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From Molecular Basis to Therapeutic Approaches in Skeletal Muscle Dysfunction

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A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Molecular Pathology, Diagnostics, and Therapeutics".

Deadline for manuscript submissions: closed (31 August 2023) | Viewed by 17782

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Special Issue Editors

Prof. Dr. Atsushi Higashitani

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Guest Editor

Graduate School of Life Sciences, Tohoku University, Sendai 980-8577, Japan
Interests: aging; Caenorhabditis elegans; calcium homeostasis; dopamine; dystrophy; heat stroke; microgravity; mitochondria

Dr. Timothy Etheridge

E-Mail Website
Guest Editor

Department of Sport and Health Science, University of Exeter, St. Luke's Campus, Exeter, Devon EX1 2LU, UK
Interests: skeletal muscle; OMICS; exercise; pharmaceuticals; healthspan; C. elegans; humans; ageing; sarcopenia

Special Issue Information

Dear Colleagues,

Skeletal muscle atrophy and dysfunction are common features of many disorders. They are caused not only by sarcopenia with aging, but also by several diseases such as diabetes, cancer cachexia, heatstroke, mitochondrial diseases, and muscular dystrophy. Muscle wasting is also caused by fractures and long-term space flight. In particular, frailty with sarcopenia is becoming a major public health problem among an aging society.

The aim of this Special Issue is the collection of original reports and literature reviews, both basic science and translational research investigation, with current knowledge from the molecular basis to therapeutic approaches to several types of skeletal muscle dysfunction.

Nutritional interventions and exercise tests have already begun in humans. However, much of the research on the molecular basis and therapeutic approaches has been developed from myotube cells, small animal models such as the nematode C. elegans and Drosophila melanogaster, and rodents, such as mice and rats. Collecting the latest results related to these basic studies will lead to the development of applications for combating human skeletal muscle dysfunction.

Prof. Dr. Atsushi Higashitani
Dr. Timothy Etheridge
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. International Journal of Molecular Sciences is an international peer-reviewed open access semimonthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. There is an Article Processing Charge (APC) for publication in this open access journal. For details about the APC please see here. 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

aging
exercise
mitochondria
muscle atrophy
muscular dystrophy
myofibrosis
myopathy
nutrients
sarcopenia
therapeutic drug

Published Papers (7 papers)

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Research

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11 pages, 1785 KiB

Open AccessArticle

Inflammasome in Skeletal Muscle: NLRP3 Is an Inflammatory Cell Stress Component in Inclusion Body Myositis

by Karsten Kummer, Imke Bertram, Sabrina Zechel, Daniel B. Hoffmann and Jens Schmidt

Int. J. Mol. Sci. 2023, 24(13), 10675; https://doi.org/10.3390/ijms241310675 - 26 Jun 2023

Cited by 5 | Viewed by 1105

Abstract

Inclusion body myositis (IBM) is a chronic, mostly treatment-resistant, inflammatory myopathy with a pathology that centers around specific interactions between inflammation and protein accumulation. The study aimed to identify the inflammasome as a key event in the complex network of pathomechanisms. Regulation of the inflammasome was assessed in a well-established pro-inflammatory cell culture model using human myoblasts and primary human myotubes. By quantitative PCR, western blot and immunocytochemistry, inflammasome markers including NLRP3 were assessed in muscle cells exposed to the cytokines IL-1β and IFN-γ. The data were corroborated by analysis of muscle biopsies from patients with IBM compared to other myositis subtypes. In the cell culture model of IBM, the NLRP3 inflammasome was significantly overexpressed, as evidenced by western blot (p = 0.03) and quantitative PCR (p < 0.01). Target genes that play a role in inflammasome assembly, T-cell migration, and MHC-I expression (p = 0.009) were highly co-upregulated. NLRP3 was significantly overexpressed in muscle biopsies from IBM samples compared to disease controls (p = 0.049), including other inflammatory myopathies. Due to the extraordinary features of the pathogenesis and the pronounced upregulation of NLRP3 in IBM, the inflammasome could serve as a key molecule that drives the inflammatory cascade as well as protein accumulation in the muscle. These data can be useful for future therapeutic developments. Full article

(This article belongs to the Special Issue From Molecular Basis to Therapeutic Approaches in Skeletal Muscle Dysfunction)

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19 pages, 3388 KiB

Open AccessArticle

In-Frame Deletion of Dystrophin Exons 8–50 Results in DMD Phenotype

by Tatiana V. Egorova, Ivan I. Galkin, Oleg A. Velyaev, Svetlana G. Vassilieva, Irina M. Savchenko, Vyacheslav A. Loginov, Marina A. Dzhenkova, Diana S. Korshunova, Olga S. Kozlova, Dmitry N. Ivankov and Anna V. Polikarpova

Int. J. Mol. Sci. 2023, 24(11), 9117; https://doi.org/10.3390/ijms24119117 - 23 May 2023

