RNF138 regulates skeletal muscle differentiation via the Wnt/β-catenin signaling pathway

作者：Wenhao Wang, Zhuohua Wang, Rui Li, Weiyi Huang, Qiao Ling, Xiaoxiao Li, Zan Li, Manqi Cao, Zhihui Zhang, Qingrong Sun, Zhijuan Liang, Hua-an Zhang, Xuan Jiang, Chuwen Lin, Yao-Qing Chen, Bo Zhao, Yu Zhao, Jian Pan, Xiaoxue Peng · 发表于：Theranostics · 年份：2025 · DOI：10.7150/thno.110925 · 被引用次数：5 · 研究领域：Muscle Physiology and Disorders、Genetics and Physical Performance

Rationale: Myogenesis is a strictly regulated process driven by signaling pathways activating muscle-specific gene expression.During myogenesis, muscle stem cells exhibit DNA damage response (DDR) features, which are essential for myoblast differentiation and skeletal muscle regeneration.However, the specific roles of DDR-associated proteins in these processes are not yet fully understood.Methods: Gene knockdown and knockout were used in cell and animal models to study RNF138's function in myoblast differentiation and skeletal muscle regeneration.Multi-omics profiling, including transcriptomics and proteomics, was conducted to identify the key proteins regulated by RNF138 in myogenesis.Protein turnover assays were utilized to investigate RNF138's role in APC protein turnover.Immunofluorescence microscopy was performed to confirm the protein colocalization and subcellular localization.Results: RNF138 expression increases during myoblast differentiation and in regenerating myofibers following muscle injury.Knockdown of RNF138 in C2C12 myoblasts impairs myogenic differentiation and fusion.Additionally, Rnf138-deficient mice exhibit delayed muscle regeneration following cardiotoxin-induced injury.Multi-omics profiling, including transcriptomics and proteomics, reveals that Wnt/-catenin signaling, a key driver of myogenic differentiation, is enhanced by RNF138.Mechanistically, RNF138 stabilizes -catenin and enhances its nuclear localization by facilitating lysosomal degradation of...