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

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.

Syndecan-4 Modulates Cell Polarity and Migration by Influencing Centrosome Positioning and Intracellular Calcium Distribution

“…Although syndecan-4 knockout mice cannot regenerate damaged muscle tissue (Cornelison et al, 2004), the details of the underlying mechanism remain unknown. Previously, we reported that syndecan-4 affects myoblast proliferation by modulating myostatin signaling and the G1/S transition in cell cycle (Keller-Pinter et al, 2018), and directional persistence of random cell migration is affected by syndecan-4-mediated Tiam-1 expression and distribution (Becsky et al, 2020). In this study, we demonstrated that syndecan-4 knockdown induced nanoscale alterations in the lamellipodial actin fiber structure of migrating myoblasts.…”

“…Here we show the effect of syndecan-4 silencing on Ca 2+ distribution, centrosome positioning, and actin nanostructure after 8 h directional migration following wound scratching. Interestingly, the average speed values of the migrating C2C12 cells were similar in the case of both random (Becsky et al, 2020) and directional migration.…”

“…Given the importance of syndecan-4 in cell migration and cytoskeletal organization, we hypothesized that this proteoglycan would affect cellular polarity, centrosome positioning, and intracellular Ca 2+ distribution during cell migration. We recently reported that syndecan-4 affects random migration and the directional persistence of migration in C2C12 cells during 18 h movement (Becsky et al, 2020). Here we show the effect of syndecan-4 silencing on Ca 2+ distribution, centrosome positioning, and actin nanostructure after 8 h directional migration following wound scratching.…”

Rac1, A Potential Target for Tumor Therapy

“…In the process of long-distance extension of cells, it is necessary to protrude a wide and flat flaky prosthetic foot on the cell surface, and Rac1 is needed to form this structure (21,22). The finger-like structures formed in lamellipodium is called filopodia, which is regulated by Cdc42 and participates in cell adhesion (23). Due to different environments, migrating cells present morphological differences (such as expansion, contraction and polarization), which are controlled by the activity levels of cytoskeleton regulatory protein Rho-GTPase (24).…”

IL-1β and TNF-α Modulation of Proliferated and Committed Myoblasts: IL-6 and COX-2-Derived Prostaglandins as Key Actors in the Mechanisms Involved

“…Skeletal muscle is a dynamic tissue with the ability to regenerate successfully following injury and to adapt in response to growth or exercise. Skeletal muscle stem cells, also named satellite cells, are the main drivers of the plasticity, maintenance, and regeneration of skeletal muscle [ 1 , 2 , 3 ]. Under resting conditions, these cells are mitotically and physiologically quiescent, but in response to increased physiological muscle loading or injury, they are activated and re-enter the cell cycle to generate satellite cell-derived myoblasts.…”