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.
Highlights
Skeletal muscle is a highly dynamic tissue that can regenerate successfully following injury, and it can change in size in response to exercise, aging, or diseases
We verified the effect of syndecan-4 (SDC4) silencing by qPCR technique and Western blotting in C2C12 mouse myoblast cell lines transfected stably with plasmids expressing shRNA specific for syndecan-4, and we tested the effect of the scrambled sequence [24]
Tiam1 plays an essential role in pivotal biological processes and has been identified as a nucleotide exchange factor (GEF), a specific activator of the small GTPase Rac1 [11]; it is specific for Cdc42 and to a lesser extent, RhoA [30]
Summary
Skeletal muscle is a highly dynamic tissue that can regenerate successfully following injury, and it can change in size in response to exercise, aging, or diseases (e.g., cancer cachexia, immobilization, muscular dystrophy). The skeletal muscle stem cells, known as satellite cells, which are localized between the muscle fiber and basal lamina, are responsible for the plasticity, maintenance, and regeneration of skeletal muscle [1,2]. Cell movement is a complex process that plays an important role in various physiological processes including regeneration, wound healing, angiogenesis, embryonic development, and immune cell responses, in addition to tumor progression and metastasis formation. One of the most important conditions for cell movement is the polarization of the cell, in terms of morphology, with the formation of a leading edge at the front and a retracting tail, and the correct positioning of the cellular components [4]. The Rho family of small GTPases, including Rac (Ras-related C3 botulinum toxin substrate 1), Cdc, and RhoA, plays a fundamental role in the development and maintenance of this front-rear polarity [8]
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