Syndecan-4 proteoglycan modulates glucose uptake and insulin sensitivity in myoblasts

Skeletal muscle glucose uptake is required for cellular metabolism and normalization of postprandial blood glucose levels. Transmembrane heparan sulfate proteoglycan syndecan-4 (SDC4) is important for muscle regeneration, cell interaction and structure, and it affects whole body metabolism, although the mechanism remains unclear. In this study, we demonstrated that SDC4 knock down increases glucose uptake by mammalian myoblasts (i.e., activated satellite cells). Silencing SDC4 increased the phosphorylation AS160 (Akt substrate of 160 kDa or TBC1D4), an important element of glucose transporter type 4 (GLUT4) translocation, and GLUT4 levels. These changes increased 2–deoxy-2–(¹⁸F)fluoro-D-glucose uptake by C2C12 myoblasts independent of insulin treatment. Mitochondrial routine respiration, electron transport system, reserve capacity, and oxidative phosphorylation were also increased following SDC4 silencing. SDC4 knockdown cells exhibited a higher GLUT4 density along the plasma membrane compared with behind it. Super-resolution direct stochastic optical reconstruction microscopy (dSTORM) imaging revealed an increased number of skeletons of the actin network following insulin treatment, but not in SDC4-silenced cells. Notably, knocking down SDC4 increased the insulin sensitivity of the cells. Our results suggest that this new mechanism can increase glucose uptake through insulin-independent signal transduction.

Proteomics data.