Researchers Shed Light on Metabolic Profile of Fragile X Mouse Model
A mouse model of fragile X syndrome has higher body weight and distinct metabolic changes relative to healthy mice and mouse models of two other neurodevelopmental disorders, a study shows.
The findings highlight not only that each mouse model exhibits a unique, sex-specific metabolic signature, but also that problems in mitochondria, which provide energy to cells, may contribute to three neurodevelopmental disorders: fragile X, Down syndrome, and 16p11.2 deletion syndrome.
This adds to the growing body of evidence indicating that fragile X’s underlying deficiency in the fragile X mental retardation protein leads to mitochondrial malformations and dysfunction in developing neurons and neuron-supporting cells, resulting in insufficient energy production and neuronal damage.
These new insights may help to identify potential therapeutic targets and approaches for these three conditions, as well as improve diagnostic methods, the researchers noted.
The study, “Distinct Basal Metabolism in Three Mouse Models of Neurodevelopmental Disorders,” was published in the journal eNeuro.
Fragile X, Down syndrome, and 16p11.2 deletion syndrome are neurodevelopmental disorders caused by distinct genetic mutations, but all are associated with intellectual disability, developmental delay, and autism spectrum disorders.
They are also associated “with higher incidence of obesity, hypertension [high blood pressure], hormonal dysfunction, heart defects and diabetes in comparison to the general population,” the researchers wrote.
“Despite this known association, the link between metabolic imbalance and neurodevelopmental disorders (NDDs) has been largely overlooked, particularly in a fundamental research setting,” the team added.
To address this knowledge gap, a team of researchers in Canada systematically characterized, reportedly for the first time, the resting energy metabolism of mouse models of fragile X, Down syndrome, and 16p11.2 deletion syndrome.
These models allow researchers not only to evaluate their ability to reproduce human features of the disease, but also to identify and quantify new disease features.
The team evaluated the animals’ body composition, metabolic measures, and blood levels of metabolites (metabolism’s intermediate or end products) related to mitochondrial function. Metabolic measures were assessed over 48 hours when mice were placed in a special, environment-controlled cage that tracked gas exchange, caloric expenditure, food consumption, and physical activity.
Since all three conditions exhibit sex-based differences, the researchers performed these analyses in both male and female mice.
Two types of females were analyzed in the model of fragile X. One with a complete loss of the disease-associated FMR1 gene — similