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Towards Understanding the Mechanisms and Curing Of Muscular Dystrophy Diseases
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Towards Understanding the Mechanisms and Curing Of Muscular Dystrophy Diseases

A special issue of Molecules (ISSN 1420-3049). This special issue belongs to the section "Medicinal Chemistry".

Deadline for manuscript submissions: closed (28 February 2015)

Special Issue Editor

Prof. Dr. Leonidas A. Phylactou

E-Mail Website
Guest Editor
Chief Executive Officer and Medical Director, The Cyprus Institute of Neurology & Genetics, PO Box 23462, Nicosia 1683, Cyprus
Interests: RNA biology; regulatory RNA molecules; extracellular vesicles; identification of genetic defects in inherited diseases
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

The journals Molecules and Pharmaceuticals will be jointly publishing a Special Issue covering the topic, “Towards Understanding the Mechanisms and Curing of Muscular Dystrophy Diseases”, and I would like to invite you to make submissions addressing the following interesting topics regarding muscular dystrophy.

Muscular dystrophies are a heterogeneous group of inherited diseases with different molecular basis, but sharing similar clinical features and dystrophic changes. Although, substantial ground has been covered on the understanding of several muscular dystrophies, more research efforts would be beneficial in this direction. Similarly, there are several pre-clinical and clinical attempts aiming at the therapy of muscular dystrophies, such as genetic, cellular, and pharmacological. It is certain that in the future, new approaches will be developed whereby optimization of current methods will be carried out.

The purpose of this Special Issue is to host research and review papers on the molecular understanding of muscular dystrophies and methods to cure them.

Prof. Dr. Leonidas A. Phylactou
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. Molecules 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

  • Muscular dystrophy
  • Muscle
  • Gene
  • Mutation
  • inherited
  • pathogenesis
  • gene therapy

Published Papers (7 papers)

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Editorial

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619 KiB  
Editorial
Special Issue—Towards Understanding the Mechanisms and Curing of Muscular Dystrophy Diseases
by Leonidas A. Phylactou
Molecules 2015, 20(7), 12944-12945; https://doi.org/10.3390/molecules200712944 - 16 Jul 2015
Viewed by 4113
Abstract
Muscular dystrophies are a heterogeneous group of inherited diseases with different molecular basss, but sharing similar clinical features and dystrophic changes. Full article
(This article belongs to the Special Issue Towards Understanding the Mechanisms and Curing Of Muscular Dystrophy Diseases)

