Biomedicines

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Open AccessEditorial

Special Issue: Pathophysiology and Therapeutic Perspectives in DMD: The Well-Defined Role of the Immune System

by Andrea Farini

Biomedicines 2021, 9(12), 1911; https://doi.org/10.3390/biomedicines9121911 - 14 Dec 2021

Viewed by 1496

Abstract

Duchenne muscular dystrophy (DMD) is the most common, lethal, muscle-wasting disease of childhood [...] Full article

(This article belongs to the Special Issue Pathophysiology and Therapeutic Perspectives in DMD: The Well-Defined Role of the Immune System)

Research

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16 pages, 3189 KiB

Open AccessArticle

Orai1–STIM1 Regulates Increased Ca²⁺ Mobilization, Leading to Contractile Duchenne Muscular Dystrophy Phenotypes in Patient-Derived Induced Pluripotent Stem Cells

by Tomoya Uchimura and Hidetoshi Sakurai

Biomedicines 2021, 9(11), 1589; https://doi.org/10.3390/biomedicines9111589 - 31 Oct 2021

Cited by 4 | Viewed by 3394

Abstract

Ca²⁺ overload is one of the factors leading to Duchenne muscular dystrophy (DMD) pathogenesis. However, the molecular targets of dystrophin deficiency-dependent Ca²⁺ overload and the correlation between Ca²⁺ overload and contractile DMD phenotypes in in vitro human models remain largely [...] Read more.

Ca²⁺ overload is one of the factors leading to Duchenne muscular dystrophy (DMD) pathogenesis. However, the molecular targets of dystrophin deficiency-dependent Ca²⁺ overload and the correlation between Ca²⁺ overload and contractile DMD phenotypes in in vitro human models remain largely elusive. In this study, we utilized DMD patient-derived induced pluripotent stem cells (iPSCs) to differentiate myotubes using doxycycline-inducible MyoD overexpression, and searched for a target molecule that mediates dystrophin deficiency-dependent Ca²⁺ overload using commercially available chemicals and siRNAs. We found that several store-operated Ca²⁺ channel (SOC) inhibitors effectively prevented Ca²⁺ overload and identified that STIM1–Orai1 is a molecular target of SOCs. These findings were further confirmed by demonstrating that STIM1–Orai1 inhibitors, CM4620, AnCoA4, and GSK797A, prevented Ca²⁺ overload in dystrophic myotubes. Finally, we evaluated CM4620, AnCoA4, and GSK7975A activities using a previously reported model recapitulating a muscle fatigue-like decline in contractile performance in DMD. All three chemicals ameliorated the decline in contractile performance, indicating that modulating STIM1–Orai1-mediated Ca²⁺ overload is effective in rescuing contractile phenotypes. In conclusion, SOCs are major contributors to dystrophin deficiency-dependent Ca²⁺ overload through STIM1–Orai1 as molecular mediators. Modulating STIM1–Orai1 activity was effective in ameliorating the decline in contractile performance in DMD. Full article

(This article belongs to the Special Issue Pathophysiology and Therapeutic Perspectives in DMD: The Well-Defined Role of the Immune System)

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16 pages, 2884 KiB

Open AccessArticle

Effect of the Non-Immunosuppressive MPT Pore Inhibitor Alisporivir on the Functioning of Heart Mitochondria in Dystrophin-Deficient mdx Mice

by Mikhail V. Dubinin, Vlada S. Starinets, Eugeny Yu. Talanov, Irina B. Mikheeva, Natalia V. Belosludtseva, Dmitriy A. Serov, Kirill S. Tenkov, Evgeniya V. Belosludtseva and Konstantin N. Belosludtsev

Biomedicines 2021, 9(9), 1232; https://doi.org/10.3390/biomedicines9091232 - 16 Sep 2021

Cited by 11 | Viewed by 2234

Abstract

Supporting mitochondrial function is one of the therapeutic strategies that improve the functioning of skeletal muscle in Duchenne muscular dystrophy (DMD). In this work, we studied the effect of a non-immunosuppressive inhibitor of mitochondrial permeability transition pore (MPTP) alisporivir (5 mg/kg/day), reducing the [...] Read more.

