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19 pages, 4960 KiB

Open AccessArticle

Acid Sphingomyelinase Controls Early Phases of Skeletal Muscle Regeneration by Shaping the Macrophage Phenotype

by Paulina Roux-Biejat, Marco Coazzoli, Pasquale Marrazzo, Silvia Zecchini, Ilaria Di Renzo, Cecilia Prata, Alessandra Napoli, Claudia Moscheni, Matteo Giovarelli, Maria Cristina Barbalace, Elisabetta Catalani, Maria Teresa Bassi, Clara De Palma, Davide Cervia, Marco Malaguti, Silvana Hrelia, Emilio Clementi and Cristiana Perrotta

Cells 2021, 10(11), 3028; https://doi.org/10.3390/cells10113028 - 5 Nov 2021

Cited by 7 | Viewed by 3207

Abstract

Skeletal muscle regeneration is a complex process involving crosstalk between immune cells and myogenic precursor cells, i.e., satellite cells. In this scenario, macrophage recruitment in damaged muscles is a mandatory step for tissue repair since pro-inflammatory M1 macrophages promote the activation of satellite [...] Read more.

Skeletal muscle regeneration is a complex process involving crosstalk between immune cells and myogenic precursor cells, i.e., satellite cells. In this scenario, macrophage recruitment in damaged muscles is a mandatory step for tissue repair since pro-inflammatory M1 macrophages promote the activation of satellite cells, stimulating their proliferation and then, after switching into anti-inflammatory M2 macrophages, they prompt satellite cells’ differentiation into myotubes and resolve inflammation. Here, we show that acid sphingomyelinase (ASMase), a key enzyme in sphingolipid metabolism, is activated after skeletal muscle injury induced in vivo by the injection of cardiotoxin. ASMase ablation shortens the early phases of skeletal muscle regeneration without affecting satellite cell behavior. Of interest, ASMase regulates the balance between M1 and M2 macrophages in the injured muscles so that the absence of the enzyme reduces inflammation. The analysis of macrophage populations indicates that these events depend on the altered polarization of M1 macrophages towards an M2 phenotype. Our results unravel a novel role of ASMase in regulating immune response during muscle regeneration/repair and suggest ASMase as a supplemental therapeutic target in conditions of redundant inflammation that impairs muscle recovery. Full article

(This article belongs to the Special Issue Muscle Homeostasis and Regeneration: From Molecular Mechanisms to Therapeutic Opportunities 2021)

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19 pages, 7266 KiB

Open AccessFeature PaperArticle

Flavonoids and Omega3 Prevent Muscle and Cardiac Damage in Duchenne Muscular Dystrophy Animal Model

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

Cells 2021, 10(11), 2917; https://doi.org/10.3390/cells10112917 - 28 Oct 2021

Cited by 2 | Viewed by 4252

Abstract

Nutraceutical products possess various anti-inflammatory, antiarrhythmic, cardiotonic, and antioxidant pharmacological activities that could be useful in preventing oxidative damage, mainly induced by reactive oxygen species. Previously published data showed that a mixture of polyphenols and polyunsaturated fatty acids, mediate an antioxidative response in [...] Read more.

Nutraceutical products possess various anti-inflammatory, antiarrhythmic, cardiotonic, and antioxidant pharmacological activities that could be useful in preventing oxidative damage, mainly induced by reactive oxygen species. Previously published data showed that a mixture of polyphenols and polyunsaturated fatty acids, mediate an antioxidative response in mdx mice, Duchenne muscular dystrophy animal model. Dystrophic muscles are characterized by low regenerative capacity, fibrosis, fiber necrosis, inflammatory process, altered autophagic flux and inadequate anti-oxidant response. FLAVOmega β is a mixture of flavonoids and docosahexaenoic acid. In this study, we evaluated the role of these supplements in the amelioration of the pathological phenotype in dystrophic mice through in vitro and in vivo assays. FLAVOmega β reduced inflammation and fibrosis, dampened reactive oxygen species production, and induced an oxidative metabolic switch of myofibers, with consequent increase of mitochondrial activity, vascularization, and fatigue resistance. Therefore, we propose FLAVOmega β as food supplement suitable for preventing muscle weakness, delaying inflammatory milieu, and sustaining physical health in patients affected from DMD. Full article

(This article belongs to the Special Issue Muscle Homeostasis and Regeneration: From Molecular Mechanisms to Therapeutic Opportunities 2021)

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15 pages, 2551 KiB

Open AccessFeature PaperArticle

Sustained Systemic Levels of IL-6 Impinge Early Muscle Growth and Induce Muscle Atrophy and Wasting in Adulthood

by Laura Pelosi, Maria Grazia Berardinelli, Laura Forcina, Francesca Ascenzi, Emanuele Rizzuto, Marco Sandri, Fabrizio De Benedetti, Bianca Maria Scicchitano and Antonio Musarò

Cells 2021, 10(7), 1816; https://doi.org/10.3390/cells10071816 - 18 Jul 2021

Cited by 15 | Viewed by 4439

Abstract

IL-6 is a pleiotropic cytokine that can exert different and opposite effects. The muscle-induced and transient expression of IL-6 can act in an autocrine or paracrine manner, stimulating anabolic pathways associated with muscle growth, myogenesis, and with regulation of energy metabolism. In contrast, [...] Read more.

