Combined magnesium and silicon ions synergistically promote functional regeneration of skeletal muscle by regulating satellite cell fate

Abstract Muscle satellite cells (MuSCs) play a vital role in skeletal muscle regeneration. However, in intractable muscle diseases such as volumetric muscle loss (VML), the quantity and function of MuSCs are significantly reduced, severely limiting the body's inherent muscle regeneration capability. In this study, we propose a novel strategy to modulate the fate of MuSCs using a combination of bioactive magnesium (Mg) and silicon (Si) ions, sustainably delivered through magnesium silicate (MgSiO3, MS) bioceramic-based scaffolds. In vitro, Mg and Si ions synergistically promote the proliferation and differentiation of MuSCs. Similarly, Mg and Si ions derived from MS/poly(L-lactic acid) (MS/PLLA) composite scaffold also increase the proliferation and differentiation ability of MuSCs. Furthermore, MS/PLLA composite scaffolds facilitate the activation of MuSCs, regeneration of muscle fiber and neovascularization, while inhibiting fibrosis, thereby effectively restoring muscle function and promoting tibialis anterior muscle functional regeneration in a VML mouse model. Mechanistically, the combination of Mg and Si ions promotes the activation and proliferation of MuSCs by activating the Notch1-Hes1 pathway. Besides, the combination of Mg and Si ions also improves the differentiation of MuSCs by up-regulating Myod and Myog, and enhances fusion by up-regulating Mymk and Mymx expression. The outcomes of our research introduce a promising approach to the treatment of skeletal muscle injuries and related diseases.