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Molecular Mechanisms of Muscular Dystrophy

A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Molecular Biology".

Deadline for manuscript submissions: closed (30 April 2022) | Viewed by 12829

Special Issue Editor

Mass Spectrometry Core Facility, UCD Conway Institute of Biomolecular & Biomedical Research, University College Dublin, Dublin, Ireland
Interests: insulin; GABA; behavior; anterior cingulate cortex; molecular imaging; MRI; RNA; myotonic dystrophy; obsessive compulsive disorder; autism
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Special Issue Information

Dear Colleagues,

Muscular dystrophies constitute a heterogeneous set of diseases primarily characterized by muscle weakness. These are often multisystem in nature and present with effects primarily on the muscular, cardiac, and central nervous systems. These diverse muscular dystrophies encompass those with myotonic (both type I and II), congenital and limb-girdle forms but also include the Duchenne, Becker, and facioscapulohumeral (FSHD) muscular dystrophies. A range of genetic mutations and splicing events across these muscular dystrophies prevent optimal protein production and disrupt effective cellular communication. Current research across muscular dystrophies implicates a role for regulatory mechanisms at the level of both transcriptomic and epigenomic events in the disease phenotype and suggests that the severity of disease is not solely dictated by events related to the underlying genetic mutation. In order to further categorize the molecular substrates underlying these diverse muscular dystrophies, their severity and potential treatment approaches, translational approaches in both cellular and animal models as well as humans are needed. This Special Issue will highlight these molecular substrates and seek to clarify novel avenues deserving of follow-up with high clinical utility.

Dr. Jeffrey Glennon
Guest Editor

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Keywords

  • Type 1 and 2 myotonic dystrophy 
  • Facioscapulohumeral (FSHD) muscular dystrophy 
  • Duchenne muscular dystrophy
  • Genomics 
  • Biochemistry 
  • Epigenetics 
  • Cellular models 
  • Animal models 
  • Pharmacology

Published Papers (5 papers)

