scholarly journals Nuclear Mechanotransduction in Skeletal Muscle

Cells ◽  
2021 ◽  
Vol 10 (2) ◽  
pp. 318
Author(s):  
Saline Jabre ◽  
Walid Hleihel ◽  
Catherine Coirault
Keyword(s):  
Skeletal Muscle ◽  
Cell Fate ◽  
Myogenic Differentiation ◽  
Chromatin Condensation ◽  
Biological Response ◽  
Nuclear Lamina ◽  
Quiescent State ◽  
Force Transmission ◽  
Muscle Plasticity ◽  
Cell Fate Decisions

Skeletal muscle is composed of multinucleated, mature muscle cells (myofibers) responsible for contraction, and a resident pool of mononucleated muscle cell precursors (MCPs), that are maintained in a quiescent state in homeostatic conditions. Skeletal muscle is remarkable in its ability to adapt to mechanical constraints, a property referred as muscle plasticity and mediated by both MCPs and myofibers. An emerging body of literature supports the notion that muscle plasticity is critically dependent upon nuclear mechanotransduction, which is transduction of exterior physical forces into the nucleus to generate a biological response. Mechanical loading induces nuclear deformation, changes in the nuclear lamina organization, chromatin condensation state, and cell signaling, which ultimately impacts myogenic cell fate decisions. This review summarizes contemporary insights into the mechanisms underlying nuclear force transmission in MCPs and myofibers. We discuss how the cytoskeleton and nuclear reorganizations during myogenic differentiation may affect force transmission and nuclear mechanotransduction. We also discuss how to apply these findings in the context of muscular disorders. Finally, we highlight current gaps in knowledge and opportunities for further research in the field.

scholarly journals The LINC complex transmits integrin-dependent tension to the nuclear lamina and represses epidermal differentiation

2020 ◽  
Author(s):  
Emma Carley ◽  
Rachel K. Stewart ◽  
Abigail Zieman ◽  
Iman Jalilian ◽  
Diane. E. King ◽  
...  
Keyword(s):  
Cell Fate ◽  
Control Cell ◽  
Nuclear Lamina ◽  
Epidermal Differentiation ◽  
Keratinocyte Differentiation ◽  
Linc Complex ◽  
Force Transmission ◽  
Cell Fate Decisions

AbstractWhile the mechanisms by which chemical signals control cell fate have been well studied, how mechanical inputs impact cell fate decisions are not well understood. Here, using the well-defined system of keratinocyte differentiation in the skin, we examine whether and how direct force transmission to the nucleus regulates epidermal cell fate. Using a molecular biosensor, we find that tension on the nucleus through Linker of Nucleoskeleton and Cytoskeleton (LINC) complexes requires integrin engagement in undifferentiated epidermal stem cells, and is released during differentiation concomitant with decreased tension on A-type lamins. LINC complex ablation in mice reveals that LINC complexes are required to repress epidermal differentiation in vivo and in vitro and influence accessibility of epidermal differentiation genes, suggesting that force transduction from engaged integrins to the nucleus plays a role in maintaining keratinocyte progenitors. This work reveals a direct mechanotransduction pathway capable of relaying adhesion-specific signals to regulate cell fate.

scholarly journals The LINC complex transmits integrin-dependent tension to the nuclear lamina and represses epidermal differentiation

eLife ◽  
2021 ◽  
Vol 10 ◽  
Author(s):  
Emma Carley ◽  
Rachel Stewart ◽  
Abigail G Zieman ◽  
Iman Jalilian ◽  
Diane E King ◽  
...  
Keyword(s):  
Cell Fate ◽  
Control Cell ◽  
Nuclear Lamina ◽  
Epidermal Differentiation ◽  
Keratinocyte Differentiation ◽  
Linc Complex ◽  
Force Transmission ◽  
Cell Fate Decisions

While the mechanisms by which chemical signals control cell fate have been well studied, how mechanical inputs impact cell fate decisions are not well understood. Here, using the well-defined system of keratinocyte differentiation in the skin, we examine whether and how direct force transmission to the nucleus regulates epidermal cell fate. Using a molecular biosensor, we find that tension on the nucleus through Linker of Nucleoskeleton and Cytoskeleton (LINC) complexes requires integrin engagement in undifferentiated epidermal stem cells, and is released during differentiation concomitant with decreased tension on A-type lamins. LINC complex ablation in mice reveals that LINC complexes are required to repress epidermal differentiation in vivo and in vitro and influence accessibility of epidermal differentiation genes, suggesting that force transduction from engaged integrins to the nucleus plays a role in maintaining keratinocyte progenitors. This work reveals a direct mechanotransduction pathway capable of relaying adhesion-specific signals to regulate cell fate.

scholarly journals Modulation of Muscle Regeneration, Myogenesis, and Adipogenesis by the Rho Family Guanine Nucleotide Exchange Factor GEFT

2005 ◽  
Vol 25 (24) ◽  
pp. 11089-11101 ◽  
Author(s):  
Brad A. Bryan ◽  
Dianne C. Mitchell ◽  
Lei Zhao ◽  
Wenbin Ma ◽  
Lewis J. Stafford ◽  
...  
Keyword(s):  
Skeletal Muscle ◽  
Cell Fate ◽  
Muscle Regeneration ◽  
Mesenchymal Cell ◽  
Skeletal Muscle Regeneration ◽  
Guanine Nucleotide ◽  
Nucleotide Exchange ◽  
Cell Fate Decisions ◽  
Guanine Nucleotide Exchange ◽  
Rho Family

ABSTRACT Rho family guanine nucleotide exchange factors (GEFs) regulate diverse cellular processes including cytoskeletal reorganization, cell adhesion, and differentiation via activation of the Rho GTPases. However, no studies have yet implicated Rho-GEFs as molecular regulators of the mesenchymal cell fate decisions which occur during development and repair of tissue damage. In this study, we demonstrate that the steady-state protein level of the Rho-specific GEF GEFT is modulated during skeletal muscle regeneration and that gene transfer of GEFT into cardiotoxin-injured mouse tibialis anterior muscle exerts a powerful promotion of skeletal muscle regeneration in vivo. In order to molecularly characterize this regenerative effect, we extrapolate the mechanism of action by examining the consequence of GEFT expression in multipotent cell lines capable of differentiating into a number of cell types, including muscle and adipocyte lineages. Our data demonstrate that endogenous GEFT is transcriptionally upregulated during myogenic differentiation and downregulated during adipogenic differentiation. Exogenous expression of GEFT promotes myogenesis of C2C12 cells via activation of RhoA, Rac1, and Cdc42 and their downstream effector proteins, while a dominant-negative mutant of GEFT inhibits this process. Moreover, we show that GEFT inhibits insulin-induced adipogenesis in 3T3L1 preadipocytes. In summary, we provide the first evidence that the Rho family signaling pathways act as potential regulators of skeletal muscle regeneration and provide the first reported molecular mechanism illustrating how a mammalian Rho family GEF controls this process by modulating mesenchymal cell fate decisions.

scholarly journals Satellite Cells in Skeletal Muscle of the Hibernating Dormouse, a Natural Model of Quiescence and Re-Activation: Focus on the Cell Nucleus

Cells ◽  
2020 ◽  
Vol 9 (4) ◽  
pp. 1050
Author(s):  
Manuela Malatesta ◽  
Manuela Costanzo ◽  
Barbara Cisterna ◽  
Carlo Zancanaro
Keyword(s):  
Skeletal Muscle ◽  
Satellite Cells ◽  
Myogenic Differentiation ◽  
Mrna Transcription ◽  
Muscle Plasticity ◽  
Quiescent Cells ◽  
Slowing Down ◽  
Nuclear Changes ◽  
Processing Factors ◽  
Perichromatin Granules

Satellite cells (SCs) participate in skeletal muscle plasticity/regeneration. Activation of SCs implies that nuclear changes underpin a new functional status. In hibernating mammals, periods of reduced metabolic activity alternate with arousals and resumption of bodily functions, thereby leading to repeated cell deactivation and reactivation. In hibernation, muscle fibers are preserved despite long periods of immobilization. The structural and functional characteristics of SC nuclei during hibernation have not been investigated yet. Using ultrastructural and immunocytochemical analysis, we found that the SCs of the hibernating edible dormouse, Glis glis, did not show apoptosis or necrosis. Moreover, their nuclei were typical of quiescent cells, showing similar amounts and distributions of heterochromatin, pre-mRNA transcription and processing factors, as well as paired box protein 7 (Pax7) and the myogenic differentiation transcription factor D (MyoD), as in euthermia. However, the finding of accumulated perichromatin granules (i.e., sites of storage/transport of spliced pre-mRNA) in SC nuclei of hibernating dormice suggested slowing down of the nucleus-to-cytoplasm transport. We conclude that during hibernation, SC nuclei maintain similar transcription and splicing activity as in euthermia, indicating an unmodified status during immobilization and hypometabolism. Skeletal muscle preservation during hibernation is presumably not due to SC activation, but rather to the maintenance of some functional activity in myofibers that is able to counteract muscle wasting.

scholarly journals Diversity of Nuclear Lamin A/C Action as a Key to Tissue-Specific Regulation of Cellular Identity in Health and Disease

2021 ◽  
Vol 9 ◽  
Author(s):  
Anna Malashicheva ◽  
Kseniya Perepelina
Keyword(s):  
Cell Differentiation ◽  
Identity Development ◽  
Cell Fate ◽  
Critical Role ◽  
Nuclear Lamina ◽  
Lamin A ◽  
Cell Fate Decisions ◽  
Genes Encoding ◽  
Specific Regulation ◽  
Differentiation Status

A-type lamins are the main structural components of the nucleus, which are mainly localized at the nucleus periphery. First of all, A-type lamins, together with B-type lamins and proteins of the inner nuclear membrane, form a stiff structure—the nuclear lamina. Besides maintaining the nucleus cell shape, A-type lamins play a critical role in many cellular events, such as gene transcription and epigenetic regulation. Nowadays it is clear that lamins play a very important role in determining cell fate decisions. Various mutations in genes encoding A-type lamins lead to damages of different types of tissues in humans, collectively known as laminopathies, and it is clear that A-type lamins are involved in the regulation of cell differentiation and stemness. However, the mechanisms of this regulation remain unclear. In this review, we discuss how A-type lamins can execute their regulatory role in determining the differentiation status of a cell. We have summarized recent data focused on lamin A/C action mechanisms in regulation of cell differentiation and identity development of stem cells of different origin. We also discuss how this knowledge can promote further research toward a deeper understanding of the role of lamin A/C mutations in laminopathies.

scholarly journals RNA-Binding Proteins Direct Myogenic Cell Fate Decisions

2021 ◽  
Author(s):  
Joshua R. Wheeler ◽  
Oscar N. Whitney ◽  
Thomas O. Vogler ◽  
Eric D. Nguyen ◽  
Bradley Pawlikowski ◽  
...  
Keyword(s):  
Skeletal Muscle ◽  
Cell Fate ◽  
Tissue Regeneration ◽  
Neuromuscular Disease ◽  
Binding Proteins ◽  
Rna Binding ◽  
Rna Binding Proteins ◽  
Myogenic Cell ◽  
Skeletal Muscle Regeneration ◽  
Cell Fate Decisions

ABSTRACTRNA-binding proteins (RBPs) are essential for skeletal muscle regeneration and RBP dysfunction causes muscle degeneration and neuromuscular disease. How ubiquitously expressed RBPs orchestrate complex tissue regeneration and direct cell fate decisions in skeletal muscle remains poorly understood. Single cell RNA-sequencing of regenerating skeletal muscle reveals that RBP expression, including numerous neuromuscular disease-associated RBPs, is temporally regulated in skeletal muscle stem cells and correlates to stages of myogenic differentiation. By combining machine learning with RBP engagement scoring, we discover that the neuromuscular disease associated RBP Hnrnpa2b1 is a differentiation-specifying regulator of myogenesis controlling myogenic cell fate transitions during terminal differentiation. The timing of RBP expression specifies cell fate transitions by providing a layer of post-transcriptional regulation needed to coordinate stem cell fate decisions during complex tissue regeneration.

scholarly journals An Overview About the Biology of Skeletal Muscle Satellite Cells

2019 ◽  
Vol 20 (1) ◽  
pp. 24-37 ◽  
Author(s):  
Laura Forcina ◽  
Carmen Miano ◽  
Laura Pelosi ◽  
Antonio Musarò
Keyword(s):  
Skeletal Muscle ◽  
Stem Cells ◽  
Satellite Cell ◽  
Muscle Tissue ◽  
Satellite Cells ◽  
Cell Biology ◽  
Regulatory Networks ◽  
Myogenic Differentiation ◽  
Cell Activity ◽  
Quiescent State

The peculiar ability of skeletal muscle tissue to operate adaptive changes during post-natal development and adulthood has been associated with the existence of adult somatic stem cells. Satellite cells, occupying an exclusive niche within the adult muscle tissue, are considered bona fide stem cells with both stem-like properties and myogenic activities. Indeed, satellite cells retain the capability to both maintain the quiescence in uninjured muscles and to be promptly activated in response to growth or regenerative signals, re-engaging the cell cycle. Activated cells can undergo myogenic differentiation or self-renewal moving back to the quiescent state. Satellite cells behavior and their fate decision are finely controlled by mechanisms involving both cell-autonomous and external stimuli. Alterations in these regulatory networks profoundly affect muscle homeostasis and the dynamic response to tissue damage, contributing to the decline of skeletal muscle that occurs under physio-pathologic conditions. Although the clear myogenic activity of satellite cells has been described and their pivotal role in muscle growth and regeneration has been reported, a comprehensive picture of inter-related mechanisms guiding muscle stem cell activity has still to be defined. Here, we reviewed the main regulatory networks determining satellite cell behavior. In particular, we focused on genetic and epigenetic mechanisms underlining satellite cell maintenance and commitment. Besides intrinsic regulations, we reported current evidences about the influence of environmental stimuli, derived from other cell populations within muscle tissue, on satellite cell biology.

scholarly journals Arsenic Directs Stem Cell Fate by Imparting Notch Signaling Into the Extracellular Matrix Niche

2020 ◽  
Vol 177 (2) ◽  
pp. 494-505
Author(s):  
Teresa Anguiano ◽  
Amrita Sahu ◽  
Baoli Qian ◽  
Wan-Yee Tang ◽  
Fabrisia Ambrosio ◽  
...  
Keyword(s):  
Skeletal Muscle ◽  
Extracellular Matrix ◽  
Stem Cell ◽  
Cell Fate ◽  
Disease Risk ◽  
Myogenic Differentiation ◽  
Muscle Metabolism ◽  
Muscle Stem Cells ◽  
Skeletal Muscle Dysfunction ◽  
Cell Niche

Abstract Compromise of skeletal muscle metabolism and composition may underlie the etiology of cardiovascular and metabolic disease risk from environmental arsenic exposures. We reported that arsenic impairs muscle maintenance and regeneration by inducing maladaptive mitochondrial phenotypes in muscle stem cells (MuSC), connective tissue fibroblasts (CTF), and myofibers. We also found that arsenic imparts a dysfunctional memory in the extracellular matrix (ECM) that disrupts the MuSC niche and is sufficient to favor the expansion and differentiation of fibrogenic MuSC subpopulations. To investigate the signaling mechanisms involved in imparting a dysfunctional ECM, we isolated skeletal muscle tissue and CTF from mice exposed to 0 or 100 μg/l arsenic in their drinking water for 5 weeks. ECM elaborated by arsenic-exposed CTF decreased myogenesis and increased fibrogenic/adipogenic MuSC subpopulations and differentiation. However, treating arsenic-exposed mice with SS-31, a mitochondrially targeted peptide that repairs the respiratory chain, reversed the arsenic-promoted CTF phenotype to one that elaborated an ECM supporting normal myogenic differentiation. SS-31 treatment also reversed arsenic-induced Notch1 expression, resulting in an improved muscle regeneration after injury. We found that persistent arsenic-induced CTF Notch1 expression caused the elaboration of dysfunctional ECM with increased expression of the Notch ligand DLL4. This DLL4 in the ECM was responsible for misdirecting MuSC myogenic differentiation. These data indicate that arsenic impairs muscle maintenance and regenerative capacity by targeting CTF mitochondria and mitochondrially directed expression of dysfunctional regulators in the stem cell niche. Therapies that restore muscle cell mitochondria may effectively treat arsenic-induced skeletal muscle dysfunction and compositional decline.

