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Special Issue "Mechanisms and Novel Therapeutic Approaches for Muscle Disease"

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A special issue of Biomedicines (ISSN 2227-9059). This special issue belongs to the section "Cell Biology and Pathology".

Deadline for manuscript submissions: 31 December 2023 | Viewed by 12052

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Special Issue Editors

Dr. Ngoc B. Lu-Nguyen

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Guest Editor

Department of Biological Sciences, School of Life Sciences and the Environment, Royal Holloway University of London, Egham TW20 0EX, UK
Interests: neuromuscular disorders; pathophysiological mechanisms; RNA therapeutics; viral vector-based gene therapy

Prof. Dr. Linda Popplewell

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Guest Editor

1. National Horizons Centre, Teesside University, Darlington DL1 1HG, UK
2. Department of Biological Sciences, School of Life Sciences and the Environment, Royal Holloway University of London, Egham TW20 0EX, UK
Interests: rare disease; neuromuscular disorders; cancers; pathophysiological mechanisms; targeted therapeutics; antisense oligonucleotides; genome editing; gene addition

Special Issue Information

Dear Colleagues,

Muscular dystrophy is a group of inherited rare diseases that causes progressive weakness and the degeneration of skeletal and cardiac muscles, with or without damaging the nerve supplied to the muscles. The diseases often affect a particular group of muscles before spreading more widely to other muscle groups, increasing the level of disability and possible deformity or even becoming life-threatening when cardiac or/and respiratory muscles are severely impaired. The global prevalence of muscular dystrophy is estimated at 3.6 per 100,000 people.

Despite being a genetic condition, it usually takes five years to properly diagnose a muscular disorder. However, disease management mostly involves symptomatic and palliative care as there is a lack of curative treatments available. Understanding the pathophysiological mechanisms underlying muscular diseases is, therefore, crucial. This is the most effective way to provide appropriate support for the development of therapeutic strategies for addressing the root cause of the pathology.

This Special Issue on “Mechanisms and Novel Therapeutic Approaches for Muscle Disease” therefore welcomes basic to translational research studies that aim to provide up-to-date insights into pathophysiological mechanisms, innovative methodologies, cellular and animal models, and novel therapeutic strategies that have a great potential for the development of a cure or modifying treatments for muscular dystrophies.

Dr. Ngoc B. Lu-Nguyen
Prof. Dr. Linda Popplewell
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.

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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

muscular dystrophy
pathophysiological mechanisms
innovative methodologies
cellular and animal models
therapeutic strategies

Published Papers (6 papers)

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Research

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Open AccessArticle

Effects of Monoamino-Oxidase-A (MAO-A) Inhibition on Skeletal Muscle Inflammation and Wasting through Pancreatic Ductal Adenocarcinoma in Triple Transgenic Mice

and

Biomedicines 2023, 11(3), 912; https://doi.org/10.3390/biomedicines11030912 - 15 Mar 2023

Viewed by 1103

Abstract

Cancer cachexia describes a syndrome of muscle wasting and lipolysis that is still largely untreatable and negatively impacts prognosis, mobility, and healthcare costs. Since upregulation of skeletal muscle monoamine-oxidase-A (MAO-A), a source of reactive oxygen species, may contribute to cachexia, we investigated the effects of the MAO-inhibitor harmine-hydrochloride (HH, intraperitoneal, 8 weeks) on muscle wasting in a triple-transgenic mouse model of pancreatic ductal adenocarcinoma (PDAC) and wild type (WT) mice. Gastrocnemius and soleus muscle cryo-cross-sections were analyzed for fiber type-specific cross-sectional area (CSA), fraction and capillarization using ATPase- and lectin-stainings. Transcripts of pro-apoptotic, -atrophic, and -inflammatory signals were determined by RT-qPCR. Furthermore, we evaluated the integrity of neuromuscular junction (NMJ, pre-/post-synaptic co-staining) and mitochondrial ultrastructure (transmission electron microscopy). MAO-A expression in gastrocnemius muscle was increased with PDAC vs. WT (immunohistochemistry: p < 0.05; Western blot: by trend). PDAC expectedly reduced fiber CSA and upregulated IL-1β in both calf muscles, while MuRF1 expression increased in soleus muscle only. Although IL-1β decreased, HH caused an additional 38.65% (p < 0.001) decrease in gastrocnemius muscle (IIBX) fiber CSA. Moreover, soleus muscle CSA remained unchanged despite the downregulation of E3-ligases FBXO32 (p < 0.05) and MuRF1 (p < 0.01) through HH. Notably, HH significantly decreased the post-synaptic NMJ area (quadriceps muscle) and glutathione levels (gastrocnemius muscle), thereby increasing mitochondrial damage and centronucleation in soleus and gastrocnemius type IIBX fibers. Moreover, although pro-atrophic/-inflammatory signals are reversed, HH unfortunately fails to stop and rather promotes PDAC-related muscle wasting, possibly via denervation or mitochondrial damage. These differential adverse vs. therapeutic effects warrant studies regarding dose-dependent benefits and risks with consideration of other targets of HH, such as the dual-specificity tyrosine phosphorylation regulated kinases 1A and B (DYRK1A/B). Full article

