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The Role of Skeletal Muscle in Neuromuscular Diseases: From Cellular...
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The Role of Skeletal Muscle in Neuromuscular Diseases: From Cellular and Molecular Players to Therapeutic Interventions

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

Deadline for manuscript submissions: closed (30 July 2021) | Viewed by 30966

Special Issue Editors

Dr. Gabriella Dobrowolny

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Guest Editor
Department of Anatomy, Histology, Forensic Medicine and Orthopedics, Sapienza University of Rome, 00161 Roma, Italy
Interests: molecular mechanisms of skeletal muscle atrophy induced by physio/pathological defects in muscle and nerve interplay
Special Issues, Collections and Topics in MDPI journals
Dr. Bianca Maria Scicchitano

E-Mail Website
Guest Editor
Sezione di Istologia ed Embriologia, Dipartimento di Scienze della Vita e Sanità Pubblica, Fondazione Policlinico Universitario A. Gemelli IRCCS, 00168 Roma, Italy
Interests: molecular mechanisms involved in the regulation of regeneration, differentiation, and hypertrophy/atrophy of skeletal muscle in normal and pathological conditions
Special Issues, Collections and Topics in MDPI journals
Dr. Giorgio Tasca

E-Mail Website
Guest Editor
The John Walton Muscular Dystrophy Research Centre, Newcastle University, Newcastle Upon Tyne NE1 3BZ, UK
Interests: neuromuscular disorders; myopathies; muscular dystrophies; facioscapulohumeral muscular dystrophy (FSHD); muscle imaging

Special Issue Information

Dear Colleagues,

Neuromuscular disorders encompass genetic and acquired diseases of lower motor neurons, peripheral nerves, motor end plate, or skeletal muscle. Novel treatments, including gene therapy, are at the horizon for many genetic neuromuscular disorders or already in place for some of them.

The neuromuscular junction (NMJ) represents the morphofunctional interface between muscle and nerve. Defects in NMJ formation and maintenance cause neuromuscular disorders, including congenital myasthenic syndromes and autoimmune myasthenia gravis, contribute to the pathogenesis of spinal muscular atrophy, amyotrophic lateral sclerosis, and can even occur during aging. The molecular machinery underlying the NMJ formation and maintenance has been deeply studied; however, the role of skeletal muscle in NMJ dismantlement still needs to be fully elucidated.

In this Special Issue entitled “The Role of Skeletal Muscle in Neuromuscular Diseases: From Cellular and Molecular Players to Therapeutic Interventions”, we aim to collect recent research advances and ongoing studies focused on the role of skeletal muscle in the etiopathogenesis of genetic neuromuscular diseases. A particular focus will be kept on identifying cellular and molecular mechanisms underpinning onset and progression of neuromuscular disorders and the role of NMJ in their pathophysiology. Moreover, we aim to gather clinical and basic scientific research providing a joint commentary on how intervention in muscle cells might attenuate neuromuscular pathological features.

We look forward to your contributions.

Dr. Gabriella Dobrowolny
Dr. Bianca Maria Scicchitano
Dr. Giorgio Tasca
Guest Editors

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. 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

  • NMJ
  • oxidative stress
  • muscle atrophy
  • aging
  • sarcopenia
  • motor neuron diseases
  • amyotrophic lateral sclerosis (ALS)
  • spinal muscular atrophy (SMA)
  • myasthenic syndrome
  • myasthenia gravis
  • muscle denervation
  • neuromuscular disorders
  • myopathies
  • muscular dystrophies

Published Papers (7 papers)

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Editorial

Jump to: Research, Review

4 pages, 204 KiB  
Editorial
The Role of Skeletal Muscle in Neuromuscular Diseases: From Cellular and Molecular Players to Therapeutic Interventions
by Gabriella Dobrowolny and Bianca Maria Scicchitano
Cells 2022, 11(7), 1207; https://0-doi-org.brum.beds.ac.uk/10.3390/cells11071207 - 3 Apr 2022
Cited by 1 | Viewed by 1731
Abstract
Genetic and acquired defects of lower motor neurons, peripheral nerves, or skeletal muscle are responsible for several neuromuscular disorders [...] Full article
(This article belongs to the Special Issue The Role of Skeletal Muscle in Neuromuscular Diseases: From Cellular and Molecular Players to Therapeutic Interventions)

