Knockdown of optineurin controls C2C12 myoblast differentiation via regulating myogenin and MyoD expressions
Knockdown of optineurin controls C2C12 myoblast differentiation via regulating myogenin and MyoD expressions
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DOI：
10.1016/j.diff.2021.11.004
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发表时间：
2021-11-26
期刊：
影响因子：
2.9
通讯作者：
Maruyama, Hirofumi
中科院分区：
文献类型：
--
作者：
Ishikawa, Kenichi;Araki, Mutsuko;Maruyama, Hirofumi
在一小部分散发性和家族性肌萎缩侧索硬化症（ALS）病例中发现了视神经磷酸酶（OPTN）突变。最近的研究表明，OPTN不仅参与ALS运动神经元死亡的病理生理机制，而且参与散发性包涵体肌炎的肌纤维变性。然而，OPTN在肌肉中的详细作用仍不清楚。最初，我们发现OPTN表达水平在小鼠失神经肌肉中显著增加，表明OPTN可能参与肌肉稳态。为了揭示OPTN在肌肉萎缩中的分子作用，我们使用用肿瘤坏死因子样细胞凋亡诱导剂（TWEAK）处理的培养的C2C12肌管作为肌肉萎缩的体外模型。我们的数据表明，OPTN对该模型中肌肉萎缩的过程没有影响。另一方面，我们发现成肌分化受到OPTN的影响。免疫印迹分析显示OPTN蛋白水平在C2C12分化过程中逐渐下降。此外，OPTN敲低抑制C2C12分化，伴随着肌细胞生成素和MyoD的mRNA和蛋白质表达水平的降低。这些结果表明，OPTN可能在肌肉稳态中具有新的功能，并在神经肌肉疾病的发病机制中发挥作用。
Mutations in optineurin (OPTN) have been identified in a small proportion of sporadic and familial amyotrophic lateral sclerosis (ALS) cases. Recent evidences suggest that OPTN would be involved in not only the patho-physiological mechanisms of motor neuron death of ALS but also myofiber degeneration of sporadic inclusion body myositis. However, the detailed role of OPTN in muscle remains unclear. Initially, we showed that OPTN expression levels were significantly increased in the denervated muscles of mice, suggesting that OPTN may be involved in muscle homeostasis. To reveal the molecular role of OPTN in muscle atrophy, we used cultured C2C12 myotubes treated with tumor necrosis factor-like inducer of apoptosis (TWEAK) as an in vitro model of muscle atrophy. Our data showed that OPTN had no effect on the process of muscle atrophy in this model. On the other hand, we found that myogenic differentiation was affected by OPTN. Immunoblotting analysis showed that OPTN protein levels gradually decreased during C2C12 differentiation. Furthermore, OPTN knockdown inhibited C2C12 differentiation, accompanied by reduction of mRNA and protein expression levels of myogenin and MyoD. These findings suggested that OPTN may have a novel function in muscle homeostasis and play a role in the pathogenesis of neuromuscular diseases.