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Myostatin and activin blockade by engineered follistatin results in hypertrophy and improves dystrophic pathology in mdx mouse more than myostatin blockade alone.
Skeletal Muscle ( IF 5.3 ) Pub Date : 2018-10-29 , DOI: 10.1186/s13395-018-0180-z
Andrea Iskenderian 1, 2 , Nan Liu 1, 2 , Qingwei Deng 2, 3 , Yan Huang 1, 2 , Chuan Shen 1, 2 , Kathleen Palmieri 2, 3 , Robert Crooker 2, 3 , Dianna Lundberg 1, 2 , Niksa Kastrapeli 1, 2 , Brian Pescatore 1, 2 , Alla Romashko 1, 2 , John Dumas 1, 2 , Robert Comeau 1, 2 , Angela Norton 1, 2 , Jing Pan 1, 2 , Haojing Rong 2, 4 , Katayoun Derakhchan 2, 4 , David E Ehmann 2, 3
Affiliation  

BACKGROUND Myostatin antagonists are being developed as therapies for Duchenne muscular dystrophy due to their strong hypertrophic effects on skeletal muscle. Engineered follistatin has the potential to combine the hypertrophy of myostatin antagonism with the anti-inflammatory and anti-fibrotic effects of activin A antagonism. METHODS Engineered follistatin was administered to C57BL/6 mice for 4 weeks, and muscle mass and myofiber size was measured. In the mdx model, engineered follistatin was dosed for 12 weeks in two studies comparing to an Fc fusion of the activin IIB receptor or an anti-myostatin antibody. Functional measurements of grip strength and tetanic force were combined with tissue analysis for markers of necrosis, inflammation, and fibrosis to evaluate improvement in dystrophic pathology. RESULTS In wild-type and mdx mice, dose-dependent increases in muscle mass and quadriceps myofiber size were observed for engineered follistatin. In mdx, increases in grip strength and tetanic force were combined with improvements in muscle markers for necrosis, inflammation, and fibrosis. Improvements in dystrophic pathology were greater for engineered follistatin than the anti-myostatin antibody. CONCLUSIONS Engineered follistatin generated hypertrophy and anti-fibrotic effects in the mdx model.

中文翻译:

工程卵泡抑素对肌生长抑制素和激活素的阻断作用比单独的肌生长抑制素阻断作用更能导致肥大,并改善mdx小鼠的营养不良病理。

背景技术由于肌生长抑制素拮抗剂对骨骼肌的强肥大作用,因此正在开发肌生长抑制素拮抗剂作为杜兴氏肌营养不良症的疗法。工程改造的卵泡抑素具有将肌生长抑制素拮抗作用的肥大与激活素A拮抗作用的抗炎和抗纤维化作用相结合的潜力。方法将工程卵泡抑素给予C57BL / 6小鼠4周,并测量肌肉质量和肌纤维大小。在mdx模型中,与激活素IIB受体或抗肌生长抑制素抗体的Fc融合物相比,在两项研究中,工程化的卵泡抑素的剂量为12周。抓握强度和强直力的功能测量与组织分析相结合,用于坏死,炎症和纤维化的标志物,以评估营养不良性病理的改善。结果在野生型和mdx小鼠中,工程卵泡抑素观察到肌肉质量和四头肌肌纤维大小的剂量依赖性增加。在mdx中,抓握强度和强直肌力量的增加与坏死,炎症和纤维化的肌肉标志物的改善相结合。工程卵泡抑素比抗肌生长抑制素抗体在营养不良病理方面的改善更大。结论工程性卵泡抑素在mdx模型中产生肥大和抗纤维化作用。
更新日期:2019-11-01
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