Supporting mitochondrial function is one of the therapeutic strategies that improve the functioning of skeletal muscle in Duchenne muscular dystrophy (DMD). In this work, we studied the effect of a non-immunosuppressive inhibitor of mitochondrial permeability transition pore (MPTP) alisporivir (5 mg/kg/day), reducing the intensity of the necrotic process and inflammation in skeletal muscles on the cardiac phenotype of dystrophin-deficient mdx mice. We found that the heart mitochondria of mdx mice show an increase in the intensity of oxidative phosphorylation and an increase in the resistance of organelles to the MPT pore opening. Alisporivir had no significant effect on the hyperfunctionalization of the heart mitochondria of mdx mice, and the state of the heart mitochondria of wild-type animals did not affect the dynamics of organelles but significantly suppressed mitochondrial biogenesis and reduced the amount of mtDNA in the heart muscle. Moreover, alisporivir suppressed mitochondrial biogenesis in the heart of wild-type mice. Alisporivir treatment resulted in a decrease in heart weight in mdx mice, which was associated with a significant modification of the transmission of excitation in the heart. The latter was also noted in the case of WT mice treated with alisporivir. The paper discusses the prospects for using alisporivir to correct the function of heart mitochondria in DMD. Full article

(This article belongs to the Special Issue Pathophysiology and Therapeutic Perspectives in DMD: The Well-Defined Role of the Immune System)

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15 pages, 4626 KiB

Open AccessArticle

Wharton’s Jelly-Derived Mesenchymal Stem Cells Reduce Fibrosis in a Mouse Model of Duchenne Muscular Dystrophy by Upregulating microRNA 499

by Sang Eon Park, Jang Bin Jeong, Shin Ji Oh, Sun Jeong Kim, Hyeongseop Kim, Alee Choi, Suk-joo Choi, Soo-young Oh, Gyu Ha Ryu, Jeehun Lee, Hong Bae Jeon and Jong Wook Chang

Biomedicines 2021, 9(9), 1089; https://doi.org/10.3390/biomedicines9091089 - 26 Aug 2021

Cited by 7 | Viewed by 2944

Abstract

The aim of this study was to evaluate the therapeutic effects and mechanisms of Wharton’s jelly-derived mesenchymal stem cells (WJ-MSCs) in an animal model of Duchenne muscular dystrophy (DMD). Mdx mice (3–5 months old) were administered five different doses of WJ-MSCs through their [...] Read more.

The aim of this study was to evaluate the therapeutic effects and mechanisms of Wharton’s jelly-derived mesenchymal stem cells (WJ-MSCs) in an animal model of Duchenne muscular dystrophy (DMD). Mdx mice (3–5 months old) were administered five different doses of WJ-MSCs through their tail veins. A week after injection, grip strength measurements, creatine kinase (CK) assays, immunohistochemistry, and western blots were performed for comparison between healthy mice, mdx control mice, and WJ-MSC-injected mdx mice. WJ-MSCs exerted dose-dependent multisystem therapeutic effects in mdx mice, by decreasing CK, recovering normal behavior, regenerating muscle, and reducing apoptosis and fibrosis in skeletal muscle. We also confirmed that miR-499-5p is significantly downregulated in mdx mice, and that intravenous injection of WJ-MSCs enhanced its expression, leading to anti-fibrotic effects via targeting TGFβR 1 and 3. Thus, WJ-MSCs may represent novel allogeneic “off-the-shelf” cellular products for the treatment of DMD and possibly other muscle disorders. Full article

(This article belongs to the Special Issue Pathophysiology and Therapeutic Perspectives in DMD: The Well-Defined Role of the Immune System)

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Review

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17 pages, 739 KiB

Open AccessReview

The Immune System in Duchenne Muscular Dystrophy Pathogenesis

by Luana Tripodi, Chiara Villa, Davide Molinaro, Yvan Torrente and Andrea Farini

Biomedicines 2021, 9(10), 1447; https://doi.org/10.3390/biomedicines9101447 - 11 Oct 2021

Cited by 20 | Viewed by 3963

Abstract

Growing evidence demonstrates the crosstalk between the immune system and the skeletal muscle in inflammatory muscle diseases and dystrophic conditions such as Duchenne Muscular Dystrophy (DMD), as well as during normal muscle regeneration. The rising of inflammation and the consequent activation of the [...] Read more.

