Rett syndrome (RTT) is an autism spectrum disorder (ASD) caused by

Rett syndrome (RTT) is an autism spectrum disorder (ASD) caused by mutations in the X-linked gene that encodes methyl-CpG binding protein 2 (MeCP2). and interpersonal interaction in male mice hemizygous for knockout. Anaplerotic therapy in 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 Dalcetrapib 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 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. Introduction Rett syndrome (RTT Online Mendelian Inheritance in Man 312750) is an autism spectrum disorder (ASD) that results in severe cognitive and motor disabilities seizures and loss of language[1]-[5]. The vast majority of RTT cases are caused by mutations in the X-linked gene for methyl-CpG binding protein 2 (MeCP2) a member of a family of transcriptional factors that binds methyl-CpG DNA base pairs[6] [7] and thus regulates gene expression. RTT affects mainly females approximately 1 in 10 0 to 15 0 children accounting for 2-3% of cases of severe mental disability[8]-[10]. There’s a developing appreciation that RTT symptoms may be as a consequence partly to defects in mitochondrial function[11]. Mitochondria convert nutrition into usable energy through cellular respiration and make most cellular ATP typically. Affected mitochondrial function continues to be associated with metabolic illnesses neurodegenerative disorders sarcopenia and maturing[12] [13]. Mitochondria in skeletal muscles from RTT sufferers have shown unusual morphology[14]-[18] aswell as reduced degrees of mitochondrial enzymes and the different parts of the electron transportation string (ETC)[14] [15]. RTT sufferers may also be reported to possess Dalcetrapib elevated serum degrees of leptin and reduced adiponectin[19] [20] metabolic read-outs from adipose tissues suggestive of general body metabolic imbalance. RTT symptoms of psychomotor abnormalities are modeled in mice with knock-outs from the gene that result in deficient MeCP2 protein[21] and these models have been shown to have mitochondrial abnormalities as well[22]. Energy deficits due to defects in substrate utilization may exist in RTT and in mouse models of the disease and may underlie some of the deleterious effects of MeCP2 deficiency as symptoms present during highly energy-dependent phases of neuromuscular and neurological development. We hypothesized that providing an anaplerotic diet would improve Rabbit polyclonal to LRRC15. adverse metabolic and psychomotor abnormalities incurred by MeCP2 deficiency. Anaplerotic strategies involve the Dalcetrapib administration of alternate substrates capable of replenishing the intermediates of the TCA cycle so that it can receive the acetyl group from acetyl coenzyme A (CoA) and provide reducing power (NADH FADH2) to the ETC to enhance mitochondrial ATP production[23]-[25]. Anaplerotic substrates include pyruvate glutamine/glutamate and precursors of propionyl-CoA (odd-chain fatty acids Dalcetrapib 5 (C5) ketone body and some amino acids)[26] [27]. An anaplerotic diet with triheptanoin (C7 triglyceride) providing 30-35% of total caloric intake has been used successfully to treat some inherited metabolic disorders the pathology of which could include energy deficiency or redox imbalance resulting from improper TCA cycle function[24] [28]-[31]. We decided whether anaplerotic treatment using dietary triheptanoin could improve health in the setting of MeCP2 deficiency. Starting at 4 weeks of age male wild type (WT) and knockout (KO) mice were fed either triheptanoin diet or an isocaloric control diet containing soybean oil (SBO). The effects of triheptanoin diet were significant. After only two weeks of treatment there was a clear improvement towards increased insulin sensitivity and glucose tolerance. Chronic treatment with triheptanoin improved motor coordination and interpersonal interaction and increased lifespan. Metabolomics analyses help to delineate the mechanisms of these effects and show that triheptanoin product restores metabolic homeostasis to improve energy availability that would be important.