now been identified across the ALS-FTD spectrum. Disruption of the neuromuscular junction is an early pathogenic event in ALS. Currently, the links between neuromuscular junction functionality and ALS-associated genes, such as CHMP2B, remain poorly understood. We have previously shown that CHMP2B transgenic mice expressing the CHMP2Bintron5 mutant specifically in neurons develop a progressive motor phenotype reminiscent of ALS. In this study, we used complementary approaches (behavior, histology, electroneuromyography, and biochemistry) to determine the extent to which neuron-specific expression of CHMP2Bintron5 could impact the skeletal muscle characteristics. We show that neuronal expression of the CHMP2Bintron5 mutant is sufficient to trigger progressive gait impairment associated with structural and functional changes in the neuromuscular junction. Indeed, CHMP2Bintron5 alters the pre-synaptic terminal organization and the synaptic transmission that ultimately lead to a switch of fast-twitch glycolytic muscle fibers to more oxidative slow-twitch muscle fibers. Taken together these data indicate that neuronal expression of CHMP2Bintron5 is sufficient to induce a synaptopathy with molecular and functional changes in the motor unit reminiscent of those found in ALS patients. Full article
(This article belongs to the Special Issue Molecular Basis of Neuromuscular Diseases)
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18 pages, 2459 KiB  
Article
β-Dystroglycan Restoration and Pathology Progression in the Dystrophic mdx Mouse: Outcome and Implication of a Clinically Oriented Study with a Novel Oral Dasatinib Formulation
by Paola Mantuano, Brigida Boccanegra, Elena Conte, Michela De Bellis, Santa Cirmi, Francesca Sanarica, Ornella Cappellari, Ilaria Arduino, Annalisa Cutrignelli, Angela Assunta Lopedota, Antonietta Mele, Nunzio Denora and Annamaria De Luca
Biomolecules 2021, 11(11), 1742; https://doi.org/10.3390/biom11111742 - 22 Nov 2021
Cited by 13 | Viewed by 2289
Abstract
ROS-activated cSrc tyrosine kinase (TK) promotes the degradation of β-dystroglycan (β-DG), a dystrophin-glycoprotein complex component, which may reinforce damaging signals in Duchenne muscular dystrophy (DMD). Therefore, cSrc-TK represents a promising therapeutic target. In mdx mice, a 4-week subcutaneous treatment with dasatinib (DAS), a [...] Read more.
ROS-activated cSrc tyrosine kinase (TK) promotes the degradation of β-dystroglycan (β-DG), a dystrophin-glycoprotein complex component, which may reinforce damaging signals in Duchenne muscular dystrophy (DMD). Therefore, cSrc-TK represents a promising therapeutic target. In mdx mice, a 4-week subcutaneous treatment with dasatinib (DAS), a pan-Src-TKs inhibitor approved as anti-leukemic agent, increased muscle β-DG, with minimal amelioration of morphofunctional indices. To address possible dose/pharmacokinetic (PK) issues, a new oral DAS/hydroxypropyl(HP)-β-cyclodextrin(CD) complex was developed and chronically administered to mdx mice. The aim was to better assess the role of β-DG in pathology progression, meanwhile confirming DAS mechanism of action over the long-term, along with its efficacy and tolerability. The 4-week old mdx mice underwent a 12-week treatment with DAS/HP-β-CD10% dissolved in drinking water, at 10 or 20 mg/kg/day. The outcome was evaluated via in vivo/ex vivo disease-relevant readouts. Oral DAS/HP-β-CD efficiently distributed in mdx mice plasma and tissues in a dose-related fashion. The new DAS formulation confirmed its main upstream mechanism of action, by reducing β-DG phosphorylation and restoring its levels dose-dependently in both diaphragm and gastrocnemius muscle. However, it modestly improved in vivo neuromuscular function, ex vivo muscle force, and histopathology, although the partial recovery of muscle elasticity and the decrease of CK and LDH plasma levels suggest an increased sarcolemmal stability of dystrophic muscles. Our clinically oriented study supports the interest in this new, pediatric-suitable DAS formulation for proper exposure and safety and for enhancing β-DG expression. This latter mechanism is, however, not sufficient by itself to impact on pathology progression. In-depth analyses will be dedicated to elucidating the mechanism limiting DAS effectiveness in dystrophic settings, meanwhile assessing its potential synergy with dystrophin-based molecular therapies. Full article
(This article belongs to the Special Issue Molecular Basis of Neuromuscular Diseases)
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22 pages, 3745 KiB  
Article
Transcriptome Analysis Reveals Altered Inflammatory Pathway in an Inducible Glial Cell Model of Myotonic Dystrophy Type 1
by Cuauhtli N. Azotla-Vilchis, Daniel Sanchez-Celis, Luis E. Agonizantes-Juárez, Rocío Suárez-Sánchez, J. Manuel Hernández-Hernández, Jorge Peña, Karla Vázquez-Santillán, Norberto Leyva-García, Arturo Ortega, Vilma Maldonado, Claudia Rangel, Jonathan J. Magaña, Bulmaro Cisneros and Oscar Hernández-Hernández
Biomolecules 2021, 11(2), 159; https://doi.org/10.3390/biom11020159 - 26 Jan 2021
Cited by 12 | Viewed by 3436
Abstract
Myotonic dystrophy type 1 (DM1), the most frequent inherited muscular dystrophy in adults, is caused by the CTG repeat expansion in the 3′UTR of the DMPK gene. Mutant DMPK RNA accumulates in nuclear foci altering diverse cellular functions including alternative splicing regulation. DM1 [...] Read more.
