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Molecular Insights into Pathogenesis and Therapy of Muscular Dystrophies
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Molecular Insights into Pathogenesis and Therapy of Muscular Dystrophies

A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Molecular Pathology, Diagnostics, and Therapeutics".

Deadline for manuscript submissions: 15 July 2024 | Viewed by 3494

Special Issue Editor

Dr. Valentina Saccone

E-Mail Website
Guest Editor
Department of Life Science and Public Health, Università Cattolica del Sacro Cuore, Largo F. Vito 1, 00168 Rome, Italy
Interests: muscular dystrophies; muscle regeneration; stem cell; epigenetics

Special Issue Information

Dear Colleagues, 

Muscular dystrophies (MDs) are genetic disorders characterized by progressive muscle weakness and degeneration. While there are many different types of muscular dystrophies, they all share common features such as muscle fiber damage, inflammation, and impaired muscle regeneration.

Ongoing research on MDs suggests that regulatory mechanisms operating at the transcriptomic and epigenetic levels play a significant role in shaping the disease phenotype. These findings challenge the notion that the severity of the diseases is exclusively determined by factors associated with the underlying genetic mutation.

This Special Issue plans to invite researchers to submit original research and review articles on exploring molecular mechanisms and targeted therapy of muscular dystrophy aiming to advance our understanding in this field.

This Special Issue focuses on the following topics:

  • The application of omics approaches to gain molecular insights into the pathogenesis of muscular dystrophy and exploring novel therapeutic strategies for intervention.
  • Gene-based therapies including gene replacement, exon skipping, and gene editing strategies.
  • Small molecules and pharmacological therapies targeting inflammation, fibrosis, and disease-associated pathways.
  • Stem cell and regenerative therapies.
  • RNA-based therapies and epigenetic modifiers.
  • Secretome and extracellular vesicles investigations in order to target the communication networks and molecular signaling involved in MD pathogenesis.
  • Personalized medicine and translational perspectives emphasizing the importance of genetic profiling and precision medicine in tailoring treatment strategies. It discusses the identification of biomarkers for disease progression and treatment response, which can guide therapy and monitor disease course.

By consolidating the latest research and advancements, this Special Issue enhances our knowledge of the molecular mechanisms underlying muscular dystrophy. It offers insights into potential therapeutic targets and strategies, ultimately contributing to the development of more effective treatments for patients with muscular dystrophy.

The findings presented in this Special Issue pave the way for the development of personalized and effective treatments for individuals affected by muscular dystrophy to restore muscle function and improve the quality of life for patients.

This Special Issue is supervised by Dr. Valentina Saccone and assisted by our Topical Advisory Panel Member Dr. Martina Sandoná (Foundation Santa Lucia).

Dr. Valentina Saccone
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. International Journal of Molecular Sciences is an international peer-reviewed open access semimonthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. There is an Article Processing Charge (APC) for publication in this open access journal. For details about the APC please see here. 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

  • muscular dystrophy
  • myogenesis
  • muscle regeneration
  • satellite cells
  • fibrosis
  • inflammation
  • omics

Published Papers (3 papers)

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Research

26 pages, 19677 KiB  
Article
The Influence of a Genetic Variant in CCDC78 on LMNA-Associated Skeletal Muscle Disease
by Nathaniel P. Mohar, Efrem M. Cox, Emily Adelizzi, Steven A. Moore, Katherine D. Mathews, Benjamin W. Darbro and Lori L. Wallrath
Int. J. Mol. Sci. 2024, 25(9), 4930; https://doi.org/10.3390/ijms25094930 - 30 Apr 2024
Viewed by 269
Abstract
Mutations in the LMNA gene-encoding A-type lamins can cause Limb–Girdle muscular dystrophy Type 1B (LGMD1B). This disease presents with weakness and wasting of the proximal skeletal muscles and has a variable age of onset and disease severity. This variability has been attributed to [...] Read more.
Mutations in the LMNA gene-encoding A-type lamins can cause Limb–Girdle muscular dystrophy Type 1B (LGMD1B). This disease presents with weakness and wasting of the proximal skeletal muscles and has a variable age of onset and disease severity. This variability has been attributed to genetic background differences among individuals; however, such variants have not been well characterized. To identify such variants, we investigated a multigeneration family in which affected individuals are diagnosed with LGMD1B. The primary genetic cause of LGMD1B in this family is a dominant mutation that activates a cryptic splice site, leading to a five-nucleotide deletion in the mature mRNA. This results in a frame shift and a premature stop in translation. Skeletal muscle biopsies from the family members showed dystrophic features of variable severity, with the muscle fibers of some family members possessing cores, regions of sarcomeric disruption, and a paucity of mitochondria, not commonly associated with LGMD1B. Using whole genome sequencing (WGS), we identified 21 DNA sequence variants that segregate with the family members possessing more profound dystrophic features and muscle cores. These include a relatively common variant in coiled-coil domain containing protein 78 (CCDC78). This variant was given priority because another mutation in CCDC78 causes autosomal dominant centronuclear myopathy-4, which causes cores in addition to centrally positioned nuclei. Therefore, we analyzed muscle biopsies from family members and discovered that those with both the LMNA mutation and the CCDC78 variant contain muscle cores that accumulated both CCDC78 and RyR1. Muscle cores containing mislocalized CCDC78 and RyR1 were absent in the less profoundly affected family members possessing only the LMNA mutation. Taken together, our findings suggest that a relatively common variant in CCDC78 can impart profound muscle pathology in combination with a LMNA mutation and accounts for variability in skeletal muscle disease phenotypes. Full article
(This article belongs to the Special Issue Molecular Insights into Pathogenesis and Therapy of Muscular Dystrophies)
18 pages, 9638 KiB  
Article
The Impact of miR-155-5p on Myotube Differentiation: Elucidating Molecular Targets in Skeletal Muscle Disorders
by Letícia Oliveira Lopes, Sarah Santiloni Cury, Diogo de Moraes, Jakeline Santos Oliveira, Grasieli de Oliveira, Otavio Cabral-Marques, Geysson Javier Fernandez, Mario Hiroyuki Hirata, Da-Zhi Wang, Maeli Dal-Pai-Silva, Robson Francisco Carvalho and Paula Paccielli Freire
Int. J. Mol. Sci. 2024, 25(3), 1777; https://doi.org/10.3390/ijms25031777 - 01 Feb 2024
Viewed by 1054
Abstract
MicroRNAs are small regulatory molecules that control gene expression. An emerging property of muscle miRNAs is the cooperative regulation of transcriptional and epitranscriptional events controlling muscle phenotype. miR-155 has been related to muscular dystrophy and muscle cell atrophy. However, the function of miR-155 [...] Read more.
MicroRNAs are small regulatory molecules that control gene expression. An emerging property of muscle miRNAs is the cooperative regulation of transcriptional and epitranscriptional events controlling muscle phenotype. miR-155 has been related to muscular dystrophy and muscle cell atrophy. However, the function of miR-155 and its molecular targets in muscular dystrophies remain poorly understood. Through in silico and in vitro approaches, we identify distinct transcriptional profiles induced by miR-155-5p in muscle cells. The treated myotubes changed the expression of 359 genes (166 upregulated and 193 downregulated). We reanalyzed muscle transcriptomic data from dystrophin-deficient patients and detected overlap with gene expression patterns in miR-155-treated myotubes. Our analysis indicated that miR-155 regulates a set of transcripts, including Aldh1l, Nek2, Bub1b, Ramp3, Slc16a4, Plce1, Dync1i1, and Nr1h3. Enrichment analysis demonstrates 20 targets involved in metabolism, cell cycle regulation, muscle cell maintenance, and the immune system. Moreover, digital cytometry confirmed a significant increase in M2 macrophages, indicating miR-155’s effects on immune response in dystrophic muscles. We highlight a critical miR-155 associated with disease-related pathways in skeletal muscle disorders. Full article
(This article belongs to the Special Issue Molecular Insights into Pathogenesis and Therapy of Muscular Dystrophies)
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18 pages, 3755 KiB  
Article
Amniotic Membrane-Derived Stromal Cells Release Extracellular Vesicles That Favor Regeneration of Dystrophic Skeletal Muscles
by Martina Sandonà, Federica Esposito, Anna Cargnoni, Antonietta Silini, Pietro Romele, Ornella Parolini and Valentina Saccone
Int. J. Mol. Sci. 2023, 24(15), 12457; https://doi.org/10.3390/ijms241512457 - 05 Aug 2023
Viewed by 1243
Abstract
Duchenne muscular dystrophy (DMD) is a muscle disease caused by mutations in the dystrophin gene characterized by myofiber fragility and progressive muscle degeneration. The genetic defect results in a reduced number of self-renewing muscle stem cells (MuSCs) and an impairment of their activation [...] Read more.
Duchenne muscular dystrophy (DMD) is a muscle disease caused by mutations in the dystrophin gene characterized by myofiber fragility and progressive muscle degeneration. The genetic defect results in a reduced number of self-renewing muscle stem cells (MuSCs) and an impairment of their activation and differentiation, which lead to the exhaustion of skeletal muscle regeneration potential and muscle replacement by fibrotic and fatty tissue. In this study, we focused on an unexplored strategy to improve MuSC function and to preserve their niche based on the regenerative properties of mesenchymal stromal cells from the amniotic membrane (hAMSCs), that are multipotent cells recognized to have a role in tissue repair in different disease models. We demonstrate that the hAMSC secretome (CM hAMSC) and extracellular vesicles (EVs) isolated thereof directly stimulate the in vitro proliferation and differentiation of human myoblasts and mouse MuSC from dystrophic muscles. Furthermore, we demonstrate that hAMSC secreted factors modulate the muscle stem cell niche in dystrophic–mdx-mice. Interestingly, local injection of EV hAMSC in mdx muscles correlated with an increase in the number of activated Pax7+/Ki67+ MuSCs and in new fiber formation. EV hAMSCs also significantly reduced muscle collagen deposition, thus counteracting fibrosis and MuSCs exhaustion, two hallmarks of DMD. Herein for the first time we demonstrate that CM hAMSC and EVs derived thereof promote muscle regeneration by supporting proliferation and differentiation of resident muscle stem cells. These results pave the way for the development of a novel treatment to counteract DMD progression by reducing fibrosis and enhancing myogenesis in dystrophic muscles. Full article
(This article belongs to the Special Issue Molecular Insights into Pathogenesis and Therapy of Muscular Dystrophies)
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