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Research

19 pages, 4383 KiB  
Article
Prime Editing Permits the Introduction of Specific Mutations in the Gene Responsible for Duchenne Muscular Dystrophy
by Cédric Happi Mbakam, Joël Rousseau, Guillaume Tremblay, Pouiré Yameogo and Jacques P. Tremblay
Int. J. Mol. Sci. 2022, 23(11), 6160; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms23116160 - 31 May 2022
Cited by 15 | Viewed by 2574
Abstract
The Prime editing technique derived from the CRISPR/Cas9 discovery permits the modification of selected nucleotides in a specific gene. We used it to insert specific point mutations in exons 9, 20, 35, 43, 55 and 61 of the Duchenne Muscular Dystrophy (DMD [...] Read more.
The Prime editing technique derived from the CRISPR/Cas9 discovery permits the modification of selected nucleotides in a specific gene. We used it to insert specific point mutations in exons 9, 20, 35, 43, 55 and 61 of the Duchenne Muscular Dystrophy (DMD) gene coding for the dystrophin protein, which is absent in DMD patients. Up to 11% and 21% desired mutations of the DMD gene in HEK293T cells were obtained with the PRIME Editor 2 (PE2) and PE3, respectively. Three repeated treatments increased the percentage of specific mutations with PE2 to 16%. An additional mutation in the protospacer adjacent motif (PAM) sequence improved the PE3 result to 38% after a single treatment. We also carried out the correction of c.428 G>A point mutation in exon 6 of the DMD gene in a patient myoblast. Myoblast electroporation showed up to 8% and 28% modifications, respectively, for one and three repeated treatments using the PE3 system. The myoblast correction led to dystrophin expression in myotubes detected by Western blot. Thus, prime editing can be used for the correction of point mutations in the DMD gene. Full article
(This article belongs to the Special Issue Molecular Mechanisms of Muscular Dystrophy)
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24 pages, 5140 KiB  
Article
Blood Transcriptome Profiling Links Immunity to Disease Severity in Myotonic Dystrophy Type 1 (DM1)
by Sylvia Nieuwenhuis, Joanna Widomska, Paul Blom, Peter-Bram A. C. ‘t Hoen, Baziel G. M. van Engelen, Jeffrey C. Glennon and on behalf of the OPTIMISTIC Consortium
Int. J. Mol. Sci. 2022, 23(6), 3081; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms23063081 - 12 Mar 2022
Cited by 3 | Viewed by 2622
Abstract
The blood transcriptome was examined in relation to disease severity in type I myotonic dystrophy (DM1) patients who participated in the Observational Prolonged Trial In DM1 to Improve QoL- Standards (OPTIMISTIC) study. This sought to (a) ascertain if transcriptome changes were associated with [...] Read more.
The blood transcriptome was examined in relation to disease severity in type I myotonic dystrophy (DM1) patients who participated in the Observational Prolonged Trial In DM1 to Improve QoL- Standards (OPTIMISTIC) study. This sought to (a) ascertain if transcriptome changes were associated with increasing disease severity, as measured by the muscle impairment rating scale (MIRS), and (b) establish if these changes in mRNA expression and associated biological pathways were also observed in the Dystrophia Myotonica Biomarker Discovery Initiative (DMBDI) microarray dataset in blood (with equivalent MIRS/DMPK repeat length). The changes in gene expression were compared using a number of complementary pathways, gene ontology and upstream regulator analyses, which suggested that symptom severity in DM1 was linked to transcriptomic alterations in innate and adaptive immunity associated with muscle-wasting. Future studies should explore the role of immunity in DM1 in more detail to assess its relevance to DM1. Full article
(This article belongs to the Special Issue Molecular Mechanisms of Muscular Dystrophy)
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13 pages, 3655 KiB  
Article
Co-Administration of Simvastatin Does Not Potentiate the Benefit of Gene Therapy in the mdx Mouse Model for Duchenne Muscular Dystrophy
by Nathalie Bourg, Ai Vu Hong, William Lostal, Abbass Jaber, Nicolas Guerchet, Guillaume Tanniou, Fanny Bordier, Emilie Bertil-Froidevaux, Christophe Georger, Nathalie Daniele, Isabelle Richard and David Israeli
Int. J. Mol. Sci. 2022, 23(4), 2016; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms23042016 - 11 Feb 2022
Cited by 5 | Viewed by 1970
Abstract
Duchenne muscular dystrophy (DMD) is the most common and cureless muscle pediatric genetic disease, which is caused by the lack or the drastically reduced expression of dystrophin. Experimental therapeutic approaches for DMD have been mainly focused in recent years on attempts to restore [...] Read more.
Duchenne muscular dystrophy (DMD) is the most common and cureless muscle pediatric genetic disease, which is caused by the lack or the drastically reduced expression of dystrophin. Experimental therapeutic approaches for DMD have been mainly focused in recent years on attempts to restore the expression of dystrophin. While significant progress was achieved, the therapeutic benefit of treated patients is still unsatisfactory. Efficiency in gene therapy for DMD is hampered not only by incompletely resolved technical issues, but likely also due to the progressive nature of DMD. It is indeed suspected that some of the secondary pathologies, which are evolving over time in DMD patients, are not fully corrected by the restoration of dystrophin expression. We recently identified perturbations of the mevalonate pathway and of cholesterol metabolism in DMD patients. Taking advantage of the mdx model for DMD, we then demonstrated that some of these perturbations are improved by treatment with the cholesterol-lowering drug, simvastatin. In the present investigation, we tested whether the combination of the restoration of dystrophin expression with simvastatin treatment could have an additive beneficial effect in the mdx model. We confirmed the positive effects of microdystrophin, and of simvastatin, when administrated separately, but detected no additive effect by their combination. Thus, the present study does not support an additive beneficial effect by combining dystrophin restoration with a metabolic normalization by simvastatin. Full article
