Srf controls satellite cell fusion through the maintenance of actin architecture

Randrianarison-Huetz, Voahangy; Papaefthymiou, Aikaterini; Herledan, Gaëlle; Noviello, Chiara; Faradova, Ulduz; Collard, Laura; Pincini, Alessandra; Schol, Emilie; Decaux, Jean‐François; Maire, Pascal; Vassilopoulos, Stéphane; Sotiropoulos, Athanassia

doi:10.1083/jcb.201705130

Cited by 63 publications

(73 citation statements)

References 52 publications

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“…2). Our evidence implies that these filaments are lamellipodia resulting from actin polymerization, causing finger-like actinbased protrusions at the muscle cells' fusion sites [44,60,62]. This reorganization of actin cytoskeletal structures, as a result of actin or actin-regulatory protein phosphorylation, is mediated by the PI3K/Akt-signal-transduction pathway [63,64].…”

Section: Discussionmentioning

confidence: 70%

“…One of the reasons for this phenomenon might be impairment in the myotubes' ability to form actin filaments ( Fig. 2), which are crucial for cell movement and the cell-cell fusion process [44,45,[58][59][60]. It has also been demonstrated that under local membrane-injury protocols, dysferlin recruitment to the injury site is impaired if the formation of actin filament protrusions is inhibited [61].…”

Section: Discussionmentioning

confidence: 99%

“…2A) was viewed with no noticeable fusion connections to the adjacent muscle cells. However, in the halofuginone-treated myotubes, a myotube of similar size appeared to have many filaments, presumably actin filaments [44,[46][47][48], connecting it to other myotubes ( Fig. 2B, yellow arrows).…”

Section: Halofuginone Has a Promotive Effect On Dysf -/Myotube Fusionmentioning

confidence: 99%

“…The above results suggested a delay in myoblast differentiation and myotube fusion in cultures derived from dysf -/mice at as early as 5 weeks of age. The delay in fusion might be due to impaired cell-cell connections by actin filaments-finger-like actin-based protrusions that have a role in cell movement and cell-cell fusion in many cell types, including satellite cells [42][43][44][45].…”

Section: Halofuginone Has a Promotive Effect On Dysf -/Myotube Fusionmentioning

confidence: 99%

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Early pathological signs in youngdysf^−/−mice are improved by halofuginone

Barzilai-Tutsch

Genin

Pines

et al. 2019

Preprint

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AbstractDysferlinopathies are a non-lethal group of late-onset muscular dystrophies. Here, we evaluated the fusion ability of primary myoblasts from young dysf−/− mice and the muscle histopathology prior to, and during early stages of disease onset. The ability of primary myoblasts of 5-weekold dysf−/− mice to form large myotubes was delayed compared to their wild-type counterparts, as evaluated by scanning electron microscopy. However, their fusion activity, as reflected by the presence of actin filaments connecting several cells, was enhanced by the antifibrotic drug halofuginone. Early dystrophic signs were already apparent in 4-week-old dysf−/− mice; their collagen level was double that in wild-type mice and continued to rise until 5 months of age. Continuous treatment with halofuginone from 4 weeks to 5 months of age reduced muscle fibrosis in a phosphorylated-Smad3 inhibition-related manner. Halofuginone also enhanced myofiber hypertrophy, reduced the percentage of centrally nucleated myofibers, and increased muscle performance. Together, the data suggest an inhibitory effect of halofuginone on the muscle histopathology at very early stages of dysferlinopathy, and better generation of force and muscle performance. These results offer new opportunities for early pharmaceutical treatment in dysferlinopathies with favorable outcomes at later stages of life.

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Section: Discussionmentioning

confidence: 70%

Section: Discussionmentioning

confidence: 99%

Section: Halofuginone Has a Promotive Effect On Dysf -/Myotube Fusionmentioning

confidence: 99%

Section: Halofuginone Has a Promotive Effect On Dysf -/Myotube Fusionmentioning

confidence: 99%

See 2 more Smart Citations

Early pathological signs in youngdysf^−/−mice are improved by halofuginone

Barzilai-Tutsch

Genin

Pines

et al. 2019

Preprint

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“…3H; Fig. S7A; Movie 5,6). However, upon GTP addition, the disassembly of Shi rings resulted in the exposure of actin bundle sides, thus allowing robust branched actin polymerization from their sides ( Fig.…”

