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Metabolic remodeling agents show beneficial effects in the dystrophin-deficient mdx mouse model

机译：代谢重塑剂在肌营养不良蛋白缺陷的mdx小鼠模型中显示出有益的作用

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Background Duchenne muscular dystrophy is a genetic disease involving a severe muscle wasting that is characterized by cycles of muscle degeneration/regeneration and culminates in early death in affected boys. Mitochondria are presumed to be involved in the regulation of myoblast proliferation/differentiation; enhancing mitochondrial activity with exercise mimetics (AMPK and PPAR-delta agonists) increases muscle function and inhibits muscle wasting in healthy mice. We therefore asked whether metabolic remodeling agents that increase mitochondrial activity would improve muscle function in mdx mice. Methods Twelve-week-old mdx mice were treated with two different metabolic remodeling agents (GW501516 and AICAR), separately or in combination, for 4 weeks. Extensive systematic behavioral, functional, histological, biochemical, and molecular tests were conducted to assess the drug(s)' effects. Results We found a gain in body and muscle weight in all treated mice. Histologic examination showed a decrease in muscle inflammation and in the number of fibers with central nuclei and an increase in fibers with peripheral nuclei, with significantly fewer activated satellite cells and regenerating fibers. Together with an inhibition of FoXO1 signaling, these results indicated that the treatments reduced ongoing muscle damage. Conclusions The three treatments produced significant improvements in disease phenotype, including an increase in overall behavioral activity and significant gains in forelimb and hind limb strength. Our findings suggest that triggering mitochondrial activity with exercise mimetics improves muscle function in dystrophin-deficient mdx mice.
机译：背景技术杜兴氏肌营养不良症是一种遗传性疾病，涉及严重的肌肉消瘦，其特征在于肌肉变性/再生的周期，并最终导致患病男孩的早期死亡。推测线粒体参与成肌细胞增殖/分化的调控;通过模拟运动（AMPK和PPAR-δ激动剂）增强线粒体活性，可以增强健康小鼠的肌肉功能并抑制肌肉消瘦。因此，我们询问增加线粒体活性的代谢重塑剂是否会改善mdx小鼠的肌肉功能。方法十二周龄mdx小鼠分别或联合使用两种不同的代谢重构剂（GW501516和AICAR）治疗4周。进行了广泛的系统行为，功能，组织学，生化和分子测试，以评估药物的作用。结果我们发现所有治疗小鼠的体重和体重都有增加。组织学检查显示，肌肉发炎的减少和中央核的纤维数量减少，而周围核的纤维增加，活化的卫星细胞和再生纤维明显减少。这些结果与对FoXO1信号的抑制一起表明，这些治疗减少了持续的肌肉损伤。结论三种治疗方法均能显着改善疾病的表型，包括总体行为活动的增加以及前肢和后肢力量的显着提高。我们的发现表明，通过模拟运动触发线粒体活动可改善肌营养不良蛋白缺乏症的mdx小鼠的肌肉功能。

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