Creatine transport and pathological changes in creatine transporter deficient mice

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.