Research

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10 pages, 1671 KiB  
Article
Circulating myomiRs in Muscle Denervation: From Surgical to ALS Pathological Condition
by Irene Casola, Bianca Maria Scicchitano, Elisa Lepore, Silvia Mandillo, Elisabetta Golini, Carmine Nicoletti, Laura Barberi, Gabriella Dobrowolny and Antonio Musarò
Cells 2021, 10(8), 2043; https://0-doi-org.brum.beds.ac.uk/10.3390/cells10082043 - 10 Aug 2021
Cited by 6 | Viewed by 1841
Abstract
ALS is a fatal neurodegenerative disease that is associated with muscle atrophy, motoneuron degeneration and denervation. Different mechanisms have been proposed to explain the pathogenesis of the disease; in this context, microRNAs have been described as biomarkers and potential pathogenetic factors for ALS. [...] Read more.
ALS is a fatal neurodegenerative disease that is associated with muscle atrophy, motoneuron degeneration and denervation. Different mechanisms have been proposed to explain the pathogenesis of the disease; in this context, microRNAs have been described as biomarkers and potential pathogenetic factors for ALS. MyomiRs are microRNAs produced by skeletal muscle, and they play an important role in tissue homeostasis; moreover, they can be released in blood circulation in pathological conditions, including ALS. However, the functional role of myomiRs in muscle denervation has not yet been fully clarified. In this study, we analyze the levels of two myomiRs, namely miR-206 and miR-133a, in skeletal muscle and blood samples of denervated mice, and we demonstrate that surgical denervation reduces the expression of both miR-206 and miR-133a, while miR-206 but not miR-133a is upregulated during the re-innervation process. Furthermore, we quantify the levels of miR-206 and miR-133a in serum samples of two ALS mouse models, characterized by different disease velocities, and we demonstrate a different modulation of circulating myomiRs during ALS disease, according to the velocity of disease progression. Moreover, taking into account surgical and pathological denervation, we describe a different response to increasing amounts of circulating miR-206, suggesting a hormetic effect of miR-206 in relation to changes in neuromuscular communication. Full article
(This article belongs to the Special Issue The Role of Skeletal Muscle in Neuromuscular Diseases: From Cellular and Molecular Players to Therapeutic Interventions)
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8 pages, 254 KiB  
Article
Anti-cN1A Antibodies Are Associated with More Severe Dysphagia in Sporadic Inclusion Body Myositis
by Matteo Lucchini, Lorenzo Maggi, Elena Pegoraro, Massimiliano Filosto, Carmelo Rodolico, Giovanni Antonini, Matteo Garibaldi, Maria Lucia Valentino, Gabriele Siciliano, Giorgio Tasca, Valeria De Arcangelis, Chiara De Fino and Massimiliano Mirabella
Cells 2021, 10(5), 1146; https://0-doi-org.brum.beds.ac.uk/10.3390/cells10051146 - 10 May 2021
Cited by 21 | Viewed by 3290
Abstract
In recent years, an autoantibody directed against the 5′-citosolic nucleotidase1A (cN1A) was identified in the sera of sporadic inclusion body myositis (s-IBM) patients with widely variable sensitivity (33%–76%) and specificity (87%–100%). We assessed the sensitivity/specificity of anti-cN1A antibodies in an Italian cohort of [...] Read more.
In recent years, an autoantibody directed against the 5′-citosolic nucleotidase1A (cN1A) was identified in the sera of sporadic inclusion body myositis (s-IBM) patients with widely variable sensitivity (33%–76%) and specificity (87%–100%). We assessed the sensitivity/specificity of anti-cN1A antibodies in an Italian cohort of s-IBM patients, searching for a potential correlation with clinical data. We collected clinical data and sera from 62 consecutive s-IBM patients and 62 other inflammatory myopathies patients. Testing for anti-cN1A antibodies was performed using a commercial ELISA. Anti-cN1A antibodies were detected in 23 s-IBM patients, resulting in a sensitivity of 37.1% with a specificity of 96.8%. Positive and negative predictive values were 92.0% and 60.6%, respectively. We did not find significant difference regarding demographic variables, nor quadriceps or finger flexor weakness. Nevertheless, we found that anti-cN1A-positive patients presented significantly lower scores in IBMFRS item 1 (swallowing, p = 0.045) and more frequently reported more severe swallowing problems, expressed as an IBMFRS item 1 score ≤ 2 (p < 0.001). We confirmed the low sensitivity and high specificity of anti-cN1A Ab in s-IBM patients with a high positive predictive value. The presence of anti-CN1A antibodies identified patients with a greater risk of more severe dysphagia. Full article
(This article belongs to the Special Issue The Role of Skeletal Muscle in Neuromuscular Diseases: From Cellular and Molecular Players to Therapeutic Interventions)

