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Experimental Cell Research Oct 2022Skeletal muscle development and regeneration is governed by the combined action of Myf5, MyoD, Mrf4 and MyoG, also known as the myogenic regulatory factors (MRFs). These... (Review)
Review
Skeletal muscle development and regeneration is governed by the combined action of Myf5, MyoD, Mrf4 and MyoG, also known as the myogenic regulatory factors (MRFs). These transcription factors are expressed in a highly spatio-temporal restricted manner, ensuring the significant functional and metabolic diversity observed between the different muscle groups. In this review, we will discuss the multiple layers of regulation that contribute to the control of the exquisite expression patterns of the MRFs in particular, and of myogenic genes in general. We will highlight all major regulatory processes that play a role in myogenesis: from those that modulate chromatin status and transcription competence, such as DNA methylation, histone modification, chromatin remodeling, or non-coding RNAs, to those that control transcript and protein processing and modification, such as alternative splicing, polyadenylation, other mRNA modifications, or post-translational protein modifications. All these processes are exquisitely and tightly coordinated to ensure the proper activation, maintenance and termination of the myogenic process.
Topics: Chromatin Assembly and Disassembly; Gene Expression; Gene Expression Regulation; Muscle Development; Muscle, Skeletal; Myogenic Regulatory Factors; Transcription Factors
PubMed: 35926660
DOI: 10.1016/j.yexcr.2022.113299 -
International Journal of Molecular... Sep 2021Primary cilia are non-motile, cell cycle-associated organelles that can be found on most vertebrate cell types. Comprised of microtubule bundles organised into an... (Review)
Review
Primary cilia are non-motile, cell cycle-associated organelles that can be found on most vertebrate cell types. Comprised of microtubule bundles organised into an axoneme and anchored by a mature centriole or basal body, primary cilia are dynamic signalling platforms that are intimately involved in cellular responses to their extracellular milieu. Defects in ciliogenesis or dysfunction in cilia signalling underlie a host of developmental disorders collectively referred to as ciliopathies, reinforcing important roles for cilia in human health. Whilst primary cilia have long been recognised to be present in striated muscle, their role in muscle is not well understood. However, recent studies indicate important contributions, particularly in skeletal muscle, that have to date remained underappreciated. Here, we explore recent revelations that the sensory and signalling functions of cilia on muscle progenitors regulate cell cycle progression, trigger differentiation and maintain a commitment to myogenesis. Cilia disassembly is initiated during myoblast fusion. However, the remnants of primary cilia persist in multi-nucleated myotubes, and we discuss their potential role in late-stage differentiation and myofiber formation. Reciprocal interactions between cilia and the extracellular matrix (ECM) microenvironment described for other tissues may also inform on parallel interactions in skeletal muscle. We also discuss emerging evidence that cilia on fibroblasts/fibro-adipogenic progenitors and myofibroblasts may influence cell fate in both a cell autonomous and non-autonomous manner with critical consequences for skeletal muscle ageing and repair in response to injury and disease. This review addresses the enigmatic but emerging role of primary cilia in satellite cells in myoblasts and myofibers during myogenesis, as well as the wider tissue microenvironment required for skeletal muscle formation and homeostasis.
Topics: Animals; Axoneme; Cell Cycle; Cell Differentiation; Centrosome; Cilia; Cytoskeleton; Extracellular Matrix; Humans; Muscle Development; Muscle Fibers, Skeletal; Muscle, Skeletal; Myoblasts; Organelles; Signal Transduction
PubMed: 34502512
DOI: 10.3390/ijms22179605 -
Cells Aug 2019Circular RNA (circRNA) is a novel class of non-coding RNA generated by pre-mRNA back splicing, which is characterized by a closed-loop structure. Although circRNAs were... (Review)
Review
Circular RNA (circRNA) is a novel class of non-coding RNA generated by pre-mRNA back splicing, which is characterized by a closed-loop structure. Although circRNAs were firstly reported decades ago, their regulatory roles have not been discovered until recently. In this review, we discussed the putative biogenesis pathways and regulatory functions of circRNAs. Recent studies showed that circRNAs are abundant in skeletal muscle tissue, and their expression levels are regulated during muscle development and aging. We, thus, characterized the expression profile of circRNAs in skeletal muscle and discussed regulatory functions and mechanism-of-action of specific circRNAs in myogenesis. The future investigation into the roles of circRNAs in both physiological and pathological conditions may provide novel insights in skeletal muscle development and provide new therapeutic strategies for muscular diseases.
