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Cited by 62Genetics and Neurodevelopmental DisordersMetabolism and Genetic DisordersMitochondrial Function and Pathology

Anaplerotic triheptanoin diet enhances mitochondrial substrate use to remodel the metabolome and improve lifespan, motor function, and sociability in MeCP2-null mice

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Park, Min Jung, Aja, Susan, Li, Qun, Degano, Alicia L., Penati, Judith, Zhuo, Justin, Roe, Charles R., Ronnett, Gabriele V.·2014·PLoS ONE
DOI 10.1371/journal.pone.0109527PMC PMC4192301
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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.

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  • A marginal increase in plasma cholesterol concentrations was reported for 49-day-old Mecp2−/y mice (Jaenisch allele) on a mixed strain background.

    “A marginal increase in plasma cholesterol concentrations was reported for 49-day-old Mecp2−/y mice (Jaenisch allele) on a mixed strain background (129/SvEv:C57BL/6:BALB/c) (Park et al., 2014).”

    From Suppression of brain cholesterol synthesis in male Mecp2-deficient mice is age dependent and not accompanied by a concurrent change in the rate of fatty acid synthesis (2017) · cites this paper as Park et al., 2014

    The Results (Figure 1K; page unavailable) report higher serum cholesterol in seven-week-old (49-day-old) Mecp2 KO mice than in four-week-old KO mice. The Animals section identifies the Jaenisch-derived mice and their mixed 129/SvEv–C57BL/6–BALB/c background. The paper does not characterize the cholesterol increase as marginal or report that seven-week-old KO mice had higher cholesterol than age-matched WT mice. (LLM, conf=0.83)

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Authors
Park, M. J., Aja, S., Li, Q., Degano, A. L., Penati, J., Zhuo, J., Roe, C. R., & Ronnett, G. V.
Affiliations
Johns Hopkins University (US)
Corresponding author
Aja, Susan
ORCID
Venue
PLoS ONE
Publisher
Public Library of Science (PLoS)
Published
2014-10-09
Volume
9
Issue
10
Pages
e109527
ISSN
1932-6203 (ISSN-L)
DOI
10.1371/journal.pone.0109527
PMC
PMC4192301
OpenAlex
W2029960467
Cited by
62
References
83
Citations by year
2026: 2 · 2025: 3 · 2024: 5 · 2023: 3 · 2022: 4 · 2021: 5 · 2020: 10 · 2019: 11 · 2018: 3 · 2017: 8 · 2016: 7 · 2015: 1
FWCI
3.50
Type
journal article
Language
en
Open access
Licence
Locations
  • PLoS ONE (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
  • Greater South Information System
Funders
  • Johns Hopkins University
  • Daegu Gyeongbuk Institute of Science and Technology
  • National Institutes of Health
  • National Institute of Diabetes and Digestive and Kidney Diseases (R01DK081472, P30DK079637)
  • National Institute of Neurological Disorders and Stroke (R01NS041079)
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetics and Neurodevelopmental Disorders
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Clinical Biochemistry › Metabolism and Genetic Disorders
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Mitochondrial Function and Pathology
Keywords
Rett syndrome, MeCP2, triheptanoin, TCA cycle, mitochondrial dysfunction, lifespan, motor function, social behavior, leptin, adiponectin, glucose tolerance, insulin sensitivity, skeletal muscle, liver metabolome, dietary therapy, autism spectrum disorder
MeSH terms
Animals, Behavior, Animal, Citric Acid Cycle, Diet, Disease Models, Animal, Humans, Longevity, Male, Mice, Inbred C57BL, Motor Activity, Phenotype, Triglycerides, Rett Syndrome, Gene Expression, Mice, Knockout, Lipid Metabolism, Mice, Methyl-CpG-Binding Protein 2, Metabolome

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