Review

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19 pages, 1701 KiB  
Review
RNA Targeting in Inherited Neuromuscular Disorders: Novel Therapeutic Strategies to Counteract Mis-Splicing
by Veronica Verdile, Gloria Guizzo, Gabriele Ferrante and Maria Paola Paronetto
Cells 2021, 10(11), 2850; https://0-doi-org.brum.beds.ac.uk/10.3390/cells10112850 - 22 Oct 2021
Cited by 3 | Viewed by 3005
Abstract
Neuromuscular disorders represent multifaceted abnormal conditions, with little or no cure, leading to patient deaths from complete muscle wasting and atrophy. Despite strong efforts in the past decades, development of effective treatments is still urgently needed. Advent of next-generation sequencing technologies has allowed [...] Read more.
Neuromuscular disorders represent multifaceted abnormal conditions, with little or no cure, leading to patient deaths from complete muscle wasting and atrophy. Despite strong efforts in the past decades, development of effective treatments is still urgently needed. Advent of next-generation sequencing technologies has allowed identification of novel genes and mutations associated with neuromuscular pathologies, highlighting splicing defects as essential players. Deciphering the significance and relative contributions of defective RNA metabolism will be instrumental to address and counteract these malignancies. We review here recent progress on the role played by alternative splicing in ensuring functional neuromuscular junctions (NMJs), and its involvement in the pathogenesis of NMJ-related neuromuscular disorders, with particular emphasis on congenital myasthenic syndromes and muscular dystrophies. We will also discuss novel strategies based on oligonucleotides designed to bind their cognate sequences in the RNA or targeting intermediary of mRNA metabolism. These efforts resulted in several chemical classes of RNA molecules that have recently proven to be clinically effective, more potent and better tolerated than previous strategies. Full article
(This article belongs to the Special Issue The Role of Skeletal Muscle in Neuromuscular Diseases: From Cellular and Molecular Players to Therapeutic Interventions)
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21 pages, 3751 KiB  
Review
Skeletal Muscle Metabolism: Origin or Prognostic Factor for Amyotrophic Lateral Sclerosis (ALS) Development?
by Cyril Quessada, Alexandra Bouscary, Frédérique René, Cristiana Valle, Alberto Ferri, Shyuan T. Ngo and Jean-Philippe Loeffler
Cells 2021, 10(6), 1449; https://0-doi-org.brum.beds.ac.uk/10.3390/cells10061449 - 9 Jun 2021
Cited by 11 | Viewed by 4647
Abstract
Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease characterized by progressive and selective loss of motor neurons, amyotrophy and skeletal muscle paralysis usually leading to death due to respiratory failure. While generally considered an intrinsic motor neuron disease, data obtained in recent [...] Read more.
Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease characterized by progressive and selective loss of motor neurons, amyotrophy and skeletal muscle paralysis usually leading to death due to respiratory failure. While generally considered an intrinsic motor neuron disease, data obtained in recent years, including our own, suggest that motor neuron protection is not sufficient to counter the disease. The dismantling of the neuromuscular junction is closely linked to chronic energy deficit found throughout the body. Metabolic (hypermetabolism and dyslipidemia) and mitochondrial alterations described in patients and murine models of ALS are associated with the development and progression of disease pathology and they appear long before motor neurons die. It is clear that these metabolic changes participate in the pathology of the disease. In this review, we summarize these changes seen throughout the course of the disease, and the subsequent impact of glucose–fatty acid oxidation imbalance on disease progression. We also highlight studies that show that correcting this loss of metabolic flexibility should now be considered a major goal for the treatment of ALS. Full article
(This article belongs to the Special Issue The Role of Skeletal Muscle in Neuromuscular Diseases: From Cellular and Molecular Players to Therapeutic Interventions)
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15 pages, 2248 KiB  
Review
Redox Homeostasis in Muscular Dystrophies
