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Signalling Pathways in Skeletal Muscle Differentiation, Histogenesis and Repair

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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 (15 December 2019) | Viewed by 74126

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Prof. Dr. Marina Bouché

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Department of Anatomical, Histological, Forensic Medicine and Orthopedic Sciences (DAHFMO), Sapienza University of Rome, 00161 Roma, Italy
Interests: striated muscles; muscle diseases; muscle immunology; intercellular communication
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Special Issue Information

Dear Colleagues,

This Special Issue aims to highlight recent and current research on signalling pathways regulating skeletal muscle differentiation, histogenesis, and remodelling. Skeletal muscle is a dynamic tissue capable of responding to a large variety of physiological stimuli by adjusting muscle fiber growth, size, metabolism, and function. Numerous recent studies have expanded our knowledge of the signalling pathways regulating these processes. It is now clear that the maintenance of muscle homeostasis depends on tightly regulated processes, involving endocrine/paracrine and cell–cell contact interactions. Alterations in any of these processes can lead to unsuccessful repair following direct mechanical trauma (acute injury) or after secondary damage due to aging or genetic neuromuscular defects. On the other hand, the formation of skeletal muscle during embryonic development and postnatal life serves as a paradigm for stem and progenitor cell maintenance, lineage specification, and terminal differentiation. In fact, many aspects of adult myogenesis resemble embryonic morphogenetic events, and similar signalling mechanisms control the genetic networks that determine cell fate during these processes. An integrative view of all aspects of muscle differentiation is paramount for a comprehensive understanding of muscle formation and maintenance. Skeletal muscle biology is studied from many different viewpoints: genetic diseases, sports medicine, physiology, immunology, developmental biology, gene regulation, and regeneration.

The focus of this Special Issue is to bring together studies that used different experimental approaches in vivo or in vitro to dissect the dynamic changes that take place during muscle building and maintenance, and their contribution to normal versus pathological muscle repair.

Prof. Dr. Marina Bouché
Guest Editor

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Keywords

signalling pathways
skeletal muscle
muscle development
muscle homeostasis
muscle atrophy
muscle dystrophies
myogenesis
satellite cells
tissue regeneration

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Published Papers (12 papers)

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Research

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17 pages, 2869 KiB

Open AccessArticle

Zeb2 Regulates Myogenic Differentiation in Pluripotent Stem Cells

by Ester Sara Di Filippo, Domiziana Costamagna, Giorgia Giacomazzi, Álvaro Cortés-Calabuig, Agata Stryjewska, Danny Huylebroeck, Stefania Fulle and Maurilio Sampaolesi

Int. J. Mol. Sci. 2020, 21(7), 2525; https://doi.org/10.3390/ijms21072525 - 5 Apr 2020

Cited by 9 | Viewed by 3465

Abstract

Skeletal muscle differentiation is triggered by a unique family of myogenic basic helix-loop-helix transcription factors, including MyoD, MRF-4, Myf-5, and Myogenin. These transcription factors bind promoters and distant regulatory regions, including E-box elements, of genes whose expression is restricted to muscle cells. Other E-box binding zinc finger proteins target the same DNA response elements, however, their function in muscle development and regeneration is still unknown. Here, we show that the transcription factor zinc finger E-box-binding homeobox 2 (Zeb2, Sip-1, Zfhx1b) is present in skeletal muscle tissues. We investigate the role of Zeb2 in skeletal muscle differentiation using genetic tools and transgenic mouse embryonic stem cells, together with single-cell RNA-sequencing and in vivo muscle engraftment capability. We show that Zeb2 over-expression has a positive impact on skeletal muscle differentiation in pluripotent stem cells and adult myogenic progenitors. We therefore propose that Zeb2 is a novel myogenic regulator and a possible target for improving skeletal muscle regeneration. The non-neural roles of Zeb2 are poorly understood. Full article

(This article belongs to the Special Issue Signalling Pathways in Skeletal Muscle Differentiation, Histogenesis and Repair)

