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Muscular Dystrophies: Pathophysiology and Therapy
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Muscular Dystrophies: Pathophysiology and Therapy

A special issue of Biomedicines (ISSN 2227-9059). This special issue belongs to the section "Molecular and Translational Medicine".

Deadline for manuscript submissions: closed (10 December 2022) | Viewed by 12268

Special Issue Editors

Dr. France Piétri-Rouxel

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Guest Editor
SU, INSERM UMRS974, AIM, Center of Research in Myology, Pitié-Salpêtrière Hospital, 75013 Paris, France
Interests: optimization of AAV-based gene therapies for DMD; muscle mass and function maintenance; pathophysiology of skeletal muscle
Dr. Sestina Falcone

E-Mail Website
Guest Editor
SU, INSERM UMRS974, AIM, Center of Research in Myology, Pitié-Salpêtrière Hospital, 75013 Paris, France
Interests: muscle mass and function maintenance; pathophysiology of skeletal muscle; clini-cal aspects; genetic and histopathology or inherited myopathies and muscular dys-trophies
Prof. Dr. Edoardo Malfatti

E-Mail Website
Guest Editor
Centre de Référence de Pathologie Neuromusculaire Nord-Est-Ile-de-France, Université Paris Est, U955 INSERM, EnvA, EFS, IMRB, F-94010 and APHP, Henri Mondor Hospital, 94010 Créteil, France
Interests: neuromuscular disorders; muscle histopathology; genetics; translational medicine
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

This Special Issue, "Muscular Dystrophies: Pathophysiology and Therapy", will focus on the pathophysiological mechanisms underlying muscular dystrophies, new animal models and methodological approaches for studying muscle dysfunction/recovery, as well as the development of innovative therapeutic strategies and ongoing clinical trials.

Muscular dystrophies are a heterogeneous group of muscle disorders that cause the progressive weakening and breakdown of skeletal/cardiac muscles over time. The diseases differ in their genetic origins, the muscles affected, outcome severity and the onset of symptoms. Among over 35 different muscular dystrophies, Duchenne muscular dystrophy accounts for nearly 50% of cases, all of which are caused by familial or spontaneous mutations of genes coding for proteins involved in muscle development or function. The loss or dysfunction of these proteins can lead to increased muscle membrane fragility, calcium alterations and protease activation, the release of pro-inflammatory cytokines, and impaired mitochondrial metabolism.

To date, no muscular dystrophies have a curative treatment available to patients. Standards of care help to slow the loss of function and breakdown of muscles, including anti-inflammatory measures, as well as respiratory and cardiac support. Corticosteroids are the first-line treatment for DMD, but they are associated with significant secondary effects.

Therapeutic strategies that address the root cause of these diseases are currently being developed for a handful of muscular dystrophies, including virus-based gene therapy and antisense drugs. In this context, the activation of the host immune system against the transgene or viral capsid, the route of administration and the accurately targeted tissue, in order to achieve the restoration of fully functional muscle in patients, remains a challenge. Therefore, strategies that aim to rescue altered proteins, as well as animal models and methodologies, must be optimized. These must be improved to achieve robust readouts, allowing the validation of treatment efficacy in clinical trials. This Special Issue is open to research studies, ranging from basic to preclinical approaches, and will also cover original articles and reviews.

Dr. France Piétri-Rouxel
Dr. Sestina Falcone
Prof. Dr. Edoardo Malfatti
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. Biomedicines 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 2600 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

  • dystrophies
  • therapeutic strategies
  • innovative methodologies and animal models
  • pathophysiology and target molecules

Published Papers (6 papers)

