Metabolic remodeling agents show beneficial effects in the dystrophin-deficient mdx mouse model.
Metabolic remodeling agents show beneficial effects in the dystrophin-deficient mdx mouse model.
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DOI：
10.1186/2044-5040-2-16
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发表时间：
2012-08-21
期刊：
影响因子：
4.9
通讯作者：
Nagaraju K
中科院分区：
文献类型：
--
作者：
Jahnke VE;Van Der Meulen JH;Johnston HK;Ghimbovschi S;Partridge T;Hoffman EP;Nagaraju K
杜氏肌营养不良症是一种遗传性疾病，涉及严重的肌肉萎缩，其特点是肌肉退化/再生循环，最终导致患病男孩过早死亡。线粒体被认为参与了成肌细胞增殖/分化的调控；在健康小鼠中，用运动模拟物（AMPK和ppar - δ激动剂）增强线粒体活性可增加肌肉功能并抑制肌肉萎缩。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。12周龄mdx小鼠分别或联合使用两种不同的代谢重塑剂（GW501516和AICAR）治疗4周。进行了广泛的系统行为、功能、组织学、生化和分子试验来评估药物的作用。我们发现所有接受治疗的小鼠的体重和肌肉重量都有所增加。组织学检查显示肌肉炎症减少，中心核纤维数量减少，外周核纤维数量增加，活化的卫星细胞和再生纤维明显减少。再加上fox01信号的抑制，这些结果表明，这些治疗减少了持续的肌肉损伤。这三种治疗方法显著改善了疾病表型，包括整体行为活动的增加和前肢和后肢力量的显著增加。我们的研究结果表明，用运动模拟物触发线粒体活动可以改善肌营养不良蛋白缺乏的mdx小鼠的肌肉功能。
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. 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. 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. 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.
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影响因子：
64.5
作者：
Narkar VA;Downes M;Yu RT;Embler E;Wang YX;Banayo E;Mihaylova MM;Nelson MC;Zou Y;Juguilon H;Kang H;Shaw RJ;Evans RM
通讯作者：
Evans RM
DOI：
10.1016/j.bbrc.2009.06.053
发表时间：
2009-08-28
影响因子：
3.1
作者：
Onopiuk, Marta;Brutkowski, Wojciech;Zablocki, Krzysztof
通讯作者：
Zablocki, Krzysztof
影响因子：
4.8
作者：
Lecker, SH;Jagoe, RT;Goldberg, AL
通讯作者：
Goldberg, AL
影响因子：
--
作者：
Dressel, U;Allen, TL;Muscat, GEO
通讯作者：
Muscat, GEO
影响因子：
4.8
作者：
Coll, Teresa;Alvarez-Guardia, David;Vazquez-Carrera, Manuel
通讯作者：
Vazquez-Carrera, Manuel