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18 pages, 3218 KiB

Open AccessArticle

Targeting PKCθ Promotes Satellite Cell Self-Renewal

by Anna Benedetti, Piera Filomena Fiore, Luca Madaro, Biliana Lozanoska-Ochser and Marina Bouché

Int. J. Mol. Sci. 2020, 21(7), 2419; https://doi.org/10.3390/ijms21072419 - 31 Mar 2020

Cited by 9 | Viewed by 3418

Abstract

Skeletal muscle regeneration following injury depends on the ability of satellite cells (SCs) to proliferate, self-renew, and eventually differentiate. The factors that regulate the process of self-renewal are poorly understood. In this study we examined the role of PKCθ in SC self-renewal and differentiation. We show that PKCθ is expressed in SCs, and its active form is localized to the chromosomes, centrosomes, and midbody during mitosis. Lack of PKCθ promotes SC symmetric self-renewal division by regulating Pard3 polarity protein localization, without affecting the overall proliferation rate. Genetic ablation of PKCθ or its pharmacological inhibition in vivo did not affect SC number in healthy muscle. By contrast, after induction of muscle injury, lack or inhibition of PKCθ resulted in a significant expansion of the quiescent SC pool. Finally, we show that lack of PKCθ does not alter the inflammatory milieu after acute injury in muscle, suggesting that the enhanced self-renewal ability of SCs in PKCθ-/- mice is not due to an alteration in the inflammatory milieu. Together, these results suggest that PKCθ plays an important role in SC self-renewal by stimulating their expansion through symmetric division, and it may represent a promising target to manipulate satellite cell self-renewal in pathological conditions. Full article

(This article belongs to the Special Issue Signalling Pathways in Skeletal Muscle Differentiation, Histogenesis and Repair)

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17 pages, 4686 KiB

Open AccessArticle

Displaced Myonuclei in Cancer Cachexia Suggest Altered Innervation

by Nissrine Daou, Medhi Hassani, Emidio Matos, Gabriela Salim De Castro, Raquel Galvao Figueredo Costa, Marilia Seelaender, Viviana Moresi, Marco Rocchi, Sergio Adamo, Zhenlin Li, Onnik Agbulut and Dario Coletti

Int. J. Mol. Sci. 2020, 21(3), 1092; https://doi.org/10.3390/ijms21031092 - 6 Feb 2020

Cited by 26 | Viewed by 6323

Abstract

An idiopathic myopathy characterized by central nuclei in muscle fibers, a hallmark of muscle regeneration, has been observed in cancer patients. In cancer cachexia skeletal muscle is incapable of regeneration, consequently, this observation remains unaccounted for. In C26-tumor bearing, cachectic mice, we observed muscle fibers with central nuclei in the absence of molecular markers of bona fide regeneration. These clustered, non-peripheral nuclei were present in NCAM-expressing muscle fibers. Since NCAM expression is upregulated in denervated myofibers, we searched for additional makers of denervation, including AchRs, MUSK, and HDAC. This last one being also consistently upregulated in cachectic muscles, correlated with an increase of central myonuclei. This held true in the musculature of patients suffering from gastrointestinal cancer, where a progressive increase in the number of central myonuclei was observed in weight stable and in cachectic patients, compared to healthy subjects. Based on all of the above, the presence of central myonuclei in cancer patients and animal models of cachexia is consistent with motor neuron loss or NMJ perturbation and could underlie a previously neglected phenomenon of denervation, rather than representing myofiber damage and regeneration in cachexia. Similarly to aging, denervation-dependent myofiber atrophy could contribute to muscle wasting in cancer cachexia. Full article

(This article belongs to the Special Issue Signalling Pathways in Skeletal Muscle Differentiation, Histogenesis and Repair)

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14 pages, 2163 KiB

Open AccessArticle

Maintenance of the Undifferentiated State in Myogenic Progenitor Cells by TGFβ Signaling is Smad Independent and Requires MEK Activation

by Tetsuaki Miyake, Arif Aziz and John C. McDermott

Int. J. Mol. Sci. 2020, 21(3), 1057; https://doi.org/10.3390/ijms21031057 - 5 Feb 2020

