Creatine transporter deficiency impairs stress adaptation and brain energetics homeostasis

• Type of Material: Article
• Authors: Hong-Ru Chen, University of Virginia; Xiaohui Zhang-Brotzge, Emory University; Yury M. Morozov, Yale University; Yuancheng Li, Emory University; Siming Wang, Georgia State University; Helen Heju Zhang, Gene Edit Biolab; Irene S. Kuan, Emory University; Elizabeth M. Fugate, Cincinnati Children's Hospital Medical Center; Hui Mao, Emory University; Yu-Yo Sun, Emory University; Pasko Rakic, Yale University; Diana M. Lindquist, Cincinnati Children's Hospital Medical Center; Antonuis DeGrauw, Emory University; Chia-Yi Kuan, Emory University
• Language: English
• Date: 2021-09-08
• Publisher: AMER SOC CLINICAL INVESTIGATION INC
• Publication Version: Final Published Version
• Copyright Statement: © 2021 Chen et al.
• License: Creative Commons Attribution 4.0 International
• Final Published Version (URL): http://dx.doi.org/10.1172/jci.insight.140173
• Title of Journal or Parent Work: JCI INSIGHT
• Volume: 6
• Issue: 17
• Grant/Funding Information: This work was supported by a Brain Research Foundation grant (BRFSG-2015-11 to CYK) and NIH grants (NS108763, NS095064, NS100419, and NS084744 to CYK; DA023999 to PR; and NS106592 to YYS).
• Keywords: AUTOPHAGY; METABOLITE; PERFORMANCE; Research & Experimental Medicine; GUANIDINOACETATE; Life Sciences & Biomedicine; ENERGY; MITOCHONDRIA; SUPPLEMENTATION; INJURY; PHOSPHORYLATION; MUSCLE; Science & Technology; Medicine, Research & Experimental
• Research Categories: Biology, Cell; Biology, Neuroscience

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/Nacetylaspartate 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.