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Anaplerotic Triheptanoin Diet Enhances Mitochondrial Substrate Use to Remodel the Metabolome and Improve Lifespan, Motor Function, and Sociability in MeCP2-Null Mice

Title
Anaplerotic Triheptanoin Diet Enhances Mitochondrial Substrate Use to Remodel the Metabolome and Improve Lifespan, Motor Function, and Sociability in MeCP2-Null Mice
Authors
Park, MJ[Park, Min Jung]Aja, S[Aja, Susan]Li, Q[Li, Qun]Degano, AL[Degano, Alicia L.]Penati, J[Penati, Judith]Zhuo, J[Zhuo, Justin]Roe, CR[Roe, Charles R.]Ronnett, GV[Ronnett, Gabriele V.]
DGIST Authors
Ronnett, GV[Ronnett, Gabriele V.]
Issue Date
2014-10-09
Citation
PLoS ONE, 9(10)
Type
Article
Article Type
Article
ISSN
1932-6203
Abstract
Rett syndrome (RTT) is an autism spectrum disorder (ASD) caused by mutations in the X-linked MECP2 gene that encodes methyl-CpG binding protein 2 (MeCP2). Symptoms range in severity and include psychomotor disabilities, seizures, ataxia, and intellectual disability. Symptom onset is between 6-18 months of age, a critical period of brain development that is highly energy-dependent. Notably, patients with RTT have evidence of mitochondrial dysfunction, as well as abnormal levels of the adipokines leptin and adiponectin, suggesting overall metabolic imbalance. We hypothesized that one contributor to RTT symptoms is energy deficiency due to defective nutrient substrate utilization by the TCA cycle. This energy deficit would lead to a metabolic imbalance, but would be treatable by providing anaplerotic substrates to the TCA cycle to enhance energy production. We show that dietary therapy with triheptanoin significantly increased longevity and improved motor function and social interaction in male mice hemizygous for Mecp2 knockout. Anaplerotic therapy in Mecp2 knockout mice also improved indicators of impaired substrate utilization, decreased adiposity, increased glucose tolerance and insulin sensitivity, decreased serum leptin and insulin, and improved mitochondrial morphology in skeletal muscle. Untargeted metabolomics of liver and skeletal muscle revealed increases in levels of TCA cycle intermediates with triheptanoin diet, as well as normalizations of glucose and fatty acid biochemical pathways consistent with the improved metabolic phenotype in Mecp2 knockout mice on triheptanoin. These results suggest that an approach using dietary supplementation with anaplerotic substrate is effective in improving symptoms and metabolic health in RTT.
URI
http://hdl.handle.net/20.500.11750/2640
DOI
10.1371/journal.pone.0109527
Publisher
Public Library of Science
Files:
There are no files associated with this item.
Collection:
Brain and Cognitive SciencesETC1. Journal Articles


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