Cited by 11 | Viewed by 2911

Abstract

Transforming growth factor β (TGFβ) is a pluripotent cytokine and regulates a myriad of biological processes. It has been established that TGFβ potently inhibits skeletal muscle differentiation; however, the molecular mechanism is not clearly defined. Previously, we reported that inhibition of the TGFβ canonical pathway by an inhibitory Smad, Smad7, does not reverse this effect on differentiation, suggesting that activation of receptor Smads (R-Smads) by TGFβ is not responsible for repression of myogenesis. In addition, pharmacological blockade of Smad3 activation by TGFβ did not reverse TGFβ’s inhibitory effect on myogenesis. In considering other pathways, we observed that TGFβ potently activates MEK/ERK, and a pharmacological inhibitor of MEK reversed TGFβ’s inhibitory effect on myogenesis, as indicated by a myogenin promoter-reporter gene, sarcomeric myosin heavy chain accumulation, and phenotypic myotube formation. Furthermore, we found that c-Jun, a known potent repressor of myogenesis, which is coincidently also a down-stream target of MEK/ERK signaling, was phosphorylated and accumulates in the nucleus in response to TGFβ activation. Taken together, these observations support a model in which TGFβ activates a MEK/ERK/c-Jun pathway to repress skeletal myogenesis, maintaining the pluripotent undifferentiated state in myogenic progenitors. Full article

(This article belongs to the Special Issue Signalling Pathways in Skeletal Muscle Differentiation, Histogenesis and Repair)

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14 pages, 1693 KiB

Open AccessArticle

Lack of PKCθ Promotes Regenerative Ability of Muscle Stem Cells in Chronic Muscle Injury

by Piera Filomena Fiore, Anna Benedetti, Martina Sandonà, Luca Madaro, Marco De Bardi, Valentina Saccone, Pier Lorenzo Puri, Cesare Gargioli, Biliana Lozanoska-Ochser and Marina Bouché

Int. J. Mol. Sci. 2020, 21(3), 932; https://doi.org/10.3390/ijms21030932 - 31 Jan 2020

Cited by 13 | Viewed by 2981

Abstract

Duchenne muscular dystrophy (DMD) is a genetic disease characterized by muscle wasting and chronic inflammation, leading to impaired satellite cells (SCs) function and exhaustion of their regenerative capacity. We previously showed that lack of PKCθ in mdx mice, a mouse model of DMD, reduces muscle wasting and inflammation, and improves muscle regeneration and performance at early stages of the disease. In this study, we show that muscle regeneration is boosted, and fibrosis reduced in mdxθ^−/− mice, even at advanced stages of the disease. This phenotype was associated with a higher number of Pax7 positive cells in mdxθ^−/− muscle compared with mdx muscle, during the progression of the disease. Moreover, the expression level of Pax7 and Notch1, the pivotal regulators of SCs self-renewal, were upregulated in SCs isolated from mdxθ^−/− muscle compared with mdx derived SCs. Likewise, the expression of the Notch ligands Delta1 and Jagged1 was higher in mdxθ^−/− muscle compared with mdx. The expression level of Delta1 and Jagged1 was also higher in PKCθ^−/− muscle compared with WT muscle following acute injury. In addition, lack of PKCθ prolonged the survival and sustained the differentiation of transplanted myogenic progenitors. Overall, our results suggest that lack of PKCθ promotes muscle repair in dystrophic mice, supporting stem cells survival and maintenance through increased Delta-Notch signaling. Full article

(This article belongs to the Special Issue Signalling Pathways in Skeletal Muscle Differentiation, Histogenesis and Repair)

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12 pages, 1470 KiB

Open AccessArticle

Myoblast Migration and Directional Persistence Affected by Syndecan-4-Mediated Tiam-1 Expression and Distribution

by Daniel Becsky, Szuzina Gyulai-Nagy, Arpad Balind, Peter Horvath, Laszlo Dux and Aniko Keller-Pinter

