State Key Laboratory for Conservation and Utilization of Subtropical Agro-Bioresources, College of Animal Science and Technology, Guangxi University, Nanning, China.
The Animal Husbandry Research Institute of Guangxi Zhuang Autonomous Region, Guangxi Agricultural Vocational University, Nanning, China.
FASEB J. 2024 Jul 31;38(14):e23808. doi: 10.1096/fj.202302599RR.
Muscle development is a multistep process regulated by diverse gene networks, and circRNAs are considered novel regulators mediating myogenesis. Here, we systematically analyzed the role and underlying regulatory mechanisms of circRBBP7 in myoblast proliferation and differentiation. Results showed that circRBBP7 has a typical circular structure and encodes a 13 -kDa protein. By performing circRBBP7 overexpression and RNA interference, we found that the function of circRBBP7 was positively correlated with the proliferation and differentiation of myoblasts. Using RNA sequencing, we identified 1633 and 532 differentially expressed genes (DEGs) during myoblast proliferation or differentiation, respectively. The DEGs were found mainly enriched in cell cycle- and skeletal muscle development-related pathways, such as the MDM2/p53 and PI3K-Akt signaling pathways. Further co-IP and IF co-localization analysis revealed that VEGFR-1 is a target of circRBBP7 in myoblasts. qRT-PCR and WB analysis further confirmed the positive correlation between VEGFR-1 and circRBBP7. Moreover, we found that in vivo transfection of circRBBP7 into injured muscle tissues significantly promoted the regeneration and repair of myofibers in mice. Therefore, we speculate that circRBBP7 may affect the activity of MDM2 by targeting VEGFR-1, altering the expression of muscle development-related genes by mediating p53 degradation, and ultimately promoting myoblast development and muscle regeneration. This study provides essential evidence that circRBBP7 can serve as a potential target for myogenesis regulation and a reference for the application of circRBBP7 in cattle genetic breeding and muscle injury treatment.
肌肉发育是一个由多种基因网络调控的多步骤过程，circRNAs 被认为是介导肌发生的新型调节因子。在这里，我们系统地分析了 circRBBP7 在成肌细胞增殖和分化中的作用及其潜在的调节机制。结果表明，circRBBP7 具有典型的环状结构，并编码一个 13kDa 的蛋白质。通过 circRBBP7 的过表达和 RNA 干扰实验，我们发现 circRBBP7 的功能与成肌细胞的增殖和分化呈正相关。通过 RNA 测序，我们分别在成肌细胞增殖或分化过程中鉴定出 1633 个和 532 个差异表达基因（DEGs）。DEGs 主要富集在细胞周期和骨骼肌发育相关途径中，如 MDM2/p53 和 PI3K-Akt 信号通路。进一步的 co-IP 和 IF 共定位分析表明，VEGFR-1 是成肌细胞中 circRBBP7 的靶基因。qRT-PCR 和 WB 分析进一步证实了 VEGFR-1 与 circRBBP7 之间的正相关关系。此外，我们发现将 circRBBP7 体内转染到受损的肌肉组织中显著促进了小鼠肌纤维的再生和修复。因此，我们推测 circRBBP7 可能通过靶向 VEGFR-1 影响 MDM2 的活性，通过介导 p53 降解改变肌肉发育相关基因的表达，最终促进成肌细胞的发育和肌肉再生。本研究为 circRBBP7 可作为肌发生调节的潜在靶点提供了重要依据，并为 circRBBP7 在牛遗传育种和肌肉损伤治疗中的应用提供了参考。
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