Growing evidence demonstrates the crosstalk between the immune system and the skeletal muscle in inflammatory muscle diseases and dystrophic conditions such as Duchenne Muscular Dystrophy (DMD), as well as during normal muscle regeneration. The rising of inflammation and the consequent activation of the immune system are hallmarks of DMD: several efforts identified the immune cells that invade skeletal muscle as CD4+ and CD8+ T cells, Tregs, macrophages, eosinophils and natural killer T cells. The severity of muscle injury and inflammation dictates the impairment of muscle regeneration and the successive replacement of myofibers with connective and adipose tissue. Since immune system activation was traditionally considered as a consequence of muscular wasting, we recently demonstrated a defect in central tolerance caused by thymus alteration and the presence of autoreactive T-lymphocytes in DMD. Although the study of innate and adaptive immune responses and their complex relationship in DMD attracted the interest of many researchers in the last years, the results are so far barely exhaustive and sometimes contradictory. In this review, we describe the most recent improvements in the knowledge of immune system involvement in DMD pathogenesis, leading to new opportunities from a clinical point-of-view. Full article

(This article belongs to the Special Issue Pathophysiology and Therapeutic Perspectives in DMD: The Well-Defined Role of the Immune System)

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11 pages, 991 KiB

Open AccessReview

Inflammation in Duchenne Muscular Dystrophy–Exploring the Role of Neutrophils in Muscle Damage and Regeneration

by Ankita Tulangekar and Tamar E. Sztal

Biomedicines 2021, 9(10), 1366; https://doi.org/10.3390/biomedicines9101366 - 01 Oct 2021

Cited by 22 | Viewed by 4210

Abstract

Duchenne muscular dystrophy (DMD) is a severe and progressive, X-linked, neuromuscular disorder caused by mutations in the dystrophin gene. In DMD, the lack of functional dystrophin protein makes the muscle membrane fragile, leaving the muscle fibers prone to damage during contraction. Muscle degeneration [...] Read more.

Duchenne muscular dystrophy (DMD) is a severe and progressive, X-linked, neuromuscular disorder caused by mutations in the dystrophin gene. In DMD, the lack of functional dystrophin protein makes the muscle membrane fragile, leaving the muscle fibers prone to damage during contraction. Muscle degeneration in DMD patients is closely associated with a prolonged inflammatory response, and while this is important to stimulate regeneration, inflammation is also thought to exacerbate muscle damage. Neutrophils are one of the first immune cells to be recruited to the damaged muscle and are the first line of defense during tissue injury or infection. Neutrophils can promote inflammation by releasing pro-inflammatory cytokines and compounds, including myeloperoxidase (MPO) and neutrophil elastase (NE), that lead to oxidative stress and are thought to have a role in prolonging inflammation in DMD. In this review, we provide an overview of the roles of the innate immune response, with particular focus on mechanisms used by neutrophils to exacerbate muscle damage and impair regeneration in DMD. Full article

(This article belongs to the Special Issue Pathophysiology and Therapeutic Perspectives in DMD: The Well-Defined Role of the Immune System)

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11 pages, 762 KiB

Open AccessReview

The War after War: Volumetric Muscle Loss Incidence, Implication, Current Therapies and Emerging Reconstructive Strategies, a Comprehensive Review

by Stefano Testa, Ersilia Fornetti, Claudia Fuoco, Carles Sanchez-Riera, Francesco Rizzo, Mario Ciccotti, Stefano Cannata, Tommaso Sciarra and Cesare Gargioli

Biomedicines 2021, 9(5), 564; https://doi.org/10.3390/biomedicines9050564 - 18 May 2021

Cited by 14 | Viewed by 3702

Abstract

Volumetric muscle loss (VML) is the massive wasting of skeletal muscle tissue due to traumatic events or surgical ablation. This pathological condition exceeds the physiological healing process carried out by the muscle itself, which owns remarkable capacity to restore damages but only when [...] Read more.

Volumetric muscle loss (VML) is the massive wasting of skeletal muscle tissue due to traumatic events or surgical ablation. This pathological condition exceeds the physiological healing process carried out by the muscle itself, which owns remarkable capacity to restore damages but only when limited in dimensions. Upon VML occurring, the affected area is severely compromised, heavily influencing the affected a person’s quality of life. Overall, this condition is often associated with chronic disability, which makes the return to duty of highly specialized professional figures (e.g., military personnel or athletes) almost impossible. The actual treatment for VML is based on surgical conservative treatment followed by physical exercise; nevertheless, the results, in terms of either lost mass and/or functionality recovery, are still poor. On the other hand, the efforts of the scientific community are focusing on reconstructive therapy aiming at muscular tissue void volume replenishment by exploiting biomimetic matrix or artificial tissue implantation. Reconstructing strategies represent a valid option to build new muscular tissue not only to recover damaged muscles, but also to better socket prosthesis in terms of anchorage surfaces and reinnervation substrates for reconstructed mass. Full article

(This article belongs to the Special Issue Pathophysiology and Therapeutic Perspectives in DMD: The Well-Defined Role of the Immune System)

