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Rising of New Signatures in Skeletal Muscle Pathologies and Their Possible Role in Disease Pathogenesis

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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 (30 April 2024) | Viewed by 7618

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Special Issue Editor

Dr. Andrea Farini

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Guest Editor

1. Stem Cell Laboratory, Department of Pathophysiology and Transplantation, Università degli Studi di Milano, Milan, Italy
2. Unit of Neurology, Fondazione IRCCS Cà Granda Ospedale Maggiore Policlinico, Centro Dino Ferrari, 20122 Milan, Italy
Interests: duchenne muscular dystrophy; inflammation; immune system; T-lymphocytes; Tregs; macrophages; skeletal muscle diseases
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Special Issue Information

Dear Colleagues,

Growing evidence demonstrates the crosstalk between the immune system and the skeletal muscle in muscular dystrophies (MDs), as well as during normal muscle regeneration. Immune cell infiltration into skeletal muscle is a notable feature of the disease pathophysiology but a multitude of secondary defects exist involving metabolic and inflammatory pathways, whose leading players are yet to be elucidated. Steroids are the only effective therapy to delay the onset and control symptoms; however, they cause side adverse effects, limiting their use.

As preliminary evidence has revealed the unique features of T cell profiling in MDs, the immuno-characterization of circulating cells and a molecular analysis of their transcriptome and secretome would allow us to identify a subpopulation of cells to be used as disease biomarkers and to decipher new pathological pathways and reveal therapeutic targets.

At the same time, new approaches emerged in the last decade. The development and normal homeostasis of both innate and adaptive immune systems have been strictly associated with gut microorganisms, the so-called microbiota. The modulation of microbiota-derived metabolites could exacerbate muscle damage via immune system activation. In parallel, genome sequencing established clinical utility for rare disease diagnosis: different approaches were employed to interpret the functional consequence of genomic variations. Although numerous genes were unsuccessfully studied as MD clinical targets, Tdark genes should provide us with novel, unexplored therapeutic information.

To accelerate the transfer of basic knowledge to the clinic, the identification of novel biomarkers and/or disease targets will improve our knowledge to design innovative therapeutic strategies, useful in delivering improved care for these disabling diseases.

Dr. Andrea Farini
Guest Editor

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Keywords

muscular dystrophies
inflammation
immune system activation
disease biomarkers
disease targets
tdark genes
gut microbiota

Published Papers (4 papers)

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Research

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11 pages, 1113 KiB

Open AccessCommunication

Increased Otoferlin Expression in B Cells Is Associated with Muscle Weakness in Untreated Juvenile Dermatomyositis: A Pilot Study

by Ameera Bukhari, Amer Khojah, Wilfredo Marin, Andrey Khramtsov, Galina Khramtsova, Christopher Costin, Gabrielle Morgan, Prathyaya Ramesh, Marisa S. Klein-Gitelman, I. Caroline Le Poole and Lauren M. Pachman

Int. J. Mol. Sci. 2023, 24(13), 10553; https://doi.org/10.3390/ijms241310553 - 23 Jun 2023

Cited by 2 | Viewed by 1213

Abstract

Otoferlin mRNA expression is increased in JDM patients’ PBMCs and muscle compared to healthy controls. This study aims to evaluate the role of otoferlin in JDM disease pathophysiology and its association with disease activity in untreated children with JDM. A total of 26 untreated JDM (88.5% female, 92.3% white, non-Hispanic) and 15 healthy controls were included in this study. Otoferlin mRNA expression was determined by qRT-PCR before and a few months after therapy. Detailed flow cytometry of various cell surface markers and cytoplasmic otoferlin was performed to identify cells expressing otoferlin. In addition, muscle otoferlin expression was evaluated in situ in six untreated JDM patients and three healthy controls. There was a significant increase in otoferlin expression in JDM children compared to controls (Median 67.5 vs. 2.1; p = 0.001). There was a positive correlation between mRNA otoferlin expression and the following disease activity markers: disease activity scores (DAS)-total (r_s = 0.62, p < 0.001); childhood myositis assessment scale (CMAS) (r_s = −0.61, p = 0.002); neopterin (r_s = 0.57, p = 0.004) and von Willebrand factor antigen (vWF: Ag) (r_s = 0.60, p = 0.004). Most of the otoferlin-positive cells were unswitched B cells (63–99.4%), with 65–75% of them expressing plasmablast markers (CD19⁺, IgM⁺, CD38^hi, CD24⁻). The findings of this pilot study suggest that otoferlin expression is associated with muscle weakness, making it a possible biomarker of disease activity. Additionally, B cells and plasmablasts were the primary cells expressing otoferlin. Full article

(This article belongs to the Special Issue Rising of New Signatures in Skeletal Muscle Pathologies and Their Possible Role in Disease Pathogenesis)

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17 pages, 2365 KiB

Open AccessArticle

Small-Molecule Inhibition of MuRF1 Prevents Early Disuse-Induced Diaphragmatic Dysfunction and Atrophy

by Fernando Ribeiro, Paula K. N. Alves, Luiz R. G. Bechara, Julio C. B. Ferreira, Siegfried Labeit and Anselmo S. Moriscot

Int. J. Mol. Sci. 2023, 24(4), 3637; https://doi.org/10.3390/ijms24043637 - 11 Feb 2023