(This article belongs to the Special Issue Mechanisms and Novel Therapeutic Approaches for Muscle Disease)

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Open AccessArticle

The von Willebrand Factor Antigen Reflects the Juvenile Dermatomyositis Disease Activity Score

and

Biomedicines 2023, 11(2), 552; https://doi.org/10.3390/biomedicines11020552 - 14 Feb 2023

Cited by 3 | Viewed by 919

Abstract

Objective: This study determined if an accessible, serologic indicator of vascular disease activity, the von Willebrand factor antigen (vWF:Ag), was useful to assess disease activity in children with juvenile dermatomyositis (JDM), a rare disease, but the most common of the pediatric inflammatory myopathies. Methods: A total of 305 children, median age 10 years, 72.5% female, 76.5% white, with definite/probable JDM at diagnosis, were enrolled in the Ann & Robert H. Lurie Cure JM Juvenile Myositis Repository, a longitudinal database. Disease Activity Score (DAS) and vWF:Ag data were obtained at each visit. These data were analyzed using generalized estimating equation (GEE) models (both linear and logistic) to determine if vWF:Ag reflects disease severity in children with JDM. A secondary analysis was performed for untreated active JDM to exclude the effect of medications on vWF:Ag. Result: The vWF:Ag test was elevated in 25% of untreated JDM. We found that patients with elevated vWF:Ag had a 2.55-fold higher DAS total (CI₉₅: 1.83–3.27, p < 0.001). Patients with difficulty swallowing had 2.57 higher odds of elevated vWF:Ag (CI_95: 1.5–4.38, p < 0.001); those with more generalized skin involvement had 2.58-fold higher odds of elevated vWF:Ag (CI₉₅: 1.27–5.23, p = 0.006); and those with eyelid peripheral blood vessel dilation had 1.32-fold higher odds of elevated vWF:Ag (CI₉₅: 1.01–1.72, p = 0.036). Untreated JDM with elevated vWF:Ag had more muscle weakness and higher muscle enzymes, neopterin and erythrocyte sedimentation rate compared to JDM patients with a normal vWF:Ag. Conclusion: vWF:Ag elevation is a widely accessible concomitant of active disease in 25% of JDM. Full article

(This article belongs to the Special Issue Mechanisms and Novel Therapeutic Approaches for Muscle Disease)

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Open AccessReview

Does β-Hydroxy-β-Methylbutyrate Have Any Potential to Support the Treatment of Duchenne Muscular Dystrophy in Humans and Animals?

Abdolvahab Ebrahimpour Gorji

Piotr Ostaszewski

Kaja Urbańska

and

Tomasz Sadkowski

Biomedicines 2023, 11(8), 2329; https://doi.org/10.3390/biomedicines11082329 - 21 Aug 2023

Viewed by 1259

Abstract

Skeletal muscle is the protein reservoir of our body and an important regulator of glucose and lipid homeostasis. The dystrophin gene is the largest gene and has a key role in skeletal muscle construction and function. Mutations in the dystrophin gene cause Duchenne and Becker muscular dystrophy in humans, mice, dogs, and cats. Duchenne muscular dystrophy (DMD) is an X-linked neuromuscular condition causing progressive muscle weakness and premature death. β-hydroxy β-methylbutyrate (HMB) prevents deleterious muscle responses under pathological conditions, including tumor and chronic steroid therapy-related muscle losses. The use of HMB as a dietary supplement allows for increasing lean weight gain; has a positive immunostimulatory effect; is associated with decreased mortality; and attenuates sarcopenia in elderly animals and individuals. This study aimed to identify some genes, metabolic pathways, and biological processes which are common for DMD and HMB based on existing literature and then discuss the consequences of that interaction. Full article

