Effect of Oral Creatine Supplementation on Plasma, Central, and Peripheral Creatine Levels in Creatine Transporter Deficiency Mice

PURPOSE: Creatine transporter deficiency (CRTD) is characterized by severe brain creatine depletion due to creatine transporter (CRT) dysfunction. Although oral creatine supplementation has been explored as a therapy, its effects under CRT-deficient conditions remain unclear. Here, we aimed to investigate the impact of oral creatine supplementation on creatine distribution in plasma, brain, and peripheral tissues using CRTD model mice. RESULTS: Oral creatine supplementation significantly increased plasma creatine in both CRT-KO and CRT-KI mice but failed to restore creatine levels in the brain. Conversely, creatine levels increased markedly in the liver and kidney. Urinary creatine and the creatine-to-creatinine ratio, a key diagnostic biomarker for CRTD, were substantially elevated, exceeding diagnostic thresholds even in WT mice. CONCLUSIONS: Oral creatine increases systemic creatine but fails to restore brain creatine under CRT-deficient conditions, underscoring the crucial role of CRT-mediated blood-brain barrier (BBB) uptake and the need to restore creatine transport across the BBB to elevate brain creatine levels. Furthermore, creatine intake should be controlled for proper diagnostic biomarker interpretation.