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Research

16 pages, 2873 KiB  
Article
Networking to Optimize Dmd exon 53 Skipping in the Brain of mdx52 Mouse Model
by Mathilde Doisy, Ophélie Vacca, Claire Fergus, Talia Gileadi, Minou Verhaeg, Amel Saoudi, Thomas Tensorer, Luis Garcia, Vincent P. Kelly, Federica Montanaro, Jennifer E. Morgan, Maaike van Putten, Annemieke Aartsma-Rus, Cyrille Vaillend, Francesco Muntoni and Aurélie Goyenvalle
Biomedicines 2023, 11(12), 3243; https://doi.org/10.3390/biomedicines11123243 - 7 Dec 2023
Viewed by 1321
Abstract
Duchenne muscular dystrophy (DMD) is caused by mutations in the DMD gene that disrupt the open reading frame and thus prevent production of functional dystrophin proteins. Recent advances in DMD treatment, notably exon skipping and AAV gene therapy, have achieved some success aimed [...] Read more.
Duchenne muscular dystrophy (DMD) is caused by mutations in the DMD gene that disrupt the open reading frame and thus prevent production of functional dystrophin proteins. Recent advances in DMD treatment, notably exon skipping and AAV gene therapy, have achieved some success aimed at alleviating the symptoms related to progressive muscle damage. However, they do not address the brain comorbidities associated with DMD, which remains a critical aspect of the disease. The mdx52 mouse model recapitulates one of the most frequent genetic pathogenic variants associated with brain involvement in DMD. Deletion of exon 52 impedes expression of two brain dystrophins, Dp427 and Dp140, expressed from distinct promoters. Interestingly, this mutation is eligible for exon skipping strategies aimed at excluding exon 51 or 53 from dystrophin mRNA. We previously showed that exon 51 skipping can restore partial expression of internally deleted yet functional Dp427 in the brain following intracerebroventricular (ICV) injection of antisense oligonucleotides (ASO). This was associated with a partial improvement of anxiety traits, unconditioned fear response, and Pavlovian fear learning and memory in the mdx52 mouse model. In the present study, we investigated in the same mouse model the skipping of exon 53 in order to restore expression of both Dp427 and Dp140. However, in contrast to exon 51, we found that exon 53 skipping was particularly difficult in mdx52 mice and a combination of multiple ASOs had to be used simultaneously to reach substantial levels of exon 53 skipping, regardless of their chemistry (tcDNA, PMO, or 2′MOE). Following ICV injection of a combination of ASO sequences, we measured up to 25% of exon 53 skipping in the hippocampus of treated mdx52 mice, but this did not elicit significant protein restoration. These findings indicate that skipping mouse dystrophin exon 53 is challenging. As such, it has not yet been possible to answer the pertinent question whether rescuing both Dp427 and Dp140 in the brain is imperative to more optimal treatment of neurological aspects of dystrophinopathy. Full article
(This article belongs to the Special Issue Muscular Dystrophies: Pathophysiology and Therapy)
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13 pages, 5202 KiB  
Article
A Dysferlin Exon 32 Nonsense Mutant Mouse Model Shows Pathological Signs of Dysferlinopathy
by Océane Ballouhey, Marie Chapoton, Benedicte Alary, Sébastien Courrier, Nathalie Da Silva, Martin Krahn, Nicolas Lévy, Noah Weisleder and Marc Bartoli
Biomedicines 2023, 11(5), 1438; https://doi.org/10.3390/biomedicines11051438 - 13 May 2023
Cited by 2 | Viewed by 1222
Abstract
Dysferlinopathies are a group of autosomal recessive muscular dystrophies caused by pathogenic variants in the DYSF gene. While several animal models of dysferlinopathy have been developed, most of them involve major disruptions of the Dysf gene locus that are not optimal for studying [...] Read more.
Dysferlinopathies are a group of autosomal recessive muscular dystrophies caused by pathogenic variants in the DYSF gene. While several animal models of dysferlinopathy have been developed, most of them involve major disruptions of the Dysf gene locus that are not optimal for studying human dysferlinopathy, which is often caused by single nucleotide substitutions. In this study, the authors describe a new murine model of dysferlinopathy that carries a nonsense mutation in Dysf exon 32, which has been identified in several patients with dysferlinopathy. This mouse model, called Dysf p.Y1159X/p.Y1159X, displays several molecular, histological, and functional defects observed in dysferlinopathy patients and other published mouse models. This mutant mouse model is expected to be useful for testing various therapeutic approaches such as termination codon readthrough, pharmacological approaches, and exon skipping. Therefore, the data presented in this study strongly support the use of this animal model for the development of preclinical strategies for the treatment of dysferlinopathies. Full article