Research

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3051 KiB  
Article
Comparative Label-Free Mass Spectrometric Analysis of Mildly versus Severely Affected mdx Mouse Skeletal Muscles Identifies Annexin, Lamin, and Vimentin as Universal Dystrophic Markers
by Ashling Holland, Michael Henry, Paula Meleady, Claudia K. Winkler, Mirjam Krautwald, Heinrich Brinkmeier and Kay Ohlendieck
Molecules 2015, 20(6), 11317-11344; https://doi.org/10.3390/molecules200611317 - 19 Jun 2015
Cited by 42 | Viewed by 7534
Abstract
The primary deficiency in the membrane cytoskeletal protein dystrophin results in complex changes in dystrophic muscles. In order to compare the degree of secondary alterations in differently affected subtypes of skeletal muscles, we have conducted a global analysis of proteome-wide changes in various [...] Read more.
The primary deficiency in the membrane cytoskeletal protein dystrophin results in complex changes in dystrophic muscles. In order to compare the degree of secondary alterations in differently affected subtypes of skeletal muscles, we have conducted a global analysis of proteome-wide changes in various dystrophin-deficient muscles. In contrast to the highly degenerative mdx diaphragm muscle, which showed considerable alterations in 35 distinct proteins, the spectrum of mildly to moderately dystrophic skeletal muscles, including interosseus, flexor digitorum brevis, soleus, and extensor digitorum longus muscle, exhibited a smaller number of changed proteins. Compensatory mechanisms and/or cellular variances may be responsible for differing secondary changes in individual mdx muscles. Label-free mass spectrometry established altered expression levels for diaphragm proteins associated with contraction, energy metabolism, the cytoskeleton, the extracellular matrix and the cellular stress response. Comparative immunoblotting verified the differences in the degree of secondary changes in dystrophin-deficient muscles and showed that the up-regulation of molecular chaperones, the compensatory increase in proteins of the intermediate filaments, the fibrosis-related increase in collagen levels and the pathophysiological decrease in calcium binding proteins is more pronounced in mdx diaphragm as compared to the less severely affected mdx leg muscles. Annexin, lamin, and vimentin were identified as universal dystrophic markers. Full article
(This article belongs to the Special Issue Towards Understanding the Mechanisms and Curing Of Muscular Dystrophy Diseases)
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1589 KiB  
Article
Non-Invasive Biomarkers for Duchenne Muscular Dystrophy and Carrier Detection
by Mónica Alejandra Anaya-Segura, Froylan Arturo García-Martínez, Luis Ángel Montes-Almanza, Benjamín-Gómez Díaz, Guillermina Ávila-Ramírez, Ikuri Alvarez-Maya, Ramón Mauricio Coral-Vázquez, Paul Mondragón-Terán, Rosa Elena Escobar-Cedillo, Noemí García-Calderón, Norma Alejandra Vázquez-Cardenas, Silvia García and Luz Berenice López-Hernández
Molecules 2015, 20(6), 11154-11172; https://doi.org/10.3390/molecules200611154 - 17 Jun 2015
Cited by 37 | Viewed by 11659
Abstract
Non-invasive biological indicators of the absence/presence or progress of the disease that could be used to support diagnosis and to evaluate the effectiveness of treatment are of utmost importance in Duchenne Muscular Dystrophy (DMD). This neuromuscular disorder affects male children, causing weakness and [...] Read more.
Non-invasive biological indicators of the absence/presence or progress of the disease that could be used to support diagnosis and to evaluate the effectiveness of treatment are of utmost importance in Duchenne Muscular Dystrophy (DMD). This neuromuscular disorder affects male children, causing weakness and disability, whereas female relatives are at risk of being carriers of the disease. A biomarker with both high sensitivity and specificity for accurate prediction is preferred. Until now creatine kinase (CK) levels have been used for DMD diagnosis but these fail to assess disease progression. Herein we examined the potential applicability of serum levels of matrix metalloproteinase 9 (MMP-9) and matrix metalloproteinase 2 (MMP-2), tissue inhibitor of metalloproteinases 1 (TIMP-1), myostatin (GDF-8) and follistatin (FSTN) as non-invasive biomarkers to distinguish between DMD steroid naïve patients and healthy controls of similar age and also for carrier detection. Our data suggest that serum levels of MMP-9, GDF-8 and FSTN are useful to discriminate DMD from controls (p < 0.05), to correlate with some neuromuscular assessments for DMD, and also to differentiate between Becker muscular dystrophy (BMD) and Limb-girdle muscular dystrophy (LGMD) patients. In DMD individuals under steroid treatment, GDF-8 levels increased as FSTN levels decreased, resembling the proportions of these proteins in healthy controls and also the baseline ratio of patients without steroids. GDF-8 and FSTN serum levels were also useful for carrier detection (p < 0.05). Longitudinal studies with larger cohorts are necessary to confirm that these molecules correlate with disease progression. The biomarkers presented herein could potentially outperform CK levels for carrier detection and also harbor potential for monitoring disease progression. Full article
(This article belongs to the Special Issue Towards Understanding the Mechanisms and Curing Of Muscular Dystrophy Diseases)
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775 KiB  
Article
Culture Conditions Affect Expression of DUX4 in FSHD Myoblasts
by Sachchida Nand Pandey, Hunain Khawaja and Yi-Wen Chen
Molecules 2015, 20(5), 8304-8315; https://doi.org/10.3390/molecules20058304 - 08 May 2015
Cited by 17 | Viewed by 6346
Abstract
Facioscapulohumeral muscular dystrophy (FSHD) is believed to be caused by aberrant expression of double homeobox 4 (DUX4) due to epigenetic changes of the D4Z4 region at chromosome 4q35. Detecting DUX4 is challenging due to its stochastic expression pattern and low transcription level. In [...] Read more.
Facioscapulohumeral muscular dystrophy (FSHD) is believed to be caused by aberrant expression of double homeobox 4 (DUX4) due to epigenetic changes of the D4Z4 region at chromosome 4q35. Detecting DUX4 is challenging due to its stochastic expression pattern and low transcription level. In this study, we examined different cDNA synthesis strategies and the sensitivity for DUX4 detection. In addition, we investigated the effects of dexamethasone and knockout serum replacement (KOSR) on DUX4 expression in culture. Our data showed that DUX4 was consistently detected in cDNA samples synthesized using Superscript III. The sensitivity of DUX4 detection was higher in the samples synthesized using oligo(dT) primers compared to random hexamers. Adding dexamethasone to the culture media significantly suppressed DUX4 expression in immortalized (1.3 fold, p < 0.01) and primary (4.7 fold, p < 0.01) FSHD myoblasts, respectively. Culture medium with KOSR increased DUX4 expression and the response is concentration dependent. The findings suggest that detection strategies and culture conditions should be carefully considered when studying DUX4 in cultured cells. Full article
(This article belongs to the Special Issue Towards Understanding the Mechanisms and Curing Of Muscular Dystrophy Diseases)
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Review