Cited by 3 | Viewed by 2323

Abstract

In clinical conditions such as diaphragm paralysis or mechanical ventilation, disuse-induced diaphragmatic dysfunction (DIDD) is a condition that poses a threat to life. MuRF1 is a key E3-ligase involved in regulating skeletal muscle mass, function, and metabolism, which contributes to the onset of DIDD. We investigated if the small-molecule mediated inhibition of MuRF1 activity (MyoMed-205) protects against early DIDD after 12 h of unilateral diaphragm denervation. Wistar rats were used in this study to determine the compound’s acute toxicity and optimal dosage. For potential DIDD treatment efficacy, diaphragm contractile function and fiber cross-sectional area (CSA) were evaluated. Western blotting investigated potential mechanisms underlying MyoMed-205’s effects in early DIDD. Our results indicate 50 mg/kg bw MyoMed-205 as a suitable dosage to prevent early diaphragmatic contractile dysfunction and atrophy following 12 h of denervation without detectable signs of acute toxicity. Mechanistically, treatment did not affect disuse-induced oxidative stress (4-HNE) increase, whereas phosphorylation of (ser632) HDAC4 was normalized. MyoMed-205 also mitigated FoxO1 activation, inhibited MuRF2, and increased phospho (ser473) Akt protein levels. These findings may suggest that MuRF1 activity significantly contributes to early DIDD pathophysiology. Novel strategies targeting MuRF1 (e.g., MyoMed-205) have potential therapeutic applications for treating early DIDD. Full article

(This article belongs to the Special Issue Rising of New Signatures in Skeletal Muscle Pathologies and Their Possible Role in Disease Pathogenesis)

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21 pages, 5236 KiB

Open AccessArticle

O-GlcNAcylation of SIRT1 Protects against Cold Stress-Induced Skeletal Muscle Damage via Amelioration of Mitochondrial Homeostasis

by Yu Cao, Meng Zhang, Ye Li, Jingjing Lu, Wanhui Zhou, Xiaoshuang Li, Hao Shi, Bin Xu and Shize Li

Int. J. Mol. Sci. 2022, 23(23), 14520; https://doi.org/10.3390/ijms232314520 - 22 Nov 2022

Cited by 5 | Viewed by 1511

Abstract

Cold stress disturbs cellular metabolic and energy homeostasis, which is one of the causes of stress-induced illnesses. O-GlcNAcylation is a nutrient-sensing pathway involved in a myriad of cellular processes. It plays a key role in metabolic homeostasis. Nevertheless, a specific sensing mechanism linking skeletal muscle to O-GlcNAcylation in cold stress is unknown. In this study, O-GlcNAcylation of SIRT1 was targeted to explore the mechanism of skeletal muscle adaptation to cold stress. Ogt mKO aggravated skeletal muscle fibrosis induced by cold stress. At the same time, Ogt gene deletion accelerated the homeostasis imbalance and oxidative stress of skeletal muscle mitochondria induced by cold stress. In vitro results showed that inhibition of SIRT1’s O-GlcNAcylation accelerated mild hypothermia induced mitochondrial homeostasis in mouse myogenic cells (C2C12 cells). However, overexpression of SIRT1’s O-GlcNAcylation improved the above phenomena. Thus, these results reveal a protective role of OGT-SIRT1 in skeletal muscle’s adaptation to cold stress, and our findings will provide new avenues to combat stress-induced diseases. Full article

(This article belongs to the Special Issue Rising of New Signatures in Skeletal Muscle Pathologies and Their Possible Role in Disease Pathogenesis)

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Review

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14 pages, 1620 KiB

Open AccessReview

Advancing Biomarker Discovery and Therapeutic Targets in Duchenne Muscular Dystrophy: A Comprehensive Review

by Monica Molinaro, Yvan Torrente, Chiara Villa and Andrea Farini

Int. J. Mol. Sci. 2024, 25(1), 631; https://doi.org/10.3390/ijms25010631 - 03 Jan 2024

Viewed by 1542

Abstract

Mounting evidence underscores the intricate interplay between the immune system and skeletal muscles in Duchenne muscular dystrophy (DMD), as well as during regular muscle regeneration. While immune cell infiltration into skeletal muscles stands out as a prominent feature in the disease pathophysiology, a myriad of secondary defects involving metabolic and inflammatory pathways persist, with the key players yet to be fully elucidated. Steroids, currently the sole effective therapy for delaying onset and symptom control, come with adverse side effects, limiting their widespread use. Preliminary evidence spotlighting the distinctive features of T cell profiling in DMD prompts the immuno-characterization of circulating cells. A molecular analysis of their transcriptome and secretome holds the promise of identifying a subpopulation of cells suitable as disease biomarkers. Furthermore, it provides a gateway to unraveling new pathological pathways and pinpointing potential therapeutic targets. Simultaneously, the last decade has witnessed the emergence of novel approaches. The development and equilibrium of both innate and adaptive immune systems are intricately linked to the gut microbiota. Modulating microbiota-derived metabolites could potentially exacerbate muscle damage through immune system activation. Concurrently, genome sequencing has conferred clinical utility for rare disease diagnosis since innovative methodologies have been deployed to interpret the functional consequences of genomic variations. Despite numerous genes falling short as clinical targets for MD, the exploration of Tdark genes holds promise for unearthing novel and uncharted therapeutic insights. In the quest to expedite the translation of fundamental knowledge into clinical applications, the identification of novel biomarkers and disease targets is paramount. This initiative not only advances our understanding but also paves the way for the design of innovative therapeutic strategies, contributing to enhanced care for individuals grappling with these incapacitating diseases. Full article

(This article belongs to the Special Issue Rising of New Signatures in Skeletal Muscle Pathologies and Their Possible Role in Disease Pathogenesis)

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