(This article belongs to the Special Issue Muscular Dystrophies: Pathophysiology and Therapy)
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17 pages, 2729 KiB  
Article
Nintedanib Reduces Muscle Fibrosis and Improves Muscle Function of the Alpha-Sarcoglycan-Deficient Mice
by Jorge Alonso-Pérez, Ana Carrasco-Rozas, Maria Borrell-Pages, Esther Fernández-Simón, Patricia Piñol-Jurado, Lina Badimon, Lutz Wollin, Cinta Lleixà, Eduard Gallardo, Montse Olivé, Jordi Díaz-Manera and Xavier Suárez-Calvet
Biomedicines 2022, 10(10), 2629; https://doi.org/10.3390/biomedicines10102629 - 19 Oct 2022
Cited by 7 | Viewed by 2412
Abstract
Sarcoglycanopathies are a group of recessive limb-girdle muscular dystrophies, characterized by progressive muscle weakness. Sarcoglycan deficiency produces instability of the sarcolemma during muscle contraction, leading to continuous muscle fiber injury eventually producing fiber loss and replacement by fibro-adipose tissue. Therapeutic strategies aiming to [...] Read more.
Sarcoglycanopathies are a group of recessive limb-girdle muscular dystrophies, characterized by progressive muscle weakness. Sarcoglycan deficiency produces instability of the sarcolemma during muscle contraction, leading to continuous muscle fiber injury eventually producing fiber loss and replacement by fibro-adipose tissue. Therapeutic strategies aiming to reduce fibro-adipose expansion could be effective in muscular dystrophies. We report the positive effect of nintedanib in a murine model of alpha-sarcoglycanopathy. We treated 14 Sgca-/- mice, six weeks old, with nintedanib 50 mg/kg every 12 h for 10 weeks and compared muscle function and histology with 14 Sgca-/- mice treated with vehicle and six wild-type littermate mice. Muscle function was assessed using a treadmill and grip strength. A cardiac evaluation was performed by echocardiography and histological study. Structural analysis of the muscles, including a detailed study of the fibrotic and inflammatory processes, was performed using conventional staining and immunofluorescence. In addition, proteomics and transcriptomics studies were carried out. Nintedanib was well tolerated by the animals treated, although we observed weight loss. Sgca-/- mice treated with nintedanib covered a longer distance on the treadmill, compared with non-treated Sgca-/- mice, and showed higher strength in the grip test. Moreover, nintedanib improved the muscle architecture of treated mice, reducing the degenerative area and the fibrotic reaction that was associated with a reversion of the cytokine expression profile. Nintedanib improved muscle function and muscle architecture by reducing muscle fibrosis and degeneration and reverting the chronic inflammatory environment suggesting that it could be a useful therapy for patients with alpha-sarcoglycanopathy. Full article
(This article belongs to the Special Issue Muscular Dystrophies: Pathophysiology and Therapy)
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13 pages, 2458 KiB  
Article
Next-Generation SINE Compound KPT−8602 Ameliorates Dystrophic Pathology in Zebrafish and Mouse Models of DMD
by Katherine G. English, Andrea L. Reid, Adrienne Samani, Gerald J. F. Coulis, S. Armando Villalta, Christopher J. Walker, Sharon Tamir and Matthew S. Alexander
Biomedicines 2022, 10(10), 2400; https://doi.org/10.3390/biomedicines10102400 - 26 Sep 2022
Cited by 2 | Viewed by 1705
Abstract
Duchenne muscular dystrophy (DMD) is a progressive, X-linked childhood neuromuscular disorder that results from loss-of-function mutations in the DYSTROPHIN gene. DMD patients exhibit muscle necrosis, cardiomyopathy, respiratory failure, and loss of ambulation. One of the major driving forces of DMD disease pathology is [...] Read more.
Duchenne muscular dystrophy (DMD) is a progressive, X-linked childhood neuromuscular disorder that results from loss-of-function mutations in the DYSTROPHIN gene. DMD patients exhibit muscle necrosis, cardiomyopathy, respiratory failure, and loss of ambulation. One of the major driving forces of DMD disease pathology is chronic inflammation. The current DMD standard of care is corticosteroids; however, there are serious side effects with long-term use, thus identifying novel anti-inflammatory and anti-fibrotic treatments for DMD is of high priority. We investigated the next-generation SINE compound, KPT−8602 (eltanexor) as an oral therapeutic to alleviate dystrophic symptoms. We performed pre-clinical evaluation of the effects of KPT−8602 in DMD zebrafish (sapje) and mouse (D2-mdx) models. KPT−8602 improved dystrophic skeletal muscle pathologies, muscle architecture and integrity, and overall outcomes in both animal models. KPT−8602 treatment ameliorated DMD pathology in D2-mdx mice, with increased locomotor behavior and improved muscle histology. KPT−8602 altered the immunological profile of the dystrophic mice, and reduced circulating osteopontin serum levels. These findings demonstrate KPT−8602 as an effective therapeutic in DMD through by promotion of an anti-inflammatory environment and overall improvement of DMD pathological outcomes. Full article
