Creatine transport and pathological changes in creatine transporter deficient mice

J Inherit Metab Dis. 2021 Jul;44(4):939-948. doi: 10.1002/jimd.12358. Epub 2021 Mar 3.


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.

Keywords: Slc6a8; brain; creatine; creatine transporter; skeletal muscle; vacuolar myopathy.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Brain Diseases, Metabolic, Inborn / genetics*
  • Brain Diseases, Metabolic, Inborn / pathology
  • Chromatography, Liquid
  • Creatine / deficiency*
  • Creatine / genetics
  • Mental Retardation, X-Linked / genetics*
  • Mental Retardation, X-Linked / pathology
  • Mice
  • Mice, Knockout
  • Plasma Membrane Neurotransmitter Transport Proteins / deficiency*
  • Plasma Membrane Neurotransmitter Transport Proteins / genetics
  • Tandem Mass Spectrometry


  • Plasma Membrane Neurotransmitter Transport Proteins
  • Creatine

Supplementary concepts

  • Creatine deficiency, X-linked