The severe impact on brain function and lack of effective therapy for patients with creatine (Cr) transporter deficiency motivated the generation of three ubiquitous Slc6a8 deficient mice (−/y). While each mouse knock-out line has similar behavioral effects at 2 to 3 months of age, other features critical to the efficient use of these mice in drug discovery are unclear or lacking: the concentration of Cr in brain and heart differ widely between mouse lines, there are limited data on histopathologic changes, and no data on Cr uptake. Here, we determined survival, measured endogenous Cr and uptake of its deuterium-labeled analogue Cr-d3 using a liquid chromatography coupled with tandem mass spectrometry assay, and performed comprehensive histopathologic examination on the Slc6a8^−/y mouse developed by Skelton et al. Our results show that Slc6a8^−/y mice have widely varying organ-specific uptake of Cr-d3, significantly diminished growth with the exception of brain, progressive vacuolar myopathy, and markedly shortened lifespan.

中文翻译：

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肌酸转运蛋白缺陷小鼠的肌酸转运和病理变化

对脑功能的严重影响和肌酸 (Cr) 转运蛋白缺乏症患者缺乏有效治疗促使产生了三只普遍存在的 Slc6a8 缺陷小鼠 (-/y)。虽然每条小鼠基因敲除品系在 2 到 3 个月大时具有相似的行为影响，但对于这些小鼠在药物发现中的有效使用至关重要的其他特征尚不清楚或缺乏：大脑和心脏中 Cr 的浓度在小鼠品系之间差异很大，关于组织病理学变化的数据有限，没有关于 Cr 摄取的数据。在这里，我们使用液相色谱结合串联质谱分析测定了存活率，测量了内源性 Cr 和氘标记的类似物 Cr-d3 的摄取，并对Slc6a8 ^{-/y进行了全面的组织病理学检查}Skelton 等人开发的鼠标。我们的结果表明，Slc6a8 ^-/y小鼠对 Cr-d3 的器官特异性摄取差异很大，除脑外的生长显着减少，进行性空泡性肌病，寿命显着缩短。