Syndecan-4–/– Mice Have Smaller Muscle Fibers, Increased Akt/mTOR/S6K1 and Notch/HES-1 Pathways, and Alterations in Extracellular Matrix Components

Abstract

Background: Extracellular matrix (ECM) remodeling is essential for skeletal muscle development and adaption in response to environmental cues such as exercise and injury. The cell surface proteoglycan syndecan-4 has been reported to be essential for muscle differentiation, but few molecular mechanisms are known. Syndecan-4 −/− mice are unable to regenerate damaged muscle, and display deficient satellite cell activation, proliferation, and differentiation. A reduced myofiber basal lamina has also been reported in syndecan-4 −/− muscle, indicating possible defects in ECM production. To get a better understanding of the underlying molecular mechanisms, we have here investigated the effects of syndecan-4 genetic ablation on molecules involved in ECM remodeling and muscle growth, both under steady state conditions and in response to exercise. Methods: Tibialis anterior (TA) muscles from sedentary and exercised syndecan-4 −/− and WT mice were analyzed by immunohistochemistry, real-time PCR and western blotting. Results: Compared to WT, we found that syndecan-4 −/− mice had reduced body weight, reduced muscle weight, muscle fibers with a smaller cross-sectional area, and reduced expression of myogenic regulatory transcription factors. Sedentary syndecan-4 −/− had also increased mRNA levels of syndecan-2, decorin, collagens, fibromodulin, biglycan, and LOX. Some of these latter ECM components were reduced at protein level, suggesting them to be more susceptible to degradation or less efficiently translated when syndecan-4 is absent. At the protein level, TRPC7 was reduced, whereas activation of the Akt/mTOR/S6K1 and Notch/HES-1 pathways were increased. Finally,

Serum syndecan‐4 is associated with nonalcoholic fatty liver disease

“…38 Encoding actinins, cadherins and calcium channel subunits, which are molecules involved in cell-matrix and cell-cell adhesions, and are therefore likely to interact functionally with SDC4. 44,45 In this study we demonstrated that SDC4 has a high predictive ability for NAFLD.…”

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

“…They described that the absence of syndecan-4 reduces the degree of barium chloride-induced muscle regeneration compared to that in the wild type. Comparing normal and syndecan-4 KO mice, Ronning et al revealed decreased MyoD and MyoG expression and smaller myotube cross-sectional area in syndecan-4 KO [ 36 , 54 ]. Importantly, during in vivo studies, the migratory ability of the cells also have high impact for the fusion events.…”

“…Importantly, during in vivo studies, the migratory ability of the cells also have high impact for the fusion events. Our previous results indicated that silencing syndecan-4 expression reduces the migration of mammalian myoblasts in vitro [ 26 , 27 ], which may explain the reduced regeneration and myotube formation in syndecan-4 KO mice [ 36 , 54 ].…”

The female syndecan-4−/− heart has smaller cardiomyocytes, augmented insulin/pSer473-Akt/pSer9-GSK-3β signaling, and lowered SCOP, pThr308-Akt/Akt and GLUT4 levels

“…Supporting a central role of syndecan-4 in stress sensing via connections in the ECM, we recently observed that syndecan-4 ablation in skeletal muscle resulted in smaller muscle fibers, alterations in ECM components and an elevated Ser473-Akt phosphorylation (pSer473-Akt) ( Rønning et al, 2020 ). The upregulation of pSer473-Akt was accompanied by an increase in phosphorylation of downstream components of Akt signaling such as mTOR and RPS6 ( Rønning et al, 2020 ).…”