Myotonic dystrophy type 1 (DM1), the most frequent inherited muscular dystrophy in adults, is caused by the CTG repeat expansion in the 3′UTR of the DMPK gene. Mutant DMPK RNA accumulates in nuclear foci altering diverse cellular functions including alternative splicing regulation. DM1 is a multisystemic condition, with debilitating central nervous system alterations. Although a defective neuroglia communication has been described as a contributor of the brain pathology in DM1, the specific cellular and molecular events potentially affected in glia cells have not been totally recognized. Thus, to study the effects of DM1 mutation on glial physiology, in this work, we have established an inducible DM1 model derived from the MIO-M1 cell line expressing 648 CUG repeats. This new model recreated the molecular hallmarks of DM1 elicited by a toxic RNA gain-of-function mechanism: accumulation of RNA foci colocalized with MBNL proteins and dysregulation of alternative splicing. By applying a microarray whole-transcriptome approach, we identified several gene changes associated with DM1 mutation in MIO-M1 cells, including the immune mediators CXCL10, CCL5, CXCL8, TNFAIP3, and TNFRSF9, as well as the microRNAs miR-222, miR-448, among others, as potential regulators. A gene ontology enrichment analyses revealed that inflammation and immune response emerged as major cellular deregulated processes in the MIO-M1 DM1 cells. Our findings indicate the involvement of an altered immune response in glia cells, opening new windows for the study of glia as potential contributor of the CNS symptoms in DM1. Full article
(This article belongs to the Special Issue Molecular Basis of Neuromuscular Diseases)
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Review

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39 pages, 1612 KiB  
Review
An Overview of Mitochondrial Protein Defects in Neuromuscular Diseases
by Federica Marra, Paola Lunetti, Rosita Curcio, Francesco Massimo Lasorsa, Loredana Capobianco, Vito Porcelli, Vincenza Dolce, Giuseppe Fiermonte and Pasquale Scarcia
Biomolecules 2021, 11(11), 1633; https://doi.org/10.3390/biom11111633 - 04 Nov 2021
Cited by 6 | Viewed by 3642
Abstract
Neuromuscular diseases (NMDs) are dysfunctions that involve skeletal muscle and cause incorrect communication between the nerves and muscles. The specific causes of NMDs are not well known, but most of them are caused by genetic mutations. NMDs are generally progressive and entail muscle [...] Read more.