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1086 KiB  
Review
Duchenne Muscular Dystrophy: From Diagnosis to Therapy
by Maria Sofia Falzarano, Chiara Scotton, Chiara Passarelli and Alessandra Ferlini
Molecules 2015, 20(10), 18168-18184; https://doi.org/10.3390/molecules201018168 - 07 Oct 2015
Cited by 178 | Viewed by 43148
Abstract
Duchenne muscular dystrophy (DMD) is an X-linked inherited neuromuscular disorder due to mutations in the dystrophin gene. It is characterized by progressive muscle weakness and wasting due to the absence of dystrophin protein that causes degeneration of skeletal and cardiac muscle. The molecular [...] Read more.
Duchenne muscular dystrophy (DMD) is an X-linked inherited neuromuscular disorder due to mutations in the dystrophin gene. It is characterized by progressive muscle weakness and wasting due to the absence of dystrophin protein that causes degeneration of skeletal and cardiac muscle. The molecular diagnostic of DMD involves a deletions/duplications analysis performed by quantitative technique such as microarray-based comparative genomic hybridization (array-CGH), Multiple Ligation Probe Assay MLPA. Since traditional methods for detection of point mutations and other sequence variants require high cost and are time consuming, especially for a large gene like dystrophin, the use of next-generation sequencing (NGS) has become a useful tool available for clinical diagnosis. The dystrophin gene is large and finely regulated in terms of tissue expression, and RNA processing and editing includes a variety of fine tuned processes. At present, there are no effective treatments and the steroids are the only fully approved drugs used in DMD therapy able to slow disease progression. In the last years, an increasing variety of strategies have been studied as a possible therapeutic approach aimed to restore dystrophin production and to preserve muscle mass, ameliorating the DMD phenotype. RNA is the most studied target for the development of clinical strategies and Antisense Oligonucleotides (AONs) are the most used molecules for RNA modulation. The identification of delivery system to enhance the efficacy and to reduce the toxicity of AON is the main purpose in this area and nanomaterials are a very promising model as DNA/RNA molecules vectors. Dystrophinopathies therefore represent a pivotal field of investigation, which has opened novel avenues in molecular biology, medical genetics and novel therapeutic options. Full article
(This article belongs to the Special Issue Towards Understanding the Mechanisms and Curing Of Muscular Dystrophy Diseases)
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1326 KiB  
Review
Current Understanding of Molecular Pathology and Treatment of Cardiomyopathy in Duchenne Muscular Dystrophy
by Tirsa L. E. Van Westering, Corinne A. Betts and Matthew J. A. Wood
Molecules 2015, 20(5), 8823-8855; https://doi.org/10.3390/molecules20058823 - 15 May 2015
Cited by 74 | Viewed by 15785
Abstract
Duchenne muscular dystrophy (DMD) is a genetic muscle disorder caused by mutations in the Dmd gene resulting in the loss of the protein dystrophin. Patients do not only experience skeletal muscle degeneration, but also develop severe cardiomyopathy by their second decade, one of [...] Read more.
Duchenne muscular dystrophy (DMD) is a genetic muscle disorder caused by mutations in the Dmd gene resulting in the loss of the protein dystrophin. Patients do not only experience skeletal muscle degeneration, but also develop severe cardiomyopathy by their second decade, one of the main causes of death. The absence of dystrophin in the heart renders cardiomyocytes more sensitive to stretch-induced damage. Moreover, it pathologically alters intracellular calcium (Ca2+) concentration, neuronal nitric oxide synthase (nNOS) localization and mitochondrial function and leads to inflammation and necrosis, all contributing to the development of cardiomyopathy. Current therapies only treat symptoms and therefore the need for targeting the genetic defect is immense. Several preclinical therapies are undergoing development, including utrophin up-regulation, stop codon read-through therapy, viral gene therapy, cell-based therapy and exon skipping. Some of these therapies are undergoing clinical trials, but these have predominantly focused on skeletal muscle correction. However, improving skeletal muscle function without addressing cardiac aspects of the disease may aggravate cardiomyopathy and therefore it is essential that preclinical and clinical focus include improving heart function. This review consolidates what is known regarding molecular pathology of the DMD heart, specifically focusing on intracellular Ca2+, nNOS and mitochondrial dysregulation. It briefly discusses the current treatment options and then elaborates on the preclinical therapeutic approaches currently under development to restore dystrophin thereby improving pathology, with a focus on the heart. Full article
(This article belongs to the Special Issue Towards Understanding the Mechanisms and Curing Of Muscular Dystrophy Diseases)
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Graphical abstract

