Systemic effect of FHL1 on neuromuscular junction and myotube formation via insulin-like growth factor and myostatin signaling pathways
Systemic effect of FHL1 on neuromuscular junction and myotube formation via insulin-like growth factor and myostatin signaling pathways
复制标题
FHL1 通过胰岛素样生长因子和肌生长抑制素信号通路对神经肌肉接头和肌管形成的全身影响
DOI：
10.1016/j.bbrc.2020.12.061
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发表时间：
2021
影响因子：
3.1
通讯作者：
肖啸
中科院分区：
文献类型：
--
作者：
吴佳梅;赵锴;杜增民;陈颖;张飞旭;蒋威;郑静;吴侠;沈成勇;肖啸
FHL 1是FHL蛋白家族的成员，作为支架蛋白维持正常的细胞结构和功能。它的突变与多种肌肉疾病有关。这些FHL 1相关肌病的特征在于症状，如进行性肌肉损失，僵硬或弯曲的脊柱，甚至在一些患者中的心脏或呼吸衰竭，这意味着不仅在肌肉中，而且在神经系统中的病理问题。此外，在具有FHL 1突变的患者中发现FHL 1蛋白水平降低，表明蛋白功能丧失是此类疾病的病理原因。这些发现提示了理解FHL 1在神经系统和肌肉稳态中的系统性作用的重要性。在此我们报道了C2 C12肌管中Fhl 1的缺失除了与MuSK磷酸化受损相关的肌管融合外，还掩盖了乙酰胆碱受体（AChR）的聚集。从机制上讲，在Fhl 1 −/− C2 C12肌管中，肌生长抑制素-SMAD 2/3信号传导增强，而IGF-PI 3 K-AKT信号传导受到抑制。逆转这些分子改变拯救AChR集群和分化赤字。这些结果表明FHL 1对AChR成簇和肌管融合具有系统性调节作用，为FHL 1相关肌病的机制研究和治疗策略的制定提供了线索。
Four-and-a-half LIM domain protein 1 (FHL1) is a member of the FHL protein family that serves as a scaffold protein to maintain normal cellular structure and function. Its mutations have been implicated in multiple muscular diseases. These FHL1 related myopathies are characterized by symptoms such as progressive muscle loss, rigid or bent spine, even cardiac or respiratory failure in some patients, which implies pathological problems not only in muscles, but also in the nervous system. Moreover, decreased FHL1 protein level has been found in patients with FHL1 mutations, indicating the protein loss-of-function as a pathological cause of such diseases. These findings suggest the significance of understanding the systemic role of FHL1 in the homeostasis of nervous system and muscle. Here we reported thatFhl1loss in C2C12 myotubes obscured acetylcholine receptor (AChR) clustering in addition to myotube fusion, which was associated with impaired MuSK phosphorylation. Mechanistically, myostatin-SMAD2/3 signaling was enhanced, whereas IGF-PI3K-AKT signaling was suppressed inFhl1−/−C2C12 myotubes. Reversion of these molecular alterations rescued AChR clustering and differentiation deficits. These data outline a systemic regulation of AChR clustering and myotube fusion by FHL1, which may offer clues for mechanism study and development of therapeutic strategies to treat FHL1 related myopathies.