Int. J. Mol. Sci. 2020, 21(3), 823; https://doi.org/10.3390/ijms21030823 - 27 Jan 2020

Cited by 11 | Viewed by 4931

Abstract

Skeletal muscle is constantly renewed in response to injury, exercise, or muscle diseases. Muscle stem cells, also known as satellite cells, are stimulated by local damage to proliferate extensively and form myoblasts that then migrate, differentiate, and fuse to form muscle fibers. The transmembrane heparan sulfate proteoglycan syndecan-4 plays multiple roles in signal transduction processes, such as regulating the activity of the small GTPase Rac1 (Ras-related C3 botulinum toxin substrate 1) by binding and inhibiting the activity of Tiam1 (T-lymphoma invasion and metastasis-1), a guanine nucleotide exchange factor for Rac1. The Rac1-mediated actin remodeling is required for cell migration. Syndecan-4 knockout mice cannot regenerate injured muscle; however, the detailed underlying mechanism is unknown. Here, we demonstrate that shRNA-mediated knockdown of syndecan-4 decreases the random migration of mouse myoblasts during live-cell microscopy. Treatment with the Rac1 inhibitor NSC23766 did not restore the migration capacity of syndecan-4 silenced cells; in fact, it was further reduced. Syndecan-4 knockdown decreased the directional persistence of migration, abrogated the polarized, asymmetric distribution of Tiam1, and reduced the total Tiam1 level of the cells. Syndecan-4 affects myoblast migration via its role in expression and localization of Tiam1; this finding may facilitate greater understanding of the essential role of syndecan-4 in the development and regeneration of skeletal muscle. Full article

(This article belongs to the Special Issue Signalling Pathways in Skeletal Muscle Differentiation, Histogenesis and Repair)

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21 pages, 3564 KiB

Open AccessArticle

Thyroid Hormone Protects from Fasting-Induced Skeletal Muscle Atrophy by Promoting Metabolic Adaptation

by Sarassunta Ucci, Alessandra Renzini, Valentina Russi, Claudia Mangialardo, Ilenia Cammarata, Giorgia Cavioli, Maria Giulia Santaguida, Camilla Virili, Marco Centanni, Sergio Adamo, Viviana Moresi and Cecilia Verga-Falzacappa

Int. J. Mol. Sci. 2019, 20(22), 5754; https://doi.org/10.3390/ijms20225754 - 15 Nov 2019

Cited by 13 | Viewed by 6173

Abstract

Thyroid hormones regulate a wide range of cellular responses, via non-genomic and genomic actions, depending on cell-specific thyroid hormone transporters, co-repressors, or co-activators. Skeletal muscle has been identified as a direct target of thyroid hormone T3, where it regulates stem cell proliferation and differentiation, as well as myofiber metabolism. However, the effects of T3 in muscle-wasting conditions have not been yet addressed. Being T3 primarily responsible for the regulation of metabolism, we challenged mice with fasting and found that T3 counteracted starvation-induced muscle atrophy. Interestingly, T3 did not prevent the activation of the main catabolic pathways, i.e., the ubiquitin-proteasome or the autophagy-lysosomal systems, nor did it stimulate de novo muscle synthesis in starved muscles. Transcriptome analyses revealed that T3 mainly affected the metabolic processes in starved muscle. Further analyses of myofiber metabolism revealed that T3 prevented the starvation-mediated metabolic shift, thus preserving skeletal muscle mass. Our study elucidated new T3 functions in regulating skeletal muscle homeostasis and metabolism in pathological conditions, opening to new potential therapeutic approaches for the treatment of skeletal muscle atrophy. Full article

(This article belongs to the Special Issue Signalling Pathways in Skeletal Muscle Differentiation, Histogenesis and Repair)

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10 pages, 2031 KiB

Open AccessArticle

Clinical Response to Personalized Exercise Therapy in Heart Failure Patients with Reduced Ejection Fraction Is Accompanied by Skeletal Muscle Histological Alterations

by Tatiana A. Lelyavina, Victoria L. Galenko, Oksana A. Ivanova, Margarita Y. Komarova, Elena V. Ignatieva, Maria A. Bortsova, Galina Y. Yukina, Natalia V. Khromova, Maria Yu. Sitnikova, Anna A. Kostareva, Alexey Sergushichev and Renata I. Dmitrieva

