Institute of Neuromuscular and Neurodegenerative Diseases.
Brain Science Research Institute, Shandong University, Jinan, Shandong 250012, China.
Chin Med J (Engl). 2019 Apr 5;132(7):805-810. doi: 10.1097/CM9.0000000000000144.
Abnormally activated mechanistic target of rapamycin (mTOR) pathway has been reported in several model animals with inherited metabolic myopathies (IMMs). However, the profiles of mTOR pathway in skeletal muscles from patients are still unknown. This study aimed to analyze the activity of mTOR pathway in IMMs muscles.
We collected muscle samples from 25 patients with mitochondrial myopathy (MM), lipid storage disease (LSD) or Pompe disease (PD). To evaluate the activity of mTOR pathway in muscle specimens, phosphorylation of S6 ribosomal protein (p-S6) and p70S6 kinase (p-p70S6K) were analyzed by Western blotting and immunohistochemistry.
Western blotting results showed that p-p70S6K/p70S6K in muscles from LSD and MM was up-regulated when compared with normal controls (NC) (NC vs. LSD, U = 2.000, P = 0.024; NC vs. MM: U = 6.000, P = 0.043). Likewise, p-S6/S6 was also up-regulated in muscles from all three subgroups of IMMs (NC vs. LSD, U = 0.000, P = 0.006; NC vs. PD, U = 0.000, P = 0.006; NC vs. MM, U = 1.000, P = 0.007). Immunohistochemical study revealed that p-S6 was mainly expressed in fibers with metabolic defect. In MM muscles, most p-S6 positive fibers showed cytochrome C oxidase (COX) deficiency (U = 5.000, P = 0.001). In LSD and PD muscles, p-S6 was mainly overexpressed in fibers with intramuscular vacuoles containing lipid droplets (U = 0.000, P = 0.002) or basophilic materials (U = 0.000, P = 0.002).
The mTOR pathway might be activated in myofibers with various metabolic defects, which might provide evidence for mTOR inhibition therapy in human IMMs.
在几种遗传性代谢性肌病（IMM）的模型动物中，已报道异常激活的雷帕霉素靶蛋白（mTOR）通路。然而，患者骨骼肌中 mTOR 通路的特征仍不清楚。本研究旨在分析 IMM 肌肉中 mTOR 通路的活性。
我们收集了 25 例线粒体肌病（MM）、脂质贮积病（LSD）或庞贝病（PD）患者的肌肉样本。通过 Western 印迹和免疫组化分析，评估肌肉标本中 mTOR 通路的活性。
Western 印迹结果显示，与正常对照组（NC）相比，LSD 和 MM 肌肉中的 p-p70S6K/p70S6K 上调（NC 与 LSD 相比，U=2.000，P=0.024；NC 与 MM 相比，U=6.000，P=0.043）。同样，所有 IMM 亚组的 p-S6/S6 也上调（NC 与 LSD 相比，U=0.000，P=0.006；NC 与 PD 相比，U=0.000，P=0.006；NC 与 MM 相比，U=1.000，P=0.007）。免疫组化研究显示，p-S6 主要表达在代谢缺陷的纤维中。在 MM 肌肉中，大多数 p-S6 阳性纤维表现出细胞色素 C 氧化酶（COX）缺乏（U=5.000，P=0.001）。在 LSD 和 PD 肌肉中，p-S6 主要在含有脂滴的肌内空泡（U=0.000，P=0.002）或嗜碱性物质（U=0.000，P=0.002）的纤维中过度表达。
mTOR 通路可能在具有各种代谢缺陷的肌纤维中被激活，这可能为人类 IMM 中的 mTOR 抑制治疗提供证据。
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