Topics: Animals; Gene Expression Regulation, Developmental; Humans; Muscle Development; Muscle, Skeletal; RNA, Circular
PubMed: 31412632
DOI: 10.3390/cells8080885 -
International Journal of Molecular... Jun 2023As an organ system, skeletal muscle is essential for the generation of energy that underpins muscle contraction, plays a critical role in controlling energy balance and... (Review)
Review
As an organ system, skeletal muscle is essential for the generation of energy that underpins muscle contraction, plays a critical role in controlling energy balance and insulin-dependent glucose homeostasis, as well as vascular well-being, and regenerates following injury. To achieve homeostasis, there is requirement for "cross-talk" between the myogenic and vascular components and their regulatory factors that comprise skeletal muscle. Accordingly, this review will describe the following: [a] the embryonic cell-signaling events important in establishing vascular and myogenic cell-lineage, the cross-talk between endothelial cells (EC) and myogenic precursors underpinning the development of muscle, its vasculature and the satellite-stem-cell (SC) pool, and the EC-SC cross-talk that maintains SC quiescence and localizes ECs to SCs and angio-myogenesis postnatally; [b] the vascular-myocyte cross-talk and the actions of insulin on vasodilation and capillary surface area important for the uptake of glucose/insulin by myofibers and vascular homeostasis, the microvascular-myocyte dysfunction that characterizes the development of insulin resistance, diabetes and hypertension, and the actions of estrogen on muscle vasodilation and growth in adults; [c] the role of estrogen in utero on the development of fetal skeletal-muscle microvascularization and myofiber hypertrophy required for metabolic/vascular homeostasis after birth; [d] the EC-SC interactions that underpin myofiber vascular regeneration post-injury; and [e] the role of the skeletal-muscle vasculature in Duchenne muscular dystrophy.
Topics: Endothelial Cells; Muscle, Skeletal; Muscle Contraction; Insulin; Glucose; Muscle Development
PubMed: 37445602
DOI: 10.3390/ijms241310425 -
Cells Oct 2023Maintenance of skeletal muscle quantity and quality is essential to ensure various vital functions of the body. Muscle homeostasis is regulated by multiple cytoskeletal... (Review)
Review
Maintenance of skeletal muscle quantity and quality is essential to ensure various vital functions of the body. Muscle homeostasis is regulated by multiple cytoskeletal proteins and myogenic transcriptional programs responding to endogenous and exogenous signals influencing cell structure and function. Since actin is an essential component in cytoskeleton dynamics, actin-binding proteins (ABPs) have been recognized as crucial players in skeletal muscle health and diseases. Hence, dysregulation of ABPs leads to muscle atrophy characterized by loss of mass, strength, quality, and capacity for regeneration. This comprehensive review summarizes the recent studies that have unveiled the role of ABPs in actin cytoskeletal dynamics, with a particular focus on skeletal myogenesis and diseases. This provides insight into the molecular mechanisms that regulate skeletal myogenesis via ABPs as well as research avenues to identify potential therapeutic targets. Moreover, this review explores the implications of non-coding RNAs (ncRNAs) targeting ABPs in skeletal myogenesis and disorders based on recent achievements in ncRNA research. The studies presented here will enhance our understanding of the functional significance of ABPs and mechanotransduction-derived myogenic regulatory mechanisms. Furthermore, revealing how ncRNAs regulate ABPs will allow diverse therapeutic approaches for skeletal muscle disorders to be developed.
Topics: Microfilament Proteins; Actins; Mechanotransduction, Cellular; Muscle, Skeletal; RNA, Untranslated; Muscle Development
PubMed: 37947600
DOI: 10.3390/cells12212523 -
Nutrients Oct 2023Age-related skeletal muscle atrophy and weakness not only reduce the quality of life of those afflicted, but also worsen the prognosis of underlying diseases. We...
Age-related skeletal muscle atrophy and weakness not only reduce the quality of life of those afflicted, but also worsen the prognosis of underlying diseases. We evaluated the effect of RGX365, a protopanaxatriol-type rare ginsenoside mixture, on improving skeletal muscle atrophy. We investigated the myogenic effect of RGX365 on mouse myoblast cells (C2C12) and dexamethasone (10 µM)-induced atrophy of differentiated C2C12. RGX365-treated myotube diameters and myosin heavy chain (MyHC) expression levels were analyzed using immunofluorescence. We evaluated the myogenic effects of RGX365 in aging sarcopenic mice. RGX365 increased myoblast differentiation and MyHC expression, and attenuated the muscle atrophy-inducing F-box (Atrogin-1) and muscle RING finger 1 (MuRF1) expression. Notably, one month of oral administration of RGX365 to 23-month-old sarcopenic mice improved muscle fiber size and the expression of skeletal muscle regeneration-associated molecules. In conclusion, rare ginsenosides, agonists of steroid receptors, can ameliorate skeletal muscle atrophy during long-term administration.
Topics: Mice; Animals; Sarcopenia; Quality of Life; Cell Line; Muscular Atrophy; Muscle, Skeletal; Muscle Fibers, Skeletal; Muscle Development
PubMed: 37836590
DOI: 10.3390/nu15194307 -
Frontiers in Immunology 2022A Krebs cycle intermediate metabolite, itaconate, has gained attention as a potential antimicrobial and autoimmune disease treatment due to its anti-inflammatory...
A Krebs cycle intermediate metabolite, itaconate, has gained attention as a potential antimicrobial and autoimmune disease treatment due to its anti-inflammatory effects. While itaconate and its derivatives pose an attractive therapeutic option for the treatment of inflammatory diseases, the effects outside the immune system still remain limited, particularly in the muscle. Therefore, we endeavored to determine if itaconate signaling impacts muscle differentiation. Utilizing the well-established C2C12 model of myogenesis, we evaluated the effects of itaconate and its derivatives on transcriptional and protein markers of muscle differentiation as well as mitochondrial function. We found itaconate and the derivatives dimethyl itaconate and 4-octyl itaconate disrupt differentiation media-induced myogenesis. A primary biological effect of itaconate is a succinate dehydrogenase (SDH) inhibitor. We find the SDH inhibitors dimethyl malonate and harzianopyridone phenocopie the anti-myogenic effects of itaconate. Furthermore, we find treatment with exogenous succinate results in blunted myogenesis. Together our data indicate itaconate and its derivatives interfere with myogenesis, potentially through inhibition of SDH and subsequent succinate accumulation. We also show 4-octyl itaconate suppresses injury-induced MYOG expression . More importantly, our findings suggest the therapeutic potential of itaconate, and its derivatives could be limited due to deleterious effects on myogenesis.
Topics: Muscle Development; Signal Transduction; Succinates; Succinic Acid
PubMed: 35265064
DOI: 10.3389/fimmu.2022.748375 -
Journal of Cachexia, Sarcopenia and... Feb 2022Most of the microRNAs (MiRs) involved in myogenesis are transcriptional regulated. The role of MiR biogenesis in myogenesis has not been characterized yet. RNA-binding...
BACKGROUND
Most of the microRNAs (MiRs) involved in myogenesis are transcriptional regulated. The role of MiR biogenesis in myogenesis has not been characterized yet. RNA-binding protein Musashi 2 (Msi2) is considered to be one of the major drivers for oncogenesis and stem cell proliferation. The functions of Msi2 in myogenesis have not been explored yet. We sought to investigate Msi2-regulated biogenesis of MiRs in myogenesis and muscle stem cell (MuSC) ageing.
METHODS
We detected the expression of Msi2 in MuSCs and differentiated myotubes by quantitative reverse transcription PCR (RT-qPCR) and western blot. Msi2-binding partner human antigen R (HuR) was identified by immunoprecipitation followed by mass spectrometry analysis. The cooperative binding of Msi2 and HuR on MiR7a-1 was analysed by RNA immunoprecipitation and electrophoresis mobility shift assays. The inhibition of the processing of pri-MiR7a-1 mediated by Msi2 and HuR was shown by Msi2 and HuR knockdown. Immunofluorescent staining, RT-qPCR and immunoblotting were used to characterize the function of MiR7a-1 in myogenesis. Msi2 and HuR up-regulate cryptochrome circadian regulator 2 (Cry2) via MiR7a-1 was confirmed by the luciferase assay and western blot. The post-transcriptional regulatory cascade was further confirmed by RNAi and overexpressing of Msi2 and HuR in MuSCs, and the in vivo function was characterized by histopathological and molecular biological methods in Msi2 knockout mice.
RESULTS
We identified a post-transcription regulatory cascade governed by a pair of RNA-binding proteins Msi2 and HuR. Msi2 is enriched in differentiated muscle cells and promotes MuSC differentiation despite its pro-proliferation functions in other cell types. Msi2 works synergistically with another RNA-binding protein HuR to repress the biogenesis of MiR7a-1 in an Msi2 dose-dependent manner to regulate the translation of the key component of the circadian core oscillator complex Cry2. Down-regulation of Cry2 (0.6-fold, vs. control, P < 0.05) mediated by MiR7a-1 represses MuSC differentiation. The disruption of this cascade leads to differentiation defects of MuSCs. In aged muscles, Msi2 (0.3-fold, vs. control, P < 0.01) expression declined, and the Cry2 protein level also decreases (0.5-fold, vs. control, P < 0.05), suggesting that the disruption of the Msi2-mediated post-transcriptional regulatory cascade could attribute to the declined ability of muscle regeneration in aged skeletal muscle.
CONCLUSIONS
Our findings have identified a new post-transcriptional cascade regulating myogenesis. The cascade is disrupted in skeletal muscle ageing, which leads to declined muscle regeneration ability.
Topics: Animals; Cell Differentiation; Mice; MicroRNAs; Muscle Development; Muscle Fibers, Skeletal; Myoblasts; RNA-Binding Proteins
PubMed: 34877814
DOI: 10.1002/jcsm.12882 -
The FEBS Journal Nov 2022Regeneration of the mammalian adult skeletal muscle is a well-orchestrated process regulated by multiple proteins and signalling pathways. Cytokines constitute a major... (Review)
Review
Regeneration of the mammalian adult skeletal muscle is a well-orchestrated process regulated by multiple proteins and signalling pathways. Cytokines constitute a major class of regulators of skeletal myogenesis. It is well established that infiltrating immune cells at the site of muscle injury secrete cytokines, which play critical roles in the myofibre repair and regeneration process. In the past 10-15 years, skeletal muscle itself has emerged as a prolific producer of cytokines. Much attention in the field has been focused on the endocrine effects of muscle-secreted cytokines (myokines) on metabolic regulation. However, ample evidence suggests that muscle-derived cytokines also regulate myogenic differentiation and muscle regeneration in an autocrine manner. In this review, we survey cytokines that meet two criteria: (a) evidence of expression by muscle cells; (b) evidence demonstrating a myogenic function. Dozens of cytokines representing several major classes make up this group, and together they regulate all steps of the myogenic process. How such a large array of cytokines coordinate their signalling to form a regulatory network is a fascinating, pressing question. Functional studies that can distinguish the source of the cytokines in vivo are also much needed in order to facilitate exploration of their full therapeutic potential.
Topics: Animals; Cell Differentiation; Cytokines; Mammals; Muscle Cells; Muscle Development; Muscle, Skeletal; Regeneration
PubMed: 35073461
DOI: 10.1111/febs.16372 -
ELife Nov 2023In vitro culture systems that structurally model human myogenesis and promote PAX7 myogenic progenitor maturation have not been established. Here we report that human...
In vitro culture systems that structurally model human myogenesis and promote PAX7 myogenic progenitor maturation have not been established. Here we report that human skeletal muscle organoids can be differentiated from induced pluripotent stem cell lines to contain paraxial mesoderm and neuromesodermal progenitors and develop into organized structures reassembling neural plate border and dermomyotome. Culture conditions instigate neural lineage arrest and promote fetal hypaxial myogenesis toward limb axial anatomical identity, with generation of sustainable uncommitted PAX7 myogenic progenitors and fibroadipogenic (PDGFRa+) progenitor populations equivalent to those from the second trimester of human gestation. Single-cell comparison to human fetal and adult myogenic progenitor /satellite cells reveals distinct molecular signatures for non-dividing myogenic progenitors in activated (//) and dormant (//) states. Our approach provides a robust 3D in vitro developmental system for investigating muscle tissue morphogenesis and homeostasis.
Topics: Humans; Muscle, Skeletal; Cell Differentiation; Fetus; Satellite Cells, Skeletal Muscle; Muscle Development; PAX7 Transcription Factor
PubMed: 37963071
DOI: 10.7554/eLife.87081