fhl2b expression ameliorates muscular dystrophy [5dpf trunk]

In muscle dystrophies, muscle fibers loose integrity and die, leading to significant suffering and a shorter life. Strikingly, the extraocular muscles (EOMs), controlling eye movements, are spared and function well despite the disease progression. Although EOMs have been shown to have important differences compared to body musculature the mechanisms underlying this inherent resistance to muscle dystrophies remain largely unknown. Here, we demonstrate important differences in gene expression as a response to muscle dystrophies between the EOMs and trunk muscle in zebrafish via transcriptomic profiling. We show that the LIM-protein Fhl2 is upregulated in response to knockout of desmin, plectin and obscurin, intermediate filament proteins causing different muscle dystrophies, and contributes to disease protection of the EOMs. Moreover, we show that ectopic expression of fhl2b can partially rescue the muscle phenotype in the zebrafish Duchenne muscular dystrophy model sapje, significantly improving their survival rate. Therefore, fhl2 is a protective agent and a candidate target gene for therapy of muscle dystrophies. To examine the effect of fhl2b overexpression in muscle in the background of the dmd/sapje mutant line at 5 dpf

在肌肉营养不良症中，肌纤维会丧失结构完整性并发生坏死，进而引发剧烈病痛并缩短患者生存期。值得注意的是，负责眼球运动的眼外肌（extraocular muscles, EOMs）即便在疾病进展过程中也可免受病变累及，始终维持正常功能。尽管已有研究证实眼外肌与躯干骨骼肌存在显著差异，但这类肌肉固有的抗肌肉营养不良症的分子机制仍未被完全阐明。本研究通过转录组分析，揭示了斑马鱼眼外肌与躯干肌在应对肌肉营养不良症时的基因表达差异。我们发现，LIM结构域蛋白Fhl2在敲除结蛋白（desmin）、网蛋白（plectin）以及obscurin后表达会上调，而该蛋白可参与介导眼外肌的疾病保护效应。此外，我们证实异位表达fhl2b基因可部分挽救斑马鱼杜氏肌营养不良症模型sapje的肌肉表型，显著提升其存活率。综上，fhl2是一种肌肉保护因子，可作为肌肉营养不良症治疗的候选靶基因。为探究在受精后5天（5 days post fertilization, 5 dpf）时，dmd/sapje突变体背景下肌肉中fhl2b过表达的效应