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18 pages, 1101 KiB

Open AccessReview

The PKA-p38MAPK-NFAT5-Organic Osmolytes Pathway in Duchenne Muscular Dystrophy: From Essential Player in Osmotic Homeostasis, Inflammation and Skeletal Muscle Regeneration to Therapeutic Target

by Sandrine Herbelet, Caroline Merckx and Boel De Paepe

Biomedicines 2021, 9(4), 350; https://doi.org/10.3390/biomedicines9040350 - 30 Mar 2021

Cited by 4 | Viewed by 3392

Abstract

In Duchenne muscular dystrophy (DMD), the absence of dystrophin from the dystrophin-associated protein complex (DAPC) causes muscle membrane instability, which leads to myofiber necrosis, hampered regeneration, and chronic inflammation. The resulting disabled DAPC-associated cellular pathways have been described both at the molecular and [...] Read more.

In Duchenne muscular dystrophy (DMD), the absence of dystrophin from the dystrophin-associated protein complex (DAPC) causes muscle membrane instability, which leads to myofiber necrosis, hampered regeneration, and chronic inflammation. The resulting disabled DAPC-associated cellular pathways have been described both at the molecular and the therapeutical level, with the Toll-like receptor nuclear factor kappa-light-chain-enhancer of activated B cells pathway (NF-ƘB), Janus kinase/signal transducer and activator of transcription proteins, and the transforming growth factor-β pathways receiving the most attention. In this review, we specifically focus on the protein kinase A/ mitogen-activated protein kinase/nuclear factor of activated T-cells 5/organic osmolytes (PKA-p38MAPK-NFAT5-organic osmolytes) pathway. This pathway plays an important role in osmotic homeostasis essential to normal cell physiology via its regulation of the influx/efflux of organic osmolytes. Besides, NFAT5 plays an essential role in cell survival under hyperosmolar conditions, in skeletal muscle regeneration, and in tissue inflammation, closely interacting with the master regulator of inflammation NF-ƘB. We describe the involvement of the PKA-p38MAPK-NFAT5-organic osmolytes pathway in DMD pathophysiology and provide a clear overview of which therapeutic molecules could be of potential benefit to DMD patients. We conclude that modulation of the PKA-p38MAPK-NFAT5-organic osmolytes pathway could be developed as supportive treatment for DMD in conjunction with genetic therapy. Full article

(This article belongs to the Special Issue Pathophysiology and Therapeutic Perspectives in DMD: The Well-Defined Role of the Immune System)

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Other

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18 pages, 568 KiB

Open AccessSystematic Review

The Efficacy of Naïve versus Modified Mesenchymal Stem Cells in Improving Muscle Function in Duchenne Muscular Dystrophy: A Systematic Review

by Oscar Yuan-Jie Shen, Yi-Fan Chen, Hong-Tao Xu and Chien-Wei Lee

Biomedicines 2021, 9(9), 1097; https://doi.org/10.3390/biomedicines9091097 - 27 Aug 2021

Cited by 5 | Viewed by 2706

Abstract

As one of the most common genetic conditions, Duchenne muscular dystrophy (DMD) is a fatal disease caused by a recessive mutation resulting in muscle weakness in both voluntary and involuntary muscles and, eventually, in death because of cardiovascular failure. Currently, there is no [...] Read more.

As one of the most common genetic conditions, Duchenne muscular dystrophy (DMD) is a fatal disease caused by a recessive mutation resulting in muscle weakness in both voluntary and involuntary muscles and, eventually, in death because of cardiovascular failure. Currently, there is no pharmacologically curative treatment of DMD, but there is evidence supporting that mesenchymal stem cells (MSCs) are a novel solution for treating DMD. This systematic review focused on elucidating the therapeutic efficacy of MSCs on the DMD in vivo model. A key issue of previous studies was the material-choice, naïve MSCs or modified MSCs; modified MSCs are activated by culture methods or genetic modification. In summary, MSCs seem to improve pulmonary and cardiac functions and thereby improve survival regardless of them being naïve or modified. The improved function of distal skeletal muscles was observed only with primed MSCs treatment but not naïve MSCs. While MSCs can provide significant benefits to DMD mouse models, there is little to no data on the results in human patients. Due to the limited number of human studies, the differences in study design, and the insufficient understanding of mechanisms of action, more rigorous comparative trials are needed to elucidate which types of MSCs and modifications have optimal therapeutic potential. Full article

(This article belongs to the Special Issue Pathophysiology and Therapeutic Perspectives in DMD: The Well-Defined Role of the Immune System)

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