Int. J. Mol. Sci. 2019, 20(21), 5514; https://doi.org/10.3390/ijms20215514 - 5 Nov 2019

Cited by 3 | Viewed by 4199

Abstract

Heart failure (HF) is associated with skeletal muscle wasting and exercise intolerance. This study aimed to evaluate the exercise-induced clinical response and histological alterations. One hundred and forty-four HF patients were enrolled. The individual training program was determined as a workload at or close to the lactate threshold (LT1); clinical data were collected before and after 12 weeks/6 months of training. The muscle biopsies from eight patients were taken before and after 12 weeks of training: histology analysis was used to evaluate muscle morphology. Most of the patients demonstrated a positive response after 12 weeks of the physical rehabilitation program in one or several parameters tested, and 30% of those showed improvement in all four of the following parameters: oxygen uptake (VO2) peak, left ventricular ejection fraction (LVEF), exercise tolerance (ET), and quality of life (QOL); the walking speed at LT1 after six months of training showed a significant rise. Along with clinical response, the histological analysis detected a small but significant decrease in both fiber and endomysium thickness after the exercise training course indicating the stabilization of muscle mechanotransduction system. Together, our data show that the beneficial effect of personalized exercise therapy in HF patients depends, at least in part, on the improvement in skeletal muscle physiological and biochemical performance. Full article

(This article belongs to the Special Issue Signalling Pathways in Skeletal Muscle Differentiation, Histogenesis and Repair)

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21 pages, 3720 KiB

Open AccessArticle

Inhibition of Phosphoinositide 3-Kinase/Protein Kinase B Signaling Hampers the Vasopressin-dependent Stimulation of Myogenic Differentiation

by Silvia Sorrentino, Alessandra Barbiera, Gabriella Proietti, Gigliola Sica, Sergio Adamo and Bianca Maria Scicchitano

Int. J. Mol. Sci. 2019, 20(17), 4188; https://doi.org/10.3390/ijms20174188 - 27 Aug 2019

Cited by 6 | Viewed by 3600

Abstract

Arginine-vasopressin (AVP) promotes muscle differentiation, hypertrophy, and regeneration through the combined activation of the calcineurin and Calcium/Calmodulin-dependent Protein Kinase (CaMK) pathways. The AVP system is impaired in several neuromuscular diseases, suggesting that AVP may act as a physiological factor in skeletal muscle. Since the Phosphoinositide 3-kinases/Protein Kinase B/mammalian Target Of Rapamycin (PI3K/Akt/mTOR) signaling plays a significant role in regulating muscle mass, we evaluated its role in the AVP myogenic effect. In L6 cells AKT1 expression was knocked down, and the AVP-dependent expression of mTOR and Forkhead box O3 (FoxO) was analyzed by Western blotting. The effect of the PI3K inhibitor LY294002 was evaluated by cellular and molecular techniques. Akt knockdown hampered the AVP-dependent mTOR expression while increased the levels of FoxO transcription factor. LY294002 treatment inhibited the AVP-dependent expression of Myocyte Enhancer Factor-2 (MEF2) and myogenin and prevented the nuclear translocation of MEF2. LY294002 also repressed the AVP-dependent nuclear export of histone deacetylase 4 (HDAC4) interfering with the formation of multifactorial complexes on the myogenin promoter. We demonstrate that the PI3K/Akt pathway is essential for the full myogenic effect of AVP and that, by targeting this pathway, one may highlight novel strategies to counteract muscle wasting in aging or neuromuscular disorders. Full article

(This article belongs to the Special Issue Signalling Pathways in Skeletal Muscle Differentiation, Histogenesis and Repair)