scholarly journals APitx2-MicroRNA Pathway Modulates Cell Proliferation in Myoblasts and Skeletal-Muscle Satellite Cells and Promotes Their Commitment to a Myogenic Cell Fate

2015 ◽  
Vol 35 (17) ◽  
pp. 2892-2909 ◽  
Author(s):  
Estefanía Lozano-Velasco ◽  
Daniel Vallejo ◽  
Francisco J. Esteban ◽  
Chris Doherty ◽  
Francisco Hernández-Torres ◽  
...  
Keyword(s):  
Skeletal Muscle ◽  
Cell Proliferation ◽  
Cell Fate ◽  
Satellite Cell ◽  
Satellite Cells ◽  
Myogenic Cell ◽  
Quiescent State ◽  
Mirna Pathway ◽  
Microrna Pathway ◽  
Skeletal Muscle Stem Cells

The acquisition of a proliferating-cell status from a quiescent state as well as the shift between proliferation and differentiation are key developmental steps in skeletal-muscle stem cells (satellite cells) to provide proper muscle regeneration. However, how satellite cell proliferation is regulated is not fully understood. Here, we report that the c-isoform of the transcription factor Pitx2 increases cell proliferation in myoblasts by downregulating microRNA 15b (miR-15b), miR-23b, miR-106b, and miR-503. ThisPitx2c-microRNA (miRNA) pathway also regulates cell proliferation in early-activated satellite cells, enhancing Myf5+satellite cells and thereby promoting their commitment to a myogenic cell fate. This study reveals unknown functions of several miRNAs in myoblast and satellite cell behavior and thus may have future applications in regenerative medicine.

scholarly journals Protein arginine methyltransferase expression and activity during myogenesis

2018 ◽  
Vol 38 (1) ◽  
Author(s):  
Nicole Y. Shen ◽  
Sean Y. Ng ◽  
Stephen L. Toepp ◽  
Vladimir Ljubicic
Keyword(s):  
Skeletal Muscle ◽  
Muscle Development ◽  
Myogenic Differentiation ◽  
Muscle Differentiation ◽  
Type I ◽  
Protein Arginine Methyltransferases ◽  
Methyl Donors ◽  
Muscle Plasticity ◽  
Expression And Activity

Despite the emerging importance of protein arginine methyltransferases (PRMTs) in regulating skeletal muscle plasticity, PRMT biology during muscle development is complex and not completely understood. Therefore, our purpose was to investigate PRMT1, -4, and -5 expression and function in skeletal muscle cells during the phenotypic remodeling elicited by myogenesis. C2C12 muscle cell maturation, assessed during the myoblast (MB) stage, and during days 1, 3, 5, and 7 of differentiation, was employed as an in vitro model of myogenesis. We observed PRMT-specific patterns of expression and activity during myogenesis. PRMT4 and -5 gene expression was unchanged, while PRMT1 mRNA and protein content were significantly induced. Cellular monomethylarginines (MMAs) and symmetric dimethylarginines (SDMAs), indicative of global and type II PRMT activities, respectively, remained steady during development, while type I PRMT activity indicator asymmetric dimethylarginines (ADMAs) increased through myogenesis. Histone 4 arginine 3 (H4R3) and H3R17 contents were elevated coincident with the myonuclear accumulation of PRMT1 and -4. Collectively, this suggests that PRMTs are methyl donors throughout myogenesis and demonstrate specificity for their protein targets. Cells were then treated with TC-E 5003 (TC-E), a selective inhibitor of PRMT1 in order to specifically examine the enzymes role during myogenic differentiation. TC-E treated cells exhibited decrements in muscle differentiation, which were consistent with attenuated mitochondrial biogenesis and respiratory function. In summary, the present study increases our understanding of PRMT1, -4, and -5 biology during the plasticity of skeletal muscle development. Our results provide evidence for a role of PRMT1, via a mitochondrially mediated mechanism, in driving the muscle differentiation program.

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