Section: Dynamin Bundles Actin Filaments In Vivomentioning

confidence: 95%

The mechanisms of dynamin-actin interaction

Zhang

Gerassimov

Lee

et al. 2019

Preprint

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Cell-cell fusion is an indispensable process in the conception, development and physiology of multicellular organisms. Here we demonstrate a direct and noncanonical role for dynamin, best known as a fission GTPase in endocytosis, in cell-cell fusion. Our genetic and cell biological analyses show that dynamin colocalizes within the F-actin-enriched podosome-like structures at the fusogenic synapse, which is required for generating invasive membrane protrusions and myoblast fusion in vivo, in an endocytosis-independent manner. Biochemical, negative stain EM and cryo-electron tomography (cryo-ET) analyses revealed that dynamin forms helices that directly bundles actin filaments by capturing multiple actin filaments at their outer rim via interactions with dynamin's proline-rich domain.GTP hydrolysis by dynamin triggers disassembly of the dynamin helix, exposes the sides of the actin filaments, promotes dynamic Arp2/3-mediated branched actin polymerization, and generates a mechanically stiff actin network. Thus, dynamin functions as a unique actin-bundling protein that enhances mechanical force generation by the F-actin network in a GTPase-dependent manner. Our findings have universal implications for understanding dynamin-actin interactions in various cellular processes beyond cell-cell fusion. 3Cell-cell fusion is essential for the conception, development, regeneration and physiology of multicellular organisms 1-3 . A common theme underlying cell-cell fusion events ranging from insects to mammals is the presence of actin-propelled invasive protrusions at the site of fusion, known as the fusogenic synapse 4-8 . Such invasive protrusions were first identified as part of an F-actin-enriched podosome-like structure (PLS) in Drosophila myoblast fusion 7 . The PLS is generated by an "attacking" fusion partner, the fusion-competent myoblast (FCM), which drills multiple invasive protrusions into the "receiving" fusion partner, the muscle founder cell, to promote cell membrane juxtaposition and fusion pore formation 7,9,10 . Although each protrusion has a diameter similar to that of a filopodium, these protrusions are mechanically stiffer and are capable of triggering mechanosensitive responses in the receiving cell 11 . Mechanoresponsive accumulations of myosin II and spectrin in the receiving cell, in turn, increase the cortical tension of the receiving cell, thus generating resisting forces against the invasive protrusions and bringing the two cell membranes to close proximity to promote cell fusion 11,12 .The invasive protrusions from the attacking cells are propelled by Arp2/3-mediated branched actin polymerization, which generates short actin filaments more suitable for mechanical work than long and linear filaments 9 . However, how the branched actin filaments are organized to generate mechanically stiff membrane protrusions during fusion is unknown.Dynamin (Dyn) is a large GTPase best known for its role in endocytosis. Dynamin catalyzes membrane fission by forming rings/helices around necks of a budding endocytic ve...

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Syndecan-4 affects myogenesis via Rac1-mediated actin remodeling and exhibits copy-number amplification and increased expression in human rhabdomyosarcoma tumors

Szabó

Varga

Végh

et al. 2022

Cell. Mol. Life Sci.

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Skeletal muscle demonstrates a high degree of regenerative capacity repeating the embryonic myogenic program under strict control. Rhabdomyosarcoma is the most common sarcoma in childhood and is characterized by impaired muscle differentiation. In this study, we observed that silencing the expression of syndecan-4, the ubiquitously expressed transmembrane heparan sulfate proteoglycan, significantly enhanced myoblast differentiation, and fusion. During muscle differentiation, the gradually decreasing expression of syndecan-4 allows the activation of Rac1, thereby mediating myoblast fusion. Single-molecule localized superresolution direct stochastic optical reconstruction microscopy (dSTORM) imaging revealed nanoscale changes in actin cytoskeletal architecture, and atomic force microscopy showed reduced elasticity of syndecan-4-knockdown cells during fusion. Syndecan-4 copy-number amplification was observed in 28% of human fusion-negative rhabdomyosarcoma tumors and was accompanied by increased syndecan-4 expression based on RNA sequencing data. Our study suggests that syndecan-4 can serve as a tumor driver gene in promoting rabdomyosarcoma tumor development. Our results contribute to the understanding of the role of syndecan-4 in skeletal muscle development, regeneration, and tumorigenesis.

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Srf controls satellite cell fusion through the maintenance of actin architecture

Abstract: This work describes a crucial role for the transcription factor Srf and F-actin scaffold to drive muscle stem cell fusion in vitro and in vivo and provides evidence of how actin cytoskeleton architecture affects myoblast fusion in vertebrates.

Cited by 63 publications

References 52 publications

Early pathological signs in youngdysf^−/−mice are improved by halofuginone

Early pathological signs in youngdysf^−/−mice are improved by halofuginone

The mechanisms of dynamin-actin interaction

Syndecan-4 affects myogenesis via Rac1-mediated actin remodeling and exhibits copy-number amplification and increased expression in human rhabdomyosarcoma tumors

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Srf controls satellite cell fusion through the maintenance of actin architecture

Abstract: This work describes a crucial role for the transcription factor Srf and F-actin scaffold to drive muscle stem cell fusion in vitro and in vivo and provides evidence of how actin cytoskeleton architecture affects myoblast fusion in vertebrates.

Cited by 63 publications

References 52 publications

Early pathological signs in youngdysf−/−mice are improved by halofuginone

Early pathological signs in youngdysf−/−mice are improved by halofuginone

The mechanisms of dynamin-actin interaction

Syndecan-4 affects myogenesis via Rac1-mediated actin remodeling and exhibits copy-number amplification and increased expression in human rhabdomyosarcoma tumors

Contact Info

Product

Resources

About

Early pathological signs in youngdysf^−/−mice are improved by halofuginone

Early pathological signs in youngdysf^−/−mice are improved by halofuginone