by Nicola Mosca, Sara Petrillo, Sara Bortolani, Mauro Monforte, Enzo Ricci, Fiorella Piemonte and Giorgio Tasca
Cells 2021, 10(6), 1364; https://0-doi-org.brum.beds.ac.uk/10.3390/cells10061364 - 1 Jun 2021
Cited by 15 | Viewed by 3930
Abstract
In recent years, growing evidence has suggested a prominent role of oxidative stress in the pathophysiology of several early- and adult-onset muscle disorders, although effective antioxidant treatments are still lacking. Oxidative stress causes cell damage by affecting protein function, membrane structure, lipid metabolism, [...] Read more.
In recent years, growing evidence has suggested a prominent role of oxidative stress in the pathophysiology of several early- and adult-onset muscle disorders, although effective antioxidant treatments are still lacking. Oxidative stress causes cell damage by affecting protein function, membrane structure, lipid metabolism, and DNA integrity, thus interfering with skeletal muscle homeostasis and functionality. Some features related to oxidative stress, such as chronic inflammation, defective regeneration, and mitochondrial damage are shared among most muscular dystrophies, and Nrf2 has been shown to be a central player in antagonizing redox imbalance in several of these disorders. However, the exact mechanisms leading to overproduction of reactive oxygen species and deregulation in the cellular antioxidants system seem to be, to a large extent, disease-specific, and the clarification of these mechanisms in vivo in humans is the cornerstone for the development of targeted antioxidant therapies, which will require testing in appropriately designed clinical trials. Full article
(This article belongs to the Special Issue The Role of Skeletal Muscle in Neuromuscular Diseases: From Cellular and Molecular Players to Therapeutic Interventions)
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19 pages, 1383 KiB  
Review
Age-Related Alterations at Neuromuscular Junction: Role of Oxidative Stress and Epigenetic Modifications
by Gabriella Dobrowolny, Alessandra Barbiera, Gigliola Sica and Bianca Maria Scicchitano
Cells 2021, 10(6), 1307; https://0-doi-org.brum.beds.ac.uk/10.3390/cells10061307 - 24 May 2021
Cited by 22 | Viewed by 11380
Abstract
With advancing aging, a decline in physical abilities occurs, leading to reduced mobility and loss of independence. Although many factors contribute to the physio-pathological effects of aging, an important event seems to be related to the compromised integrity of the neuromuscular system, which [...] Read more.
With advancing aging, a decline in physical abilities occurs, leading to reduced mobility and loss of independence. Although many factors contribute to the physio-pathological effects of aging, an important event seems to be related to the compromised integrity of the neuromuscular system, which connects the brain and skeletal muscles via motoneurons and the neuromuscular junctions (NMJs). NMJs undergo severe functional, morphological, and molecular alterations during aging and ultimately degenerate. The effect of this decline is an inexorable decrease in skeletal muscle mass and strength, a condition generally known as sarcopenia. Moreover, several studies have highlighted how the age-related alteration of reactive oxygen species (ROS) homeostasis can contribute to changes in the neuromuscular junction morphology and stability, leading to the reduction in fiber number and innervation. Increasing evidence supports the involvement of epigenetic modifications in age-dependent alterations of the NMJ. In particular, DNA methylation, histone modifications, and miRNA-dependent gene expression represent the major epigenetic mechanisms that play a crucial role in NMJ remodeling. It is established that environmental and lifestyle factors, such as physical exercise and nutrition that are susceptible to change during aging, can modulate epigenetic phenomena and attenuate the age-related NMJs changes. This review aims to highlight the recent epigenetic findings related to the NMJ dysregulation during aging and the role of physical activity and nutrition as possible interventions to attenuate or delay the age-related decline in the neuromuscular system. Full article
(This article belongs to the Special Issue The Role of Skeletal Muscle in Neuromuscular Diseases: From Cellular and Molecular Players to Therapeutic Interventions)
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