PDF(Pubmed)
Abstract：
In muscular dystrophies, muscle fibers loose integrity and die, causing significant suffering and premature death. Strikingly, the extraocular muscles (EOMs) are spared, functioning well despite the disease progression. Although EOMs have been shown to differ from body musculature, the mechanisms underlying this inherent resistance to muscle dystrophies remain unknown. Here, we demonstrate important differences in gene expression as a response to muscle dystrophies between the EOMs and trunk muscles in zebrafish via transcriptomic profiling. We show that the LIM-protein Fhl2 is increased in response to the knockout of desmin, plectin and obscurin, cytoskeletal proteins whose knockout causes 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. Therefore, Fhl2 is a protective agent and a candidate target gene for therapy of muscular dystrophies.
摘要：
在肌肉营养不良中，肌肉纤维松散的完整性和死亡，造成重大痛苦和过早死亡。引人注目的是，眼外肌(EOM)幸免，尽管疾病进展，但功能良好。尽管EOM已被证明与人体肌肉组织不同，这种对肌肉营养不良的固有抵抗力的潜在机制仍然未知。这里,我们通过转录组学分析证明了斑马鱼EOMs和躯干肌之间的基因表达对肌肉营养不良的反应的重要差异。我们表明LIM-蛋白Fhl2响应于desmin的敲除而增加，plectin和obsccurin,敲除导致不同肌肉营养不良的细胞骨架蛋白，并有助于EOM的疾病保护。此外，我们表明fhl2b的异位表达可以部分挽救斑马鱼Duchenne肌营养不良模型sapje的肌肉表型，显着提高他们的生存。因此,Fhl2是保护剂和用于治疗肌营养不良的候选靶基因。