(This article belongs to the Special Issue Mechanisms and Novel Therapeutic Approaches for Muscle Disease)

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Open AccessReview

Dilated Cardiomyopathy: A Comprehensive Approach to Diagnosis and Risk Stratification

André Ferreira

Vera Ferreira

Miguel Marques Antunes

Ana Lousinha

Tiago Pereira-da-Silva

and

Biomedicines 2023, 11(3), 834; https://doi.org/10.3390/biomedicines11030834 - 09 Mar 2023

Cited by 1 | Viewed by 4789

Abstract

Dilated cardiomyopathy (DCM) represents one of the most common causes of non-ischemic heart failure, characterised by ventricular dilation alongside systolic dysfunction. Despite advances in therapy, DCM mortality rates remain high, and it is one of the leading causes of heart transplantation. It was recently recognised that many patients present minor structural cardiac abnormalities and express different arrhythmogenic phenotypes before overt heart-failure symptoms. This has raised several diagnostic and management challenges, including the differential diagnosis with other phenotypically similar conditions, the identification of patients at increased risk of malignant arrhythmias, and of those who will have a worse response to medical therapy. Recent developments in complementary diagnostic procedures, namely cardiac magnetic resonance and genetic testing, have shed new light on DCM understanding and management. The present review proposes a comprehensive and systematic approach to evaluating DCM, focusing on an improved diagnostic pathway and a structured stratification of arrhythmic risk that incorporates novel imaging modalities and genetic test results, which are critical for guiding clinical decision-making and improving outcomes. Full article

(This article belongs to the Special Issue Mechanisms and Novel Therapeutic Approaches for Muscle Disease)

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Open AccessReview

A Brief Review of Duchenne Muscular Dystrophy Treatment Options, with an Emphasis on Two Novel Strategies

Ahlke Heydemann

and

Maria Siemionow

Biomedicines 2023, 11(3), 830; https://doi.org/10.3390/biomedicines11030830 - 09 Mar 2023

Cited by 1 | Viewed by 2394

Abstract

Despite the full cloning of the Dystrophin cDNA 35 years ago, no effective treatment exists for the Duchenne Muscular Dystrophy (DMD) patients who have a mutation in this gene. Many treatment options have been considered, investigated preclinically and some clinically, but none have circumvented all barriers and effectively treated the disease without burdening the patients with severe side-effects. However, currently, many novel therapies are in the pipelines of research labs and pharmaceutical companies and many of these have progressed to clinical trials. A brief review of these promising therapies is presented, followed by a description of two novel technologies that when utilized together effectively treat the disease in the mdx mouse model. One novel technology is to generate chimeric cells from the patient’s own cells and a normal donor. The other technology is to systemically transplant these cells into the femur via the intraosseous route. Full article

(This article belongs to the Special Issue Mechanisms and Novel Therapeutic Approaches for Muscle Disease)

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Open AccessHypothesis

When Size Really Matters: The Eccentricities of Dystrophin Transcription and the Hazards of Quantifying mRNA from Very Long Genes

John C. W. Hildyard

and

Richard J. Piercy

Biomedicines 2023, 11(7), 2082; https://doi.org/10.3390/biomedicines11072082 - 24 Jul 2023

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Abstract

At 2.3 megabases in length, the dystrophin gene is enormous: transcription of a single mRNA requires approximately 16 h. Principally expressed in skeletal muscle, the dystrophin protein product protects the muscle sarcolemma against contraction-induced injury, and dystrophin deficiency results in the fatal muscle-wasting disease, Duchenne muscular dystrophy. This gene is thus of key clinical interest, and therapeutic strategies aimed at eliciting dystrophin restoration require quantitative analysis of its expression. Approaches for quantifying dystrophin at the protein level are well-established, however study at the mRNA level warrants closer scrutiny: measured expression values differ in a sequence-dependent fashion, with significant consequences for data interpretation. In this manuscript, we discuss these nuances of expression and present evidence to support a transcriptional model whereby the long transcription time is coupled to a short mature mRNA half-life, with dystrophin transcripts being predominantly nascent as a consequence. We explore the effects of such a model on cellular transcriptional dynamics and then discuss key implications for the study of dystrophin gene expression, focusing on both conventional (qPCR) and next-gen (RNAseq) approaches. Full article

(This article belongs to the Special Issue Mechanisms and Novel Therapeutic Approaches for Muscle Disease)

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