FGF8 rescues motor deficits in zebrafish model of limb-girdle muscular dystrophy R18
FGF8 rescues motor deficits in zebrafish model of limb-girdle muscular dystrophy R18
复制标题
FGF8 挽救肢带型肌营养不良症 R18 斑马鱼模型的运动缺陷
DOI：
10.1016/j.bbrc.2023.02.046
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发表时间：
2023
影响因子：
3.1
通讯作者：
Tse William Ka Fai
中科院分区：
文献类型：
--
作者：
Ulhaq Zulvikar Syambani;Ogino Yukiko;Tse William Ka Fai
编码转运蛋白颗粒复合体11 （TRAPPC11）的基因变异导致四肢带状肌营养不良R18 （LGMD R18）。虽然最近已经确定了几个与肌病相关的基因，但遗传原因和导致突变到疾病表型的信号事件之间的相关性仍然不清楚。在这里，我们利用斑马鱼通过使用反义介导的敲低策略特异性灭活trappc11来模拟LGMD R18，并评估了由此产生的肌肉表型。靶向消融trappc11显示由于肌肉组织紊乱和肌肉纤维化导致骨骼肌功能受损。我们的研究结果指出，缺乏功能性trappc11的鱼会抑制FGF8，从而导致Notch信号的异常激活，最终刺激骨骼肌上皮-间质转化（EMT）和纤维化变化。综上所述，我们的研究提供了FGF8在LGMD R18发病机制中的作用及其治疗潜力。
Variants in the gene encoding trafficking protein particle complex 11 (TRAPPC11) cause limb-girdle muscular dystrophy R18 (LGMD R18). Although recently several genes related to myopathies have been identified, correlations between genetic causes and signaling events that lead from mutation to the disease phenotype are still mostly unclear. Here, we utilized zebrafish to model LGMD R18 by specifically inactivatingtrappc11using antisense-mediated knockdown strategies and evaluated the resulting muscular phenotypes. Targeted ablation oftrappc11showed compromised skeletal muscle function due to muscle disorganization and myofibrosis. Our findings pinpoint that fish lacking functional trappc11 suppressed FGF8, which resulted in the aberrant activation of Notch signaling and eventually stimulated epithelial-mesenchymal transition (EMT) and fibrotic changes in the skeletal muscle. In summary, our study provides the role of FGF8 in the pathogenesis and its therapeutic potential of LGMD R18.