(This article belongs to the Special Issue Molecular Mechanisms of Muscular Dystrophy)
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16 pages, 3096 KiB  
Article
Skeletal Ryanodine Receptors Are Involved in Impaired Myogenic Differentiation in Duchenne Muscular Dystrophy Patients
by Pierre Meyer, Cécile Notarnicola, Albano C. Meli, Stefan Matecki, Gérald Hugon, Jérémy Salvador, Mirna Khalil, Léonard Féasson, Claude Cances, Jérôme Cottalorda, Isabelle Desguerre, Jean-Marie Cuisset, Pascal Sabouraud, Alain Lacampagne, Hugues Chevassus, François Rivier and Gilles Carnac
Int. J. Mol. Sci. 2021, 22(23), 12985; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms222312985 - 30 Nov 2021
Cited by 7 | Viewed by 2169
Abstract
Duchenne muscular dystrophy (DMD) is characterized by progressive muscle wasting following repeated muscle damage and inadequate regeneration. Impaired myogenesis and differentiation play a major role in DMD as well as intracellular calcium (Ca2+) mishandling. Ca2+ release from the sarcoplasmic reticulum [...] Read more.
Duchenne muscular dystrophy (DMD) is characterized by progressive muscle wasting following repeated muscle damage and inadequate regeneration. Impaired myogenesis and differentiation play a major role in DMD as well as intracellular calcium (Ca2+) mishandling. Ca2+ release from the sarcoplasmic reticulum is mostly mediated by the type 1 ryanodine receptor (RYR1) that is required for skeletal muscle differentiation in animals. The study objective was to determine whether altered RYR1-mediated Ca2+ release contributes to myogenic differentiation impairment in DMD patients. The comparison of primary cultured myoblasts from six boys with DMD and five healthy controls highlighted delayed myoblast differentiation in DMD. Silencing RYR1 expression using specific si-RNA in a healthy control induced a similar delayed differentiation. In DMD myotubes, resting intracellular Ca2+ concentration was increased, but RYR1-mediated Ca2+ release was not changed compared with control myotubes. Incubation with the RYR-calstabin interaction stabilizer S107 decreased resting Ca2+ concentration in DMD myotubes to control values and improved calstabin1 binding to the RYR1 complex. S107 also improved myogenic differentiation in DMD. Furthermore, intracellular Ca2+ concentration was correlated with endomysial fibrosis, which is the only myopathologic parameter associated with poor motor outcome in patients with DMD. This suggested a potential relationship between RYR1 dysfunction and motor impairment. Our study highlights RYR1-mediated Ca2+ leakage in human DMD myotubes and its key role in myogenic differentiation impairment. RYR1 stabilization may be an interesting adjunctive therapeutic strategy in DMD. Full article
(This article belongs to the Special Issue Molecular Mechanisms of Muscular Dystrophy)
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13 pages, 1714 KiB  
Article
Differential Effects of Halofuginone Enantiomers on Muscle Fibrosis and Histopathology in Duchenne Muscular Dystrophy
by Sharon Mordechay, Shaun Smullen, Paul Evans, Olga Genin, Mark Pines and Orna Halevy
Int. J. Mol. Sci. 2021, 22(13), 7063; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms22137063 - 30 Jun 2021
Cited by 4 | Viewed by 2291
Abstract
Progressive loss of muscle and muscle function is associated with significant fibrosis in Duchenne muscular dystrophy (DMD) patients. Halofuginone, an analog of febrifugine, prevents fibrosis in various animal models, including those of muscular dystrophies. Effects of (+)/(−)-halofuginone enantiomers on motor coordination and diaphragm [...] Read more.
Progressive loss of muscle and muscle function is associated with significant fibrosis in Duchenne muscular dystrophy (DMD) patients. Halofuginone, an analog of febrifugine, prevents fibrosis in various animal models, including those of muscular dystrophies. Effects of (+)/(−)-halofuginone enantiomers on motor coordination and diaphragm histopathology in mdx mice, the mouse model for DMD, were examined. Four-week-old male mice were treated with racemic halofuginone, or its separate enantiomers, for 10 weeks. Controls were treated with saline. Racemic halofuginone-treated mice demonstrated better motor coordination and balance than controls. However, (+)-halofuginone surpassed the racemic form’s effect. No effect was observed for (−)-halofuginone, which behaved like the control. A significant reduction in collagen content and degenerative areas, and an increase in utrophin levels were observed in diaphragms of mice treated with racemic halofuginone. Again, (+)-halofuginone was more effective than the racemic form, whereas (−)-halofuginone had no effect. Both racemic and (+)-halofuginone increased diaphragm myofiber diameters, with no effect for (−)-halofuginone. No effects were observed for any of the compounds tested in an in-vitro cell viability assay. These results, demonstrating a differential effect of the halofuginone enantiomers and superiority of (+)-halofuginone, are of great importance for future use of (+)-halofuginone as a DMD antifibrotic therapy. Full article
(This article belongs to the Special Issue Molecular Mechanisms of Muscular Dystrophy)
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