Role Of Musashi-2 In Skeletal Muscle Metabolism And Its Underlying Mechanism

Skeletal muscle is the largest organ regulating whole-body metabolism, and its metabolic capacity changes with exercise, nutrition, and disease. Discovering new master regulators of muscle quality may lead to new training methods and the prevention of metabolic syndrome. Musashi-2 (Msi2) is an RNA-binding protein that influences neuronal cell differentiation by regulating protein translation through binding specific mRNAs. We found that Msi2 is expressed in skeletal muscle cells, with higher expression in slow-twitch muscles than in fast-twitch muscles. However, the role of Msi2 in skeletal muscle remains unknown. PURPOSE: The purpose of this study is to elucidate the function of Msi2 in skeletal muscle metabolism.s METHODS: Biochemical and histological analyses were performed on soleus muscles from Msi2-knockout (KO) and wild-type (WT) mice. The Msi2 gene was transferred to the tibialis anterior muscle by DNA electroporation. Satellite cells isolated from WT and KO mice were differentiated into myotubes, and metabolism-related protein expression was compared between genotypes. RESULTS: The soleus muscle of Msi2 KO mice appeared paler than the typical red color in WT mice. Histology showed a significant reduction in type IIa fibers (-43.4%, p < 0.05), known for high metabolic capacity, in KO mice. Myoglobin, an oxygen-binding protein, was reduced in the KO soleus muscle (-50.0%, p < 0.05), while Msi2 overexpression increased myoglobin in the tibialis anterior (+26.7%, p < 0.05). KO-derived myotubes also exhibited reduced myoglobin (-69.5%, p < 0.05), suggesting that Msi2 directly affects oxidative phosphorylation in skeletal muscle cells. CONCLUSIONS: Msi2 plays a role in the metabolic properties of skeletal muscle, particularly in maintaining type IIa fibers and regulating the expression of energy metabolism-related proteins like myoglobin. Msi2 could be a target for improving muscle metabolic capacity and supporting muscle homeostasis. Supported by: grants from the Japan Society for the Promotion of Science, the FOREST Program of the Japan Science and Technology Agency