Neuromuscular diseases (NMDs) are dysfunctions that involve skeletal muscle and cause incorrect communication between the nerves and muscles. The specific causes of NMDs are not well known, but most of them are caused by genetic mutations. NMDs are generally progressive and entail muscle weakness and fatigue. Muscular impairments can differ in onset, severity, prognosis, and phenotype. A multitude of possible injury sites can make diagnosis of NMDs difficult. Mitochondria are crucial for cellular homeostasis and are involved in various metabolic pathways; for this reason, their dysfunction can lead to the development of different pathologies, including NMDs. Most NMDs due to mitochondrial dysfunction have been associated with mutations of genes involved in mitochondrial biogenesis and metabolism. This review is focused on some mitochondrial routes such as the TCA cycle, OXPHOS, and β-oxidation, recently found to be altered in NMDs. Particular attention is given to the alterations found in some genes encoding mitochondrial carriers, proteins of the inner mitochondrial membrane able to exchange metabolites between mitochondria and the cytosol. Briefly, we discuss possible strategies used to diagnose NMDs and therapies able to promote patient outcome. Full article
(This article belongs to the Special Issue Molecular Basis of Neuromuscular Diseases)
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23 pages, 985 KiB  
Review
Circulating Biomarkers in Neuromuscular Disorders: What Is Known, What Is New
by Andrea Barp, Amanda Ferrero, Silvia Casagrande, Roberta Morini and Riccardo Zuccarino
Biomolecules 2021, 11(8), 1246; https://doi.org/10.3390/biom11081246 - 20 Aug 2021
Cited by 8 | Viewed by 3777
Abstract
The urgent need for new therapies for some devastating neuromuscular diseases (NMDs), such as Duchenne muscular dystrophy or amyotrophic lateral sclerosis, has led to an intense search for new potential biomarkers. Biomarkers can be classified based on their clinical value into different categories: [...] Read more.
The urgent need for new therapies for some devastating neuromuscular diseases (NMDs), such as Duchenne muscular dystrophy or amyotrophic lateral sclerosis, has led to an intense search for new potential biomarkers. Biomarkers can be classified based on their clinical value into different categories: diagnostic biomarkers confirm the presence of a specific disease, prognostic biomarkers provide information about disease course, and therapeutic biomarkers are designed to predict or measure treatment response. Circulating biomarkers, as opposed to instrumental/invasive ones (e.g., muscle MRI or nerve ultrasound, muscle or nerve biopsy), are generally easier to access and less “time-consuming”. In addition to well-known creatine kinase, other promising molecules seem to be candidate biomarkers to improve the diagnosis, prognosis and prediction of therapeutic response, such as antibodies, neurofilaments, and microRNAs. However, there are some criticalities that can complicate their application: variability during the day, stability, and reliable performance metrics (e.g., accuracy, precision and reproducibility) across laboratories. In the present review, we discuss the application of biochemical biomarkers (both validated and emerging) in the most common NMDs with a focus on their diagnostic, prognostic/predictive and therapeutic application, and finally, we address the critical issues in the introduction of new biomarkers. Full article
(This article belongs to the Special Issue Molecular Basis of Neuromuscular Diseases)
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Other

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13 pages, 2379 KiB  
Brief Report
Exosome microRNAs in Amyotrophic Lateral Sclerosis: A Pilot Study
by Francesca Pregnolato, Lidia Cova, Alberto Doretti, Donatella Bardelli, Vincenzo Silani and Patrizia Bossolasco
Biomolecules 2021, 11(8), 1220; https://doi.org/10.3390/biom11081220 - 16 Aug 2021
Cited by 9 | Viewed by 2941
Abstract
The pathogenesis of amyotrophic lateral sclerosis (ALS), a lethal neurodegenerative disease, remains undisclosed. Mutations in ALS related genes have been identified, albeit the majority of cases are unmutated. Clinical pathology of ALS suggests a prion-like cell-to-cell diffusion of the disease possibly mediated by [...] Read more.
The pathogenesis of amyotrophic lateral sclerosis (ALS), a lethal neurodegenerative disease, remains undisclosed. Mutations in ALS related genes have been identified, albeit the majority of cases are unmutated. Clinical pathology of ALS suggests a prion-like cell-to-cell diffusion of the disease possibly mediated by exosomes, small endocytic vesicles involved in the propagation of RNA molecules and proteins. In this pilot study, we focused on exosomal microRNAs (miRNAs), key regulators of many signaling pathways. We analyzed serum-derived exosomes from ALS patients in comparison with healthy donors. Exosomes were obtained by a commercial kit. Purification of miRNAs was performed using spin column chromatography and RNA was reverse transcribed into cDNA. All samples were run on the miRCURY LNATM Universal RT miRNA PCR Serum/Plasma Focus panel. An average of 29 miRNAs were detectable per sample. The supervised analysis did not identify any statistically significant difference among the groups indicating that none of the miRNA of our panel has a strong pathological role in ALS. However, selecting samples with the highest miRNA content, six biological processes shared across miRNAs through the intersection of the GO categories were identified. Our results, combined to those reported in the literature, indicated that further investigation is needed to elucidate the role of exosome-derived miRNA in ALS. Full article
(This article belongs to the Special Issue Molecular Basis of Neuromuscular Diseases)
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