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Creatine transport and pathological changes in creatine transporter deficient mice
Adam M Wawro1, Chandresh R Gajera1, Steven A Baker1
1Department of Pathology, Stanford University, Stanford, California, USA.
Abstract:
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.
Insights
Creatine transporter deficiency in Slc6a8-/y mice leads to shortened lifespan, growth deficits, and muscle disease. These mice exhibit varied creatine uptake, impacting their use in drug discovery for brain function disorders.
Area of Science:
- Neuroscience
- Genetics
- Biochemistry
Background:
- Creatine (Cr) transporter deficiency severely impacts brain function, with limited therapeutic options.
- Existing Slc6a8 knockout mouse models show behavioral changes but lack comprehensive data on creatine levels, histopathology, and uptake.
Purpose of the Study:
- To characterize the Slc6a8-/y mouse model for creatine transporter deficiency.
- To assess survival, creatine levels, creatine uptake, and histopathological changes in this model.
Main Methods:
- Utilized liquid chromatography coupled with tandem mass spectrometry to measure endogenous creatine and deuterium-labeled creatine (Cr-d3) uptake.
- Performed comprehensive histopathological examinations.
- Monitored survival and growth parameters.
Main Results:
- Slc6a8-/y mice displayed organ-specific variations in Cr-d3 uptake.
- Significant growth reduction was observed, excluding the brain.
- Progressive vacuolar myopathy and a markedly shortened lifespan were noted.
Conclusions:
- The Slc6a8-/y mouse model exhibits distinct physiological and pathological characteristics relevant to creatine transporter deficiency.
- Varied creatine uptake across organs presents challenges for drug discovery applications.
- This model offers insights into the disease but requires careful consideration of its limitations.
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