(This article belongs to the Special Issue Muscular Dystrophies: Pathophysiology and Therapy)
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18 pages, 8390 KiB  
Article
Long-Term Systemic Treatment of a Mouse Model Displaying Chronic FSHD-like Pathology with Antisense Therapeutics That Inhibit DUX4 Expression
by Ngoc Lu-Nguyen, George Dickson, Alberto Malerba and Linda Popplewell
Biomedicines 2022, 10(7), 1623; https://doi.org/10.3390/biomedicines10071623 - 7 Jul 2022
Cited by 6 | Viewed by 2082
Abstract
Silencing the expression of the double homeobox 4 (DUX4) gene offers great potential for the treatment of facioscapulohumeral muscular dystrophy (FSHD). Several research groups have recently reported promising results using systemic antisense therapy in a transgenic small animal model of FSHD, [...] Read more.
Silencing the expression of the double homeobox 4 (DUX4) gene offers great potential for the treatment of facioscapulohumeral muscular dystrophy (FSHD). Several research groups have recently reported promising results using systemic antisense therapy in a transgenic small animal model of FSHD, the ACTA1-MCM/FLExDUX4 mouse model. However, the treatment was applied in non-DUX4-induced mice or shortly after DUX4 activation, which resulted in conditions that do not correctly represent the situation in a clinic. Here, we generated progressive FSHD-like pathology in ACTA1-MCM/FLExDUX4 mice and then treated the animals with vivoPMO-PACS4, an antisense compound that efficiently downregulates DUX4. To best mimic the translation of this treatment in clinical settings, the systemic antisense oligonucleotide administration was delayed to 3 weeks after the DUX4 activation so that the pathology was established at the time of the treatment. The chronic administration of vivoPMO-PACS4 for 8 weeks downregulated the DUX4 expression by 60%. Consequently, the treated mice showed an increase by 18% in body-wide muscle mass and 32% in muscle strength, and a reduction in both myofiber central nucleation and muscle fibrosis by up to 29% and 37%, respectively. Our results in a more suitable model of FSHD pathology confirm the efficacy of vivoPMO-PACS4 administration, and highlight the significant benefit provided by the long-term treatment of the disease. Full article
(This article belongs to the Special Issue Muscular Dystrophies: Pathophysiology and Therapy)
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17 pages, 3342 KiB  
Article
Skeletal Muscle Cells Derived from Induced Pluripotent Stem Cells: A Platform for Limb Girdle Muscular Dystrophies
by Celine Bruge, Marine Geoffroy, Manon Benabides, Emilie Pellier, Evelyne Gicquel, Jamila Dhiab, Lucile Hoch, Isabelle Richard and Xavier Nissan
Biomedicines 2022, 10(6), 1428; https://doi.org/10.3390/biomedicines10061428 - 16 Jun 2022
Cited by 3 | Viewed by 2745
Abstract
Limb girdle muscular dystrophies (LGMD), caused by mutations in 29 different genes, are the fourth most prevalent group of genetic muscle diseases. Although the link between LGMD and its genetic origins has been determined, LGMD still represent an unmet medical need. Here, we [...] Read more.
Limb girdle muscular dystrophies (LGMD), caused by mutations in 29 different genes, are the fourth most prevalent group of genetic muscle diseases. Although the link between LGMD and its genetic origins has been determined, LGMD still represent an unmet medical need. Here, we describe a platform for modeling LGMD based on the use of human induced pluripotent stem cells (hiPSC). Thanks to the self-renewing and pluripotency properties of hiPSC, this platform provides a renewable and an alternative source of skeletal muscle cells (skMC) to primary, immortalized, or overexpressing cells. We report that skMC derived from hiPSC express the majority of the genes and proteins that cause LGMD. As a proof of concept, we demonstrate the importance of this cellular model for studying LGMDR9 by evaluating disease-specific phenotypes in skMC derived from hiPSC obtained from four patients. Full article
(This article belongs to the Special Issue Muscular Dystrophies: Pathophysiology and Therapy)
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