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.

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

“…The concentrations in the Mecp2 −/y mice (98.9 ± 0.8 mg/dl, n=9) were not significantly different than in their Mecp2 +/y controls (89.2 ± 11.2 mg/dl, n=8). 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). In 70-day-old Mecp2 −/y mice (Bird allele) on a 129S6/SvEv background, plasma total cholesterols were about 50% higher than in their wildtype controls (Buchovecky et al, 2013).…”

Rett Syndrome: A Focus on Gut Microbiota

“…Beneficial effects have also been obtained with choline-rich [52] or anaplerotic triheptanoin diets [53]. …”

Metabolic Dysfunctions in Amyotrophic Lateral Sclerosis Pathogenesis and Potential Metabolic Treatments

“…The ability of triheptanoin to provide both acetyl-CoA and propionyl-CoA makes it an ideal metabolic treatment for disorders with deficient levels of TCA cycle intermediates and impairments in energy production. For instance, triheptanoin alleviated metabolic disturbances associated with several neurological and neuromuscular disorders and improved symptoms in models of epilepsy (Willis et al, 2010; Thomas et al, 2012; Hadera et al, 2014), Canavan disease (Francis et al, 2014), autism disorders (Park et al, 2014) and Alzheimer's Disease (Aso et al, 2013) as well as patients and a mouse model of glucose transporter 1 deficiency (Marin-Valencia et al, 2013; Pascual et al, 2014; Mochel et al, 2016), and patients with Huntington's disease (Mochel et al, 2010; Adanyeguh et al, 2015). In chronically “epileptic” mice it was shown that triheptanoin partially restores reduced TCA cycle intermediate and metabolite levels (Willis et al, 2010; Hadera et al, 2014).…”