765 KiB  
Review
Model Organisms in the Fight against Muscular Dystrophy: Lessons from Drosophila and Zebrafish
by Emilie Plantié, Marta Migocka-Patrzałek, Małgorzata Daczewska and Krzysztof Jagla
Molecules 2015, 20(4), 6237-6253; https://doi.org/10.3390/molecules20046237 - 09 Apr 2015
Cited by 45 | Viewed by 10435
Abstract
Muscular dystrophies (MD) are a heterogeneous group of genetic disorders that cause muscle weakness, abnormal contractions and muscle wasting, often leading to premature death. More than 30 types of MD have been described so far; those most thoroughly studied are Duchenne muscular dystrophy [...] Read more.
Muscular dystrophies (MD) are a heterogeneous group of genetic disorders that cause muscle weakness, abnormal contractions and muscle wasting, often leading to premature death. More than 30 types of MD have been described so far; those most thoroughly studied are Duchenne muscular dystrophy (DMD), myotonic dystrophy type 1 (DM1) and congenital MDs. Structurally, physiologically and biochemically, MDs affect different types of muscles and cause individual symptoms such that genetic and molecular pathways underlying their pathogenesis thus remain poorly understood. To improve our knowledge of how MD-caused muscle defects arise and to find efficacious therapeutic treatments, different animal models have been generated and applied. Among these, simple non-mammalian Drosophila and zebrafish models have proved most useful. This review discusses how zebrafish and Drosophila MD have helped to identify genetic determinants of MDs and design innovative therapeutic strategies with a special focus on DMD, DM1 and congenital MDs. Full article
(This article belongs to the Special Issue Towards Understanding the Mechanisms and Curing Of Muscular Dystrophy Diseases)
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