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Review

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18 pages, 1022 KiB

Open AccessReview

Stem Cell Aging in Skeletal Muscle Regeneration and Disease

by Hiroyuki Yamakawa, Dai Kusumoto, Hisayuki Hashimoto and Shinsuke Yuasa

Int. J. Mol. Sci. 2020, 21(5), 1830; https://doi.org/10.3390/ijms21051830 - 6 Mar 2020

Cited by 104 | Viewed by 15586

Abstract

Skeletal muscle comprises 30–40% of the weight of a healthy human body and is required for voluntary movements in humans. Mature skeletal muscle is formed by multinuclear cells, which are called myofibers. Formation of myofibers depends on the proliferation, differentiation, and fusion of muscle progenitor cells during development and after injury. Muscle progenitor cells are derived from muscle satellite (stem) cells (MuSCs), which reside on the surface of the myofiber but beneath the basement membrane. MuSCs play a central role in postnatal maintenance, growth, repair, and regeneration of skeletal muscle. In sedentary adult muscle, MuSCs are mitotically quiescent, but are promptly activated in response to muscle injury. Physiological and chronological aging induces MuSC aging, leading to an impaired regenerative capability. Importantly, in pathological situations, repetitive muscle injury induces early impairment of MuSCs due to stem cell aging and leads to early impairment of regeneration ability. In this review, we discuss (1) the role of MuSCs in muscle regeneration, (2) stem cell aging under physiological and pathological conditions, and (3) prospects related to clinical applications of controlling MuSCs. Full article

(This article belongs to the Special Issue Signalling Pathways in Skeletal Muscle Differentiation, Histogenesis and Repair)

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17 pages, 779 KiB

Open AccessReview

DUX4 Signalling in the Pathogenesis of Facioscapulohumeral Muscular Dystrophy

by Kenji Rowel Q. Lim, Quynh Nguyen and Toshifumi Yokota

Int. J. Mol. Sci. 2020, 21(3), 729; https://doi.org/10.3390/ijms21030729 - 22 Jan 2020

Cited by 46 | Viewed by 8490

Abstract

Facioscapulohumeral muscular dystrophy (FSHD) is a disabling inherited muscular disorder characterized by asymmetric, progressive muscle weakness and degeneration. Patients display widely variable disease onset and severity, and sometimes present with extra-muscular symptoms. There is a consensus that FSHD is caused by the aberrant production of the double homeobox protein 4 (DUX4) transcription factor in skeletal muscle. DUX4 is normally expressed during early embryonic development, and is then effectively silenced in all tissues except the testis and thymus. Its reactivation in skeletal muscle disrupts numerous signalling pathways that mostly converge on cell death. Here, we review studies on DUX4-affected pathways in skeletal muscle and provide insights into how understanding these could help explain the unique pathogenesis of FSHD. Full article

(This article belongs to the Special Issue Signalling Pathways in Skeletal Muscle Differentiation, Histogenesis and Repair)

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15 pages, 482 KiB

Open AccessReview

Role of Transforming Growth Factor-β in Skeletal Muscle Fibrosis: A Review

by Ahmed Ismaeel, Jeong-Su Kim, Jeffrey S. Kirk, Robert S. Smith, William T. Bohannon and Panagiotis Koutakis

Int. J. Mol. Sci. 2019, 20(10), 2446; https://doi.org/10.3390/ijms20102446 - 17 May 2019

Cited by 94 | Viewed by 10952

Abstract

Transforming growth factor-beta (TGF-β) isoforms are cytokines involved in a variety of cellular processes, including myofiber repair and regulation of connective tissue formation. Activation of the TGF-β pathway contributes to pathologic fibrosis in most organs. Here, we have focused on examining the evidence demonstrating the involvement of TGF-β in the fibrosis of skeletal muscle particularly. The TGF-β pathway plays a role in different skeletal muscle myopathies, and TGF-β signaling is highly induced in these diseases. In this review, we discuss different molecular mechanisms of TGF-β-mediated skeletal muscle fibrosis and highlight different TGF-β-targeted treatments that target these relevant pathways. Full article

(This article belongs to the Special Issue Signalling Pathways in Skeletal Muscle Differentiation, Histogenesis and Repair)

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