Cited by 2 | Viewed by 2032

Abstract

Mutations that prevent the production of proteins in the DMD gene cause Duchenne muscular dystrophy. Most frequently, these are deletions leading to reading-frame shift. The “reading-frame rule” states that deletions that preserve ORF result in a milder Becker muscular dystrophy. By removing several exons, new genome editing tools enable reading-frame restoration in DMD with the production of BMD-like dystrophins. However, not every truncated dystrophin with a significant internal loss functions properly. To determine the effectiveness of potential genome editing, each variant should be carefully studied in vitro or in vivo. In this study, we focused on the deletion of exons 8–50 as a potential reading-frame restoration option. Using the CRISPR-Cas9 tool, we created the novel mouse model DMDdel8-50, which has an in-frame deletion in the DMD gene. We compared DMDdel8-50 mice to C57Bl6/CBA background control mice and previously generated DMDdel8-34 KO mice. We discovered that the shortened protein was expressed and correctly localized on the sarcolemma. The truncated protein, on the other hand, was unable to function like a full-length dystrophin and prevent disease progression. On the basis of protein expression, histological examination, and physical assessment of the mice, we concluded that the deletion of exons 8–50 is an exception to the reading-frame rule. Full article

(This article belongs to the Special Issue From Molecular Basis to Therapeutic Approaches in Skeletal Muscle Dysfunction)

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12 pages, 3329 KiB

Open AccessArticle

Denervation Drives YAP/TAZ Activation in Muscular Fibro/Adipogenic Progenitors

by Felipe S. Gallardo, Adriana Córdova-Casanova, Alexia Bock-Pereda, Daniela L. Rebolledo, Andrea Ravasio, Juan Carlos Casar and Enrique Brandan

Int. J. Mol. Sci. 2023, 24(6), 5585; https://doi.org/10.3390/ijms24065585 - 15 Mar 2023

Viewed by 1760

Abstract

Loss of motoneuron innervation (denervation) is a hallmark of neurodegeneration and aging of the skeletal muscle. Denervation induces fibrosis, a response attributed to the activation and expansion of resident fibro/adipogenic progenitors (FAPs), i.e., multipotent stromal cells with myofibroblast potential. Using in vivo and in silico approaches, we revealed FAPs as a novel cell population that activates the transcriptional coregulators YAP/TAZ in response to skeletal muscle denervation. Here, we found that denervation induces the expression and transcriptional activity of YAP/TAZ in whole muscle lysates. Using the Pdgfra^H2B:EGFP/+ transgenic reporter mice to trace FAPs, we demonstrated that denervation leads to increased YAP expression that accumulates within FAPs nuclei. Consistently, re-analysis of published single-nucleus RNA sequencing (snRNA-seq) data indicates that FAPs from denervated muscles have a higher YAP/TAZ signature level than control FAPs. Thus, our work provides the foundations to address the functional role of YAP/TAZ in FAPs in a neurogenic pathological context, which could be applied to develop novel therapeutic approaches for the treatment of muscle disorders triggered by motoneuron degeneration. Full article

(This article belongs to the Special Issue From Molecular Basis to Therapeutic Approaches in Skeletal Muscle Dysfunction)

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13 pages, 2297 KiB

Open AccessArticle

Assessment of the Impact of Physical Activity on the Musculoskeletal System in Early Degenerative Knee Joint Lesions in an Animal Model

by Jaromir Jarecki, Izabela Polkowska, Waldemar Kazimierczak, Magdalena Wójciak, Ireneusz Sowa, Sławomir Dresler and Tomasz Blicharski

Int. J. Mol. Sci. 2023, 24(4), 3540; https://doi.org/10.3390/ijms24043540 - 10 Feb 2023

Cited by 1 | Viewed by 1591

Abstract

Osteoarthritis (OA) is one of the most prevalent diseases of the osteoarticular system. Progressive destruction of joints is accompanied by development of pathological changes in the muscle tissue, i.e., weakening, atrophy, and remodelling (sarcopenia). The aim of the present study is to assess the impact of physical activity on the musculoskeletal system in an animal model of early degenerative lesions in the knee joint. The study involved 30 male Wistar rats. The animals were allocated to three subgroups of 10 animals each. Each animal from the three subgroups received sodium iodoacetate by injection into the patellar ligament of the right knee joint, whereas saline was administered through the patellar ligament in the left knee joint. The rats in the first group were stimulated to exercise on a treadmill. The animals in the second group were allowed to lead a natural lifestyle (no treadmill stimulation). In the third group, all parts of the right hind limb muscle were injected with Clostridium botulinum toxin type A. The study demonstrated that, compared to the active rats, bone density in the immobilised rats decreased, as indicated by the densitometric assessment of the whole body and the examination of rats’ hind limbs and knee joints alone. This clearly evidenced the impact of physical activity on bone mineralisation. The weight of both fat and muscle tissues in the physically inactive rats was reduced. Additionally, the adipose tissue had higher weight in the entire right hind limbs, where monoiodoacetic acid was administered to the knee joint. The animal model clearly showed the importance of physical activity in the early stages of OA, as it slows down the process of joint destruction, bone atrophy, and muscle wasting, whereas physical inactivity contributes to progression of generalised changes in the musculoskeletal system. Full article

