Oxford Neuromuscular Centre, Department of Physiology, Anatomy and Genetics, University of Oxford, Oxford, OX1 3PT, UK.
Skelet Muscle. 2017 Oct 24;7(1):22. doi: 10.1186/s13395-017-0139-5.
Duchenne muscular dystrophy (DMD) is a lethal X-linked muscle wasting disorder caused by the absence of dystrophin, a large cytoskeletal muscle protein. Increasing the levels of the dystrophin-related-protein utrophin is a highly promising therapy for DMD and has been shown to improve pathology in dystrophin-deficient mice. One contributing factor to muscle wasting in DMD is mitochondrial pathology that contributes to oxidative stress and propagates muscle damage. The purpose of this study was to assess whether utrophin could attenuate mitochondria pathology and oxidative stress.
Skeletal muscles from wildtype C57BL/10, dystrophin-deficient mdx, dystrophin/utrophin double knockout (dko) and dystrophin-deficient mdx/utrophin over-expressing mdx-Fiona transgenic mice were assessed for markers of mitochondrial damage.
Using transmission electron microscopy, we show that high levels of utrophin ameliorate the aberrant structure and localisation of mitochondria in mdx mice whereas absence of utrophin worsened these features in dko mice. Elevated utrophin also reverts markers of protein oxidation and oxidative stress, elevated in mdx and dko mice, to wildtype levels. These changes were observed independently of a shift in oxidative phenotype.
These findings show that utrophin levels influence mitochondrial pathology and oxidative stress. While utrophin deficiency worsens the pathology, utrophin over-expression in dystrophic muscle benefits mitochondria and attenuates the downstream pathology associated with aberrant mitochondrial function.
杜氏肌营养不良症（DMD）是一种致命的 X 连锁肌肉消耗性疾病，由肌营养不良蛋白缺失引起，肌营养不良蛋白是一种大型细胞骨架肌肉蛋白。增加肌联蛋白相关蛋白 utrophin 的水平是治疗 DMD 的一种很有前途的方法，已被证明可改善肌营养不良蛋白缺乏的小鼠的病理。DMD 中肌肉消耗的一个促成因素是线粒体病理学，它会导致氧化应激并传播肌肉损伤。本研究的目的是评估 utrophin 是否可以减轻线粒体病理学和氧化应激。
评估野生型 C57BL/10、肌营养不良蛋白缺乏型 mdx、肌营养不良蛋白/肌联蛋白双敲除（dko）和肌营养不良蛋白缺乏型 mdx/utrophin 过表达 mdx-Fiona 转基因小鼠的骨骼肌中与线粒体损伤相关的标志物。
使用透射电子显微镜，我们发现高水平的 utrophin 可改善 mdx 小鼠中异常的线粒体结构和定位，而 utrophin 的缺失会使 dko 小鼠的这些特征恶化。utrophin 的升高还可使 mdx 和 dko 小鼠中升高的蛋白质氧化和氧化应激标志物恢复至野生型水平。这些变化与氧化表型的改变无关。
这些发现表明 utrophin 水平会影响线粒体病理学和氧化应激。虽然 utrophin 缺乏会加重病理，但在营养不良的肌肉中过表达 utrophin 可使线粒体受益，并减轻与异常线粒体功能相关的下游病理。
