Abstract
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.
Highlights
A population of resident stem cells accounts for skeletal muscle plasticity, maintenance, and regeneration [1, 2]
The satellite cells are quiescent in the healthy muscle; they are stimulated by local damage to proliferate extensively and form myoblasts that will subsequently migrate, differentiate, and fuse to form muscle fibers (Fig. 1a)
To monitor the process of myoblast differentiation, we evaluated the amount of three myogenic transcription factors, Myf5, MyoD, MyoG, and desmin, a muscle-specific intermediate filament
Summary
A population of resident stem cells (i.e., satellite cells) accounts for skeletal muscle plasticity, maintenance, and regeneration [1, 2]. Satellite cells are mitotically and physiologically quiescent in healthy muscles until stimulated by local damage. After a skeletal muscle injury, an intense regenerative program is initiated. The transcription factors that regulate myogenesis and muscle differentiation include members of the MyoD family [MyoD, Myf, MRF4, and MyoG (myogenin)], known as myogenic regulatory factors (MRFs). MRFs appear in distinctive spatial and temporal patterns during embryonic development and regeneration of striated muscle. Myf and MyoD are expressed earlier, whereas MyoG and MRF4 are expressed later in somatic cells during limb development and differentiation of in vitro cell cultures [4]
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