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Creatine transporter deficiency impairs stress adaptation and brain energetics homeostasis
Hong-Ru Chen, … , Ton DeGrauw, Chia-Yi Kuan
Hong-Ru Chen, … , Ton DeGrauw, Chia-Yi Kuan
Published July 29, 2021
Citation Information: JCI Insight. 2021;6(17):e140173. https://doi.org/10.1172/jci.insight.140173.
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Research Article Metabolism Neuroscience

Creatine transporter deficiency impairs stress adaptation and brain energetics homeostasis

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Abstract

The creatine transporter (CrT) maintains brain creatine (Cr) levels, but the effects of its deficiency on energetics adaptation under stress remain unclear. There are also no effective treatments for CrT deficiency, the second most common cause of X-linked intellectual disabilities. Herein, we examined the consequences of CrT deficiency in brain energetics and stress-adaptation responses plus the effects of intranasal Cr supplementation. We found that CrT-deficient (CrT–/y) mice harbored dendritic spine and synaptic dysgenesis. Nurtured newborn CrT–/y mice maintained baseline brain ATP levels, with a trend toward signaling imbalance between the p-AMPK/autophagy and mTOR pathways. Starvation elevated the signaling imbalance and reduced brain ATP levels in P3 CrT–/y mice. Similarly, CrT–/y neurons and P10 CrT–/y mice showed an imbalance between autophagy and mTOR signaling pathways and greater susceptibility to cerebral hypoxia-ischemia and ischemic insults. Notably, intranasal administration of Cr after cerebral ischemia increased the brain Cr/N-acetylaspartate ratio, partially averted the signaling imbalance, and reduced infarct size more potently than intraperitoneal Cr injection. These findings suggest important functions for CrT and Cr in preserving the homeostasis of brain energetics in stress conditions. Moreover, intranasal Cr supplementation may be an effective treatment for congenital CrT deficiency and acute brain injury.

Authors

Hong-Ru Chen, Xiaohui Zhang-Brotzge, Yury M. Morozov, Yuancheng Li, Siming Wang, Helen Heju Zhang, Irena S. Kuan, Elizabeth M. Fugate, Hui Mao, Yu-Yo Sun, Pasko Rakic, Diana M. Lindquist, Ton DeGrauw, Chia-Yi Kuan

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Figure 8

Post-stroke intranasal Cr delivery reduces brain injury and signaling imbalance.

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Post-stroke intranasal Cr delivery reduces brain injury and signaling im...
(A) CrT distribution in murine brain based on anti-CrT/anti–β-galactosidase immuno-EM labeling in CrT+/– mice. Arrows indicate robust immunoreaction deposits on the extracellular surface of endothelial cells in the blood vessel lumen (bvl) and endothelial basement membrane (bm). Scale bars: 1 μm. (B) CrT–/y neurons internalized Cr from the medium containing 500 μM Cr at approximately 40% efficiency compared with CrT+/y neurons (n = 3). (C and D) Cerebral blood flow (CBF) was evaluated by laser speckle contrast imaging (LSCI) immediately after photothrombosis and reassessed 24 hours later in CrT+/y and CrT–/y mice, with or without intranasal Cr supplementation (n = 4 for each condition). (E and F) Immunoblotting and quantification of the p-AMPK/autophagy and mTOR signaling pathway activity in stroke-injured CrT+/y and CrT–/y hemispheres, with or without intranasal Cr supplementation, at 24 hours of recovery. Intranasal Cr supplementation showed significant attenuation of stroke-induced p-AMPK/autophagy signaling and better-preserved mTOR activity. The violin plots in F are from 3 independent experiments; all other data are shown as mean ± SEM. Statistical significance was determined using Student’s t test (B) or 2-way ANOVA followed by Tukey’s multiple comparison post hoc test (D and F).

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