title: Anaplerotic triheptanoin diet enhances mitochondrial substrate use to remodel the metabolome and improve lifespan, motor function, and sociability in MeCP2-null mice.
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.
authors.affiliation: The Center for Metabolism and Obesity Research, The Johns Hopkins University, School of Medicine, Baltimore, MD, United States of America; Department of Neuroscience, The Johns Hopkins University, School of Medicine, Baltimore, MD, United States of America.
authors.forename: Min Jung
authors.initials: MJ
authors.lastname: Park
authors.affiliation: The Center for Metabolism and Obesity Research, The Johns Hopkins University, School of Medicine, Baltimore, MD, United States of America; Department of Neuroscience, The Johns Hopkins University, School of Medicine, Baltimore, MD, United States of America.
authors.forename: Susan
authors.initials: S
authors.lastname: Aja
authors.affiliation: The Center for Metabolism and Obesity Research, The Johns Hopkins University, School of Medicine, Baltimore, MD, United States of America; Department of Neuroscience, The Johns Hopkins University, School of Medicine, Baltimore, MD, United States of America.
authors.forename: Qun
authors.initials: Q
authors.lastname: Li
authors.affiliation: The Center for Metabolism and Obesity Research, The Johns Hopkins University, School of Medicine, Baltimore, MD, United States of America; Department of Neuroscience, The Johns Hopkins University, School of Medicine, Baltimore, MD, United States of America; Departamento de Química Biológica, CIQUIBIC-CONICET, Universidad Nacional de Córdoba, Córdoba, Argentina.
authors.forename: Alicia L
authors.initials: AL
authors.lastname: Degano
authors.affiliation: Department of Neuroscience, The Johns Hopkins University, School of Medicine, Baltimore, MD, United States of America.
authors.forename: Judith
authors.initials: J
authors.lastname: Penati
authors.affiliation: Department of Neuroscience, The Johns Hopkins University, School of Medicine, Baltimore, MD, United States of America.
authors.forename: Justin
authors.initials: J
authors.lastname: Zhuo
authors.affiliation: The Center for Metabolism and Obesity Research, The Johns Hopkins University, School of Medicine, Baltimore, MD, United States of America; Department of Neuroscience, The Johns Hopkins University, School of Medicine, Baltimore, MD, United States of America.
authors.forename: Charles R
authors.initials: CR
authors.lastname: Roe
authors.affiliation: The Center for Metabolism and Obesity Research, The Johns Hopkins University, School of Medicine, Baltimore, MD, United States of America; Department of Neuroscience, The Johns Hopkins University, School of Medicine, Baltimore, MD, United States of America; Department of Neurology, The Johns Hopkins University, School of Medicine, Baltimore, MD, United States of America; Department of Biological Chemistry, The Johns Hopkins University, School of Medicine, Baltimore, MD, United States of America; Department of Brain Sciences, DGIST, Daegu, South Korea.
authors.forename: Gabriele V
authors.initials: GV
authors.lastname: Ronnett
mesh_terms: D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects; D002952:Citric Acid Cycle / Q000187:drug effects* / Q000235:genetics; D004032:Diet; D004195:Disease Models, Animal; D015870:Gene Expression; D006801:Humans; D050356:Lipid Metabolism / Q000187:drug effects; D008136:Longevity / Q000187:drug effects*; D008297:Male; D055442:Metabolome / Q000187:drug effects; D051783:Methyl-CpG-Binding Protein 2 / Q000172:deficiency / Q000235:genetics*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009043:Motor Activity / Q000187:drug effects*; D010641:Phenotype; D015518:Rett Syndrome / Q000178:diet therapy* / Q000235:genetics / Q000503:physiopathology / Q000523:psychology; D014280:Triglycerides / Q000008:administration & dosage*
chemical_list: C497393:Mecp2 protein, mouse; D051783:Methyl-CpG-Binding Protein 2; D014280:Triglycerides; C531010:triheptanoin