<br>Filamin C通过稳定dishevelled-2抑制自噬和线粒体自噬来调节骨骼肌萎缩,Molecular Therapy - Nucleic Acids

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Filamin C通过稳定dishevelled-2抑制自噬和线粒体自噬来调节骨骼肌萎缩
Molecular Therapy - Nucleic Acids ( IF 6.5 ) Pub Date : 2021-11-29 , DOI: 10.1016/j.omtn.2021.11.022
Shunshun Han ₁ , Can Cui ₁ , Xiyu Zhao ₁ , Yao Zhang ₁ , Yun Zhang ₂ , Jing Zhao ₁ , Xiaoxu Shen ₁ , Haorong He ₁ , Jianping Wang ₃ , Menggen Ma ₄ , Diyan Li ₁ , Qing Zhu ₁ , Huadong Yin ₁

Affiliation

FilaminC (Flnc) 是肌动蛋白结合蛋白家族的成员，优先在心肌和骨骼肌组织中表达。尽管已知它与肌原纤维肌病相关的蛋白质相互作用，但其在骨骼肌中的独特作用仍然很大程度上未知。在本研究中，我们分别使用鸡原代成肌细胞和动物模型鉴定了 Flnc 的生物学功能。从结果中我们观察到，生长速度快的鸡（肉鸡）骨骼肌的生长速度和质量显着高于生长速度慢的鸡（蛋鸡）。此外，我们发现Flnc在肉鸡骨骼肌中的表达高于蛋鸡。我们的结果表明，Flnc 在骨骼肌中高表达，尤其是在肉鸡骨骼肌中的表达量高于蛋鸡。这表明Flnc在成肌细胞发育中发挥着积极的调节作用。在动物模型中，Flnc 敲低会导致肌肉萎缩，而 Flnc 过度表达则会促进肌肉肥大。我们还发现Flnc与dishevelled-2 (Dvl2)相互作用，激活wnt/β-连环蛋白信号通路，并控制骨骼肌发育。 Flnc 还通过减少 Dvl2 泛素化来拮抗 LC3 介导的自噬系统。此外，Flnc 敲低激活并显着增加线粒体自噬。总之，这些结果表明 Flnc 的缺失会诱导自噬或线粒体自噬并调节肌肉萎缩。

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Filamin C regulates skeletal muscle atrophy by stabilizing dishevelled-2 to inhibit autophagy and mitophagy

FilaminC (Flnc) is a member of the actin binding protein family, which is preferentially expressed in the cardiac and skeletal muscle tissues. Although it is known to interact with proteins associated with myofibrillar myopathy, its unique role in skeletal muscle remains largely unknown. In this study, we identify the biological functions of Flnc and using chicken primary myoblast cells and animal models, respectively. From the results, we observe that the growth rate and mass of the skeletal muscle of fast-growing chickens (broilers) were significantly higher than those in slow-growing chickens (layers). Furthermore, we find that the expression of Flnc in the skeletal muscle of broilers was higher than that in the layers. Our results indicated that Flnc was highly expressed in the skeletal muscle, especially in the skeletal muscle of broilers than in layers. This suggests that Flnc plays a positive regulatory role in myoblast development. Flnc knockdown resulted in muscle atrophy, whereas the overexpression of Flnc promotes muscle hypertrophy in an animal model. We also found that Flnc interacted with dishevelled-2 (Dvl2), activated the wnt/β-catenin signaling pathway, and controlled skeletal muscle development. Flnc also antagonized the LC3-mediated autophagy system by decreasing Dvl2 ubiquitination. Moreover, Flnc knockdown activated and significantly increased mitophagy. In summary, these results indicate that the absence of Flnc induces autophagy or mitophagy and regulates muscle atrophy.

更新日期：2021-11-29

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