O-Glucose glycan modification was first discovered in Japan in the epidermal growth factor-like domain of blood coagulation factors [1]. Two xylose residues extend O-glucose via α1,3 linkages, forming a linear trisaccharide structure. The discovery and functional analysis of the protein O-glucosyltransferase POGLUT1, which is responsible for the transfer of O-glucose, has shown that O-glucose glycan modification is essential for the activation of Notch signaling in Drosophila and mice [2, 3]. Mutations in POGLUT1 cause limb-girdle muscular dystrophy type R21 in humans (Fig. 81.1) [4, 5]. In these patients, a decrease in POGLUT1 enzyme activity results in a decrease in Notch signaling and the number of satellite cells, which are stem cells of the skeletal muscle. In addition, a decrease in the binding ability of laminin ligands due to a decrease in matriglycan, the core M3 type O-mannose glycan, expressed on α-dystroglycan in muscle fibers is observed. Furthermore, a unique progressive fatty degeneration from the inside to the outside is observed in the skeletal muscles of patients. These studies are advancing our understanding of the control mechanisms of stem cell functions, including satellite cells and mesenchymal progenitor cells, while also clarifying the homeostasis and pathology of skeletal muscles, areas that have been receiving increasing attention in recent years.