miR‐136‐5p/FZD4 axis is critical for Wnt signaling‐mediated myogenesis and skeletal muscle regeneration

• Published in: Journal of cellular physiology 2024-12, Vol.239 (12), p.e31046-n/a
• Main Authors: Zhang, Donghao, Yin, Lingqian, Lin, Zhongzhen, Yu, Chunlin, Li, Jingjing, Ren, Peng, Yang, Chaowu, Qiu, Mohan, Liu, Yiping
• Format: Article
• Language: English
• Subjects: Animal production; Animals; Barium chloride; beta Catenin - genetics; beta Catenin - metabolism; C2C12; Cell differentiation; Cell Differentiation - genetics; Cell Line; Cell proliferation; Cell Proliferation - genetics; Differentiation; Frizzled Receptors - genetics; Frizzled Receptors - metabolism; FZD4; Gastrocnemius muscle; Humans; Injuries; Male; Mice; Mice, Inbred C57BL; MicroRNAs - genetics; MicroRNAs - metabolism; miR‐136‐5p; Muscle Development - genetics; Muscle, Skeletal - metabolism; Muscles; Musculoskeletal system; Myoblasts; Myoblasts - metabolism; Myogenesis; Regeneration; Regeneration - genetics; Regeneration - physiology; Signal transduction; Skeletal muscle; skeletal muscle regeneration; Tcf protein; Transcription factors; Wnt protein; Wnt Signaling Pathway - genetics
• ISSN: 0021-9541; 1097-4652; 1097-4652
• DOI: 10.1002/jcp.31046

Skeletal muscle can undergo a regenerative process in response to injury or disease to maintain muscle quality and function. Myogenesis depends on the proliferation and differentiation of myoblasts, and miRNAs can maintain the balance between them by precisely regulating many key factors in the myogenic network. Here, we found that miR‐136‐5p was significantly upregulated during the proliferation and differentiation of C2C12 cells. We demonstrate that miR‐136‐5p acts as a myogenic negative regulator during the development of mouse C2C12 myoblasts. In terms of mechanism, miR‐136‐5p inhibits the formation of β‐catenin/LEF/TCF DNA‐binding factor transcriptional regulatory complex by targeting FZD4, a gating protein in the Wnt signaling pathway, thereby enhancing downstream myogenic factors and finally promoting myoblast proliferation and differentiation. In addition, in BaCl2‐induced muscle injury mouse model, miR‐136‐5p knockdown accelerated the regeneration of skeletal muscle after injury, and further led to the improvement of gastrocnemius muscle mass and muscle fiber diameter, while being suppressed by shFZD4 lentivirus infection. In summary, these results demonstrate the essential role of miR‐136‐5p/FZD4 axis in skeletal muscle regeneration. Given the conservation of miR‐136‐5p among species, miR‐136‐5p may be a new target for treating human skeletal muscle injury and improving the production of animal meat products.