IL-6 is a pleiotropic cytokine that can exert different and opposite effects. The muscle-induced and transient expression of IL-6 can act in an autocrine or paracrine manner, stimulating anabolic pathways associated with muscle growth, myogenesis, and with regulation of energy metabolism. In contrast, under pathologic conditions, including muscular dystrophy, cancer associated cachexia, aging, chronic inflammatory diseases, and other pathologies, the plasma levels of IL-6 significantly increase, promoting muscle wasting. Nevertheless, the specific physio-pathological role exerted by IL-6 in the maintenance of differentiated phenotype remains to be addressed. The purpose of this study was to define the role of increased plasma levels of IL-6 on muscle homeostasis and the mechanisms contributing to muscle loss. Here, we reported that increased plasma levels of IL-6 promote alteration in muscle growth at early stage of postnatal life and induce muscle wasting by triggering a shift of the slow-twitch fibers toward a more sensitive fast fiber phenotype. These findings unveil a role for IL-6 as a potential biomarker of stunted growth and skeletal muscle wasting. Full article

(This article belongs to the Special Issue Muscle Homeostasis and Regeneration: From Molecular Mechanisms to Therapeutic Opportunities 2021)

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Review

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25 pages, 2009 KiB

Open AccessReview

DUX4 Role in Normal Physiology and in FSHD Muscular Dystrophy

by Emanuele Mocciaro, Valeria Runfola, Paola Ghezzi, Maria Pannese and Davide Gabellini

Cells 2021, 10(12), 3322; https://doi.org/10.3390/cells10123322 - 26 Nov 2021

Cited by 31 | Viewed by 7875

Abstract

In the last decade, the sequence-specific transcription factor double homeobox 4 (DUX4) has gone from being an obscure entity to being a key factor in important physiological and pathological processes. We now know that expression of DUX4 is highly regulated and restricted to [...] Read more.

In the last decade, the sequence-specific transcription factor double homeobox 4 (DUX4) has gone from being an obscure entity to being a key factor in important physiological and pathological processes. We now know that expression of DUX4 is highly regulated and restricted to the early steps of embryonic development, where DUX4 is involved in transcriptional activation of the zygotic genome. While DUX4 is epigenetically silenced in most somatic tissues of healthy humans, its aberrant reactivation is associated with several diseases, including cancer, viral infection and facioscapulohumeral muscular dystrophy (FSHD). DUX4 is also translocated, giving rise to chimeric oncogenic proteins at the basis of sarcoma and leukemia forms. Hence, understanding how DUX4 is regulated and performs its activity could provide relevant information, not only to further our knowledge of human embryonic development regulation, but also to develop therapeutic approaches for the diseases associated with DUX4. Here, we summarize current knowledge on the cellular and molecular processes regulated by DUX4 with a special emphasis on FSHD muscular dystrophy. Full article

(This article belongs to the Special Issue Muscle Homeostasis and Regeneration: From Molecular Mechanisms to Therapeutic Opportunities 2021)

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18 pages, 1506 KiB

Open AccessReview

Therapeutic Implications of miRNAs for Muscle-Wasting Conditions

by Laura Yedigaryan and Maurilio Sampaolesi

Cells 2021, 10(11), 3035; https://doi.org/10.3390/cells10113035 - 5 Nov 2021

Cited by 19 | Viewed by 4986

Abstract

MicroRNAs (miRNAs) are small, non-coding RNA molecules that are mainly involved in translational repression by binding to specific messenger RNAs. Recently, miRNAs have emerged as biomarkers, relevant for a multitude of pathophysiological conditions, and cells can selectively sort miRNAs into extracellular vesicles for [...] Read more.

MicroRNAs (miRNAs) are small, non-coding RNA molecules that are mainly involved in translational repression by binding to specific messenger RNAs. Recently, miRNAs have emerged as biomarkers, relevant for a multitude of pathophysiological conditions, and cells can selectively sort miRNAs into extracellular vesicles for paracrine and endocrine effects. In the overall context of muscle-wasting conditions, a multitude of miRNAs has been implied as being responsible for the typical dysregulation of anabolic and catabolic pathways. In general, chronic muscle disorders are associated with the main characteristic of a substantial loss in muscle mass. Muscular dystrophies (MDs) are a group of genetic diseases that cause muscle weakness and degeneration. Typically, MDs are caused by mutations in those genes responsible for upholding the integrity of muscle structure and function. Recently, the dysregulation of miRNA levels in such pathological conditions has been reported. This revelation is imperative for both MDs and other muscle-wasting conditions, such as sarcopenia and cancer cachexia. The expression levels of miRNAs have immense potential for use as potential diagnostic, prognostic and therapeutic biomarkers. Understanding the role of miRNAs in muscle-wasting conditions may lead to the development of novel strategies for the improvement of patient management. Full article

(This article belongs to the Special Issue Muscle Homeostasis and Regeneration: From Molecular Mechanisms to Therapeutic Opportunities 2021)

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15 pages, 1591 KiB

Open AccessReview

Rho GTPases in Skeletal Muscle Development and Homeostasis

by Sonia Rodríguez-Fdez and Xosé R. Bustelo

Cells 2021, 10(11), 2984; https://doi.org/10.3390/cells10112984 - 2 Nov 2021

Cited by 18 | Viewed by 4191

Abstract

Rho guanosine triphosphate hydrolases (GTPases) are molecular switches that cycle between an inactive guanosine diphosphate (GDP)-bound and an active guanosine triphosphate (GTP)-bound state during signal transduction. As such, they regulate a wide range of both cellular and physiological processes. In this review, we [...] Read more.