(This article belongs to the Special Issue From Molecular Basis to Therapeutic Approaches in Skeletal Muscle Dysfunction)

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15 pages, 3038 KiB

Open AccessArticle

Mitochonic Acid 5 Improves Duchenne Muscular Dystrophy and Parkinson’s Disease Model of Caenorhabditis elegans

by Xintong Wu, Satoi Nagasawa, Kasumi Muto, Maiko Ueda, Chitose Suzuki, Takaaki Abe and Atsushi Higashitani

Int. J. Mol. Sci. 2022, 23(17), 9572; https://doi.org/10.3390/ijms23179572 - 24 Aug 2022

Cited by 6 | Viewed by 3455

Abstract

Mitochonic Acid 5 (MA-5) enhances mitochondrial ATP production, restores fibroblasts from mitochondrial disease patients and extends the lifespan of the disease model “Mitomouse”. Additionally, MA-5 interacts with mitofilin and modulates the mitochondrial inner membrane organizing system (MINOS) in mammalian cultured cells. Here, we used the nematode Caenorhabditis elegans to investigate whether MA-5 improves the Duchenne muscular dystrophy (DMD) model. Firstly, we confirmed the efficient penetration of MA-5 in the mitochondria of C. elegans. MA-5 also alleviated symptoms such as movement decline, muscular tone, mitochondrial fragmentation and Ca²⁺ accumulation of the DMD model. To assess the effect of MA-5 on mitochondria perturbation, we employed a low concentration of rotenone with or without MA-5. MA-5 significantly suppressed rotenone-induced mitochondria reactive oxygen species (ROS) increase, mitochondrial network fragmentation and nuclear destruction in body wall muscles as well as endogenous ATP levels decline. In addition, MA-5 suppressed rotenone-induced degeneration of dopaminergic cephalic (CEP) neurons seen in the Parkinson’s disease (PD) model. Furthermore, the application of MA-5 reduced mitochondrial swelling due to the immt-1 null mutation. These results indicate that MA-5 has broad mitochondrial homing and MINOS stabilizing activity in metazoans and may be a therapeutic agent for these by ameliorating mitochondrial dysfunction in DMD and PD. Full article

(This article belongs to the Special Issue From Molecular Basis to Therapeutic Approaches in Skeletal Muscle Dysfunction)

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Review

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16 pages, 1526 KiB

Open AccessReview

The Function and Regulation Mechanism of Non-Coding RNAs in Muscle Development

by Yaling Yang, Jian Wu, Wujun Liu, Yumin Zhao and Hong Chen

Int. J. Mol. Sci. 2023, 24(19), 14534; https://doi.org/10.3390/ijms241914534 - 26 Sep 2023

Cited by 1 | Viewed by 977

Abstract

Animal skeletal muscle growth is regulated by a complex molecular network including some non-coding RNAs (ncRNAs). In this paper, we review the non-coding RNAs related to the growth and development of common animal skeletal muscles, aiming to provide a reference for the in-depth study of the role of ncRNAs in the development of animal skeletal muscles, and to provide new ideas for the improvement of animal production performance. Full article

(This article belongs to the Special Issue From Molecular Basis to Therapeutic Approaches in Skeletal Muscle Dysfunction)

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23 pages, 657 KiB

Open AccessReview

Prevalence and Mechanisms of Skeletal Muscle Atrophy in Metabolic Conditions

by Lauren Jun, Megan Robinson, Thangiah Geetha, Tom L. Broderick and Jeganathan Ramesh Babu

Int. J. Mol. Sci. 2023, 24(3), 2973; https://doi.org/10.3390/ijms24032973 - 03 Feb 2023

Cited by 14 | Viewed by 6221

Abstract

Skeletal muscle atrophy is prevalent in a myriad of pathological conditions, such as diabetes, denervation, long-term immobility, malnutrition, sarcopenia, obesity, Alzheimer’s disease, and cachexia. This is a critically important topic that has significance in the health of the current society, particularly older adults. The most damaging effect of muscle atrophy is the decreased quality of life from functional disability, increased risk of fractures, decreased basal metabolic rate, and reduced bone mineral density. Most skeletal muscle in humans contains slow oxidative, fast oxidative, and fast glycolytic muscle fiber types. Depending on the pathological condition, either oxidative or glycolytic muscle type may be affected to a greater extent. This review article discusses the prevalence of skeletal muscle atrophy and several mechanisms, with an emphasis on high-fat, high-sugar diet patterns, obesity, and diabetes, but including other conditions such as sarcopenia, Alzheimer’s disease, cancer cachexia, and heart failure. Full article

(This article belongs to the Special Issue From Molecular Basis to Therapeutic Approaches in Skeletal Muscle Dysfunction)

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