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Muscular Dystrophy: From Molecular Basis to Therapies

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

Deadline for manuscript submissions: 15 May 2024 | Viewed by 12138

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Special Issue Editors

Dr. Francesca Sciandra

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Guest Editor

Istituto di Scienze e Tecnologie Chimiche “Giulio Natta” – SCITEC Sede di Roma, Largo F. Vito 1, 00168 Rome, Italy
Interests: dystroglycan and dystroglycanopathies; extracellular matrix; muscle regeneration; small molecules therapy

Dr. Kinga I. Gawlik

E-Mail Website
Guest Editor

Institutionen för Experimentell Medicinsk Vetenskap, Lund, Sweden
Interests: laminins; congenital muscular dystrophy; inflammation; gene therapy; genetic modifiers; mouse models; preclinical studies

Special Issue Information

Dear Colleagues,

Muscular dystrophies are a group of genetic diseases primarily characterized by progressive muscle weakness and degeneration of the skeletal muscles. Loss of muscle function has detrimental consequences for patients’ well-being, and there is currently no existing treatment. Muscular dystrophies arise from mutations in genes that encode for proteins possessing a wide range of biological functions in skeletal muscle. Many of these proteins provide structural stability to the sarcolemma and the nuclear envelope, whereas others are involved in muscle contraction, transcription regulation, protein post-translational modifications, protein turnover and intracellular trafficking. Remarkable progress has been made in recent decades toward the development of targeted therapeutic interventions for muscular dystrophies. Alongside the use of antisense oligonucleotides to induce exon skipping and reduce or silence the expression of the mutated gene, gene editing based on the CRISPR-CAS9 technique is also undergoing testing. Other therapeutic approaches for muscular dystrophies include gene therapy, stem cell delivery, the use of small molecules and drug repurposing. This Special Issue aims to provide a collection of original research and review articles, offering an open access platform through which to address the molecular players involved in muscular dystrophies and discuss the current progress of therapeutic approaches.

Dr. Francesca Sciandra
Dr. Kinga I. Gawlik
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. 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

muscular dystrophies
muscle regeneration
extracellular matrix
satellite cells
therapeutic approaches
animal models
clinical trials

Published Papers (5 papers)

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Research

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20 pages, 16729 KiB

Open AccessArticle

Mitochondrial Transplantation Therapy Ameliorates Muscular Dystrophy in mdx Mouse Model

by Mikhail V. Dubinin, Irina B. Mikheeva, Anastasia E. Stepanova, Anastasia D. Igoshkina, Alena A. Cherepanova, Alena A. Semenova, Vyacheslav A. Sharapov, Igor I. Kireev and Konstantin N. Belosludtsev

Biomolecules 2024, 14(3), 316; https://doi.org/10.3390/biom14030316 - 07 Mar 2024

Cited by 1 | Viewed by 1944

Abstract

Duchenne muscular dystrophy is caused by loss of the dystrophin protein. This pathology is accompanied by mitochondrial dysfunction contributing to muscle fiber instability. It is known that mitochondria-targeted in vivo therapy mitigates pathology and improves the quality of life of model animals. In the present work, we applied mitochondrial transplantation therapy (MTT) to correct the pathology in dystrophin-deficient mdx mice. Intramuscular injections of allogeneic mitochondria obtained from healthy animals into the hind limbs of mdx mice alleviated skeletal muscle injury, reduced calcium deposits in muscles and serum creatine kinase levels, and improved the grip strength of the hind limbs and motor activity of recipient mdx mice. We noted normalization of the mitochondrial ultrastructure and sarcoplasmic reticulum/mitochondria interactions in mdx muscles. At the same time, we revealed a decrease in the efficiency of oxidative phosphorylation in the skeletal muscle mitochondria of recipient mdx mice accompanied by a reduction in lipid peroxidation products (MDA products) and reduced calcium overloading. We found no effect of MTT on the expression of mitochondrial signature genes (Drp1, Mfn2, Ppargc1a, Pink1, Parkin) and on the level of mtDNA. Our results show that systemic MTT mitigates the development of destructive processes in the quadriceps muscle of mdx mice. Full article

(This article belongs to the Special Issue Muscular Dystrophy: From Molecular Basis to Therapies)

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22 pages, 5322 KiB

Open AccessArticle

Proteome Profiling of the Dystrophic mdx Mice Diaphragm

by Olga Mucha, Małgorzata Myszka, Paulina Podkalicka, Bianka Świderska, Agata Malinowska, Józef Dulak and Agnieszka Łoboda

Biomolecules 2023, 13(11), 1648; https://doi.org/10.3390/biom13111648 - 13 Nov 2023

Cited by 2 | Viewed by 1107

Abstract

Mdx mice with a spontaneous mutation in exon 23 of the Dmd gene represent the most common model to investigate the pathophysiology of Duchenne muscular dystrophy (DMD). The disease, caused by the lack of functional dystrophin, is characterized by irreversible impairment of muscle functions, with the diaphragm affected earlier and more severely than other skeletal muscles. We applied a label-free (LF) method and the more thorough tandem mass tag (TMT)-based method to analyze differentially expressed proteins in the diaphragm of 6-week-old mdx mice. The comparison of both methods revealed 88 commonly changed proteins. A more in-depth analysis of the TMT-based method showed 953 significantly changed proteins, with 867 increased and 86 decreased in dystrophic animals (q-value < 0.05, fold-change threshold: 1.5). Consequently, several dysregulated processes were demonstrated, including the immune response, fibrosis, translation, and programmed cell death. Interestingly, in the dystrophic diaphragm, we found a significant decrease in the expression of enzymes generating hydrogen sulfide (H₂S), suggesting that alterations in the metabolism of this gaseous mediator could modulate DMD progression, which could be a potential target for pharmacological intervention. Full article

(This article belongs to the Special Issue Muscular Dystrophy: From Molecular Basis to Therapies)

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Review

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33 pages, 2928 KiB

Open AccessReview

The Dysferlinopathies Conundrum: Clinical Spectra, Disease Mechanism and Genetic Approaches for Treatments

by Saeed Anwar and Toshifumi Yokota

Biomolecules 2024, 14(3), 256; https://doi.org/10.3390/biom14030256 - 21 Feb 2024

Viewed by 2889

Abstract

Dysferlinopathies refer to a spectrum of muscular dystrophies that cause progressive muscle weakness and degeneration. They are caused by mutations in the DYSF gene, which encodes the dysferlin protein that is crucial for repairing muscle membranes. This review delves into the clinical spectra of dysferlinopathies, their molecular mechanisms, and the spectrum of emerging therapeutic strategies. We examine the phenotypic heterogeneity of dysferlinopathies, highlighting the incomplete understanding of genotype-phenotype correlations and discussing the implications of various DYSF mutations. In addition, we explore the potential of symptomatic, pharmacological, molecular, and genetic therapies in mitigating the disease’s progression. We also consider the roles of diet and metabolism in managing dysferlinopathies, as well as the impact of clinical trials on treatment paradigms. Furthermore, we examine the utility of animal models in elucidating disease mechanisms. By culminating the complexities inherent in dysferlinopathies, this write up emphasizes the need for multidisciplinary approaches, precision medicine, and extensive collaboration in research and clinical trial design to advance our understanding and treatment of these challenging disorders. Full article

(This article belongs to the Special Issue Muscular Dystrophy: From Molecular Basis to Therapies)

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31 pages, 1687 KiB

Open AccessReview

Pharmacotherapeutic Approaches to Treatment of Muscular Dystrophies

by Alan Rawls, Bridget K. Diviak, Cameron I. Smith, Grant W. Severson, Sofia A. Acosta and Jeanne Wilson-Rawls

Biomolecules 2023, 13(10), 1536; https://doi.org/10.3390/biom13101536 - 17 Oct 2023

Cited by 1 | Viewed by 2821

Abstract

Muscular dystrophies are a heterogeneous group of genetic muscle-wasting disorders that are subdivided based on the region of the body impacted by muscle weakness as well as the functional activity of the underlying genetic mutations. A common feature of the pathophysiology of muscular dystrophies is chronic inflammation associated with the replacement of muscle mass with fibrotic scarring. With the progression of these disorders, many patients suffer cardiomyopathies with fibrosis of the cardiac tissue. Anti-inflammatory glucocorticoids represent the standard of care for Duchenne muscular dystrophy, the most common muscular dystrophy worldwide; however, long-term exposure to glucocorticoids results in highly adverse side effects, limiting their use. Thus, it is important to develop new pharmacotherapeutic approaches to limit inflammation and fibrosis to reduce muscle damage and promote repair. Here, we examine the pathophysiology, genetic background, and emerging therapeutic strategies for muscular dystrophies. Full article

(This article belongs to the Special Issue Muscular Dystrophy: From Molecular Basis to Therapies)

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35 pages, 9137 KiB

Open AccessReview

Extracellular Matrix Proteomics: The mdx-4cv Mouse Diaphragm as a Surrogate for Studying Myofibrosis in Dystrophinopathy

by Paul Dowling, Stephen Gargan, Margit Zweyer, Dieter Swandulla and Kay Ohlendieck

Biomolecules 2023, 13(7), 1108; https://doi.org/10.3390/biom13071108 - 12 Jul 2023

Cited by 6 | Viewed by 2445

Abstract

The progressive degeneration of the skeletal musculature in Duchenne muscular dystrophy is accompanied by reactive myofibrosis, fat substitution, and chronic inflammation. Fibrotic changes and reduced tissue elasticity correlate with the loss in motor function in this X-chromosomal disorder. Thus, although dystrophinopathies are due to primary abnormalities in the DMD gene causing the almost-complete absence of the cytoskeletal Dp427-M isoform of dystrophin in voluntary muscles, the excessive accumulation of extracellular matrix proteins presents a key histopathological hallmark of muscular dystrophy. Animal model research has been instrumental in the characterization of dystrophic muscles and has contributed to a better understanding of the complex pathogenesis of dystrophinopathies, the discovery of new disease biomarkers, and the testing of novel therapeutic strategies. In this article, we review how mass-spectrometry-based proteomics can be used to study changes in key components of the endomysium, perimysium, and epimysium, such as collagens, proteoglycans, matricellular proteins, and adhesion receptors. The mdx-4cv mouse diaphragm displays severe myofibrosis, making it an ideal model system for large-scale surveys of systematic alterations in the matrisome of dystrophic fibers. Novel biomarkers of myofibrosis can now be tested for their appropriateness in the preclinical and clinical setting as diagnostic, pharmacodynamic, prognostic, and/or therapeutic monitoring indicators. Full article

(This article belongs to the Special Issue Muscular Dystrophy: From Molecular Basis to Therapies)

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