Rho guanosine triphosphate hydrolases (GTPases) are molecular switches that cycle between an inactive guanosine diphosphate (GDP)-bound and an active guanosine triphosphate (GTP)-bound state during signal transduction. As such, they regulate a wide range of both cellular and physiological processes. In this review, we will summarize recent work on the role of Rho GTPase-regulated pathways in skeletal muscle development, regeneration, tissue mass homeostatic balance, and metabolism. In addition, we will present current evidence that links the dysregulation of these GTPases with diseases caused by skeletal muscle dysfunction. Overall, this information underscores the critical role of a number of members of the Rho GTPase subfamily in muscle development and the overall metabolic balance of mammalian species. Full article

(This article belongs to the Special Issue Muscle Homeostasis and Regeneration: From Molecular Mechanisms to Therapeutic Opportunities 2021)

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14 pages, 993 KiB

Open AccessReview

Restoring the Cell Cycle and Proliferation Competence in Terminally Differentiated Skeletal Muscle Myotubes

by Deborah Pajalunga and Marco Crescenzi

Cells 2021, 10(10), 2753; https://doi.org/10.3390/cells10102753 - 14 Oct 2021

Cited by 14 | Viewed by 7010

Abstract

Terminal differentiation is an ill-defined, insufficiently characterized, nonproliferation state. Although it has been classically deemed irreversible, it is now clear that at least several terminally differentiated (TD) cell types can be brought back into the cell cycle. We are striving to uncover the [...] Read more.

Terminal differentiation is an ill-defined, insufficiently characterized, nonproliferation state. Although it has been classically deemed irreversible, it is now clear that at least several terminally differentiated (TD) cell types can be brought back into the cell cycle. We are striving to uncover the molecular bases of terminal differentiation, whose fundamental understanding is a goal in itself. In addition, the field has sought to acquire the ability to make TD cells proliferate. Attaining this end would probe the very molecular mechanisms we are trying to understand. Equally important, it would be invaluable in regenerative medicine, for tissues depending on TD cells and devoid of significant self-repair capabilities. The skeletal muscle has long been used as a model system to investigate the molecular foundations of terminal differentiation. Here, we summarize more than 50 years of studies in this field. Full article

(This article belongs to the Special Issue Muscle Homeostasis and Regeneration: From Molecular Mechanisms to Therapeutic Opportunities 2021)

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21 pages, 2487 KiB

Open AccessReview

Muscle Regeneration and RNA: New Perspectives for Ancient Molecules

by Giulia Buonaiuto, Fabio Desideri, Valeria Taliani and Monica Ballarino

Cells 2021, 10(10), 2512; https://doi.org/10.3390/cells10102512 - 23 Sep 2021

Cited by 5 | Viewed by 5156

Abstract

The ability of the ribonucleic acid (RNA) to self-replicate, combined with a unique cocktail of chemical properties, suggested the existence of an RNA world at the origin of life. Nowadays, this hypothesis is supported by innovative high-throughput and biochemical approaches, which definitively revealed [...] Read more.

The ability of the ribonucleic acid (RNA) to self-replicate, combined with a unique cocktail of chemical properties, suggested the existence of an RNA world at the origin of life. Nowadays, this hypothesis is supported by innovative high-throughput and biochemical approaches, which definitively revealed the essential contribution of RNA-mediated mechanisms to the regulation of fundamental processes of life. With the recent development of SARS-CoV-2 mRNA-based vaccines, the potential of RNA as a therapeutic tool has received public attention. Due to its intrinsic single-stranded nature and the ease with which it is synthesized in vitro, RNA indeed represents the most suitable tool for the development of drugs encompassing every type of human pathology. The maximum effectiveness and biochemical versatility is achieved in the guise of non-coding RNAs (ncRNAs), which are emerging as multifaceted regulators of tissue specification and homeostasis. Here, we report examples of coding and ncRNAs involved in muscle regeneration and discuss their potential as therapeutic tools. Small ncRNAs, such as miRNA and siRNA, have been successfully applied in the treatment of several diseases. The use of longer molecules, such as lncRNA and circRNA, is less advanced. However, based on the peculiar properties discussed below, they represent an innovative pool of RNA biomarkers and possible targets of clinical value. Full article

(This article belongs to the Special Issue Muscle Homeostasis and Regeneration: From Molecular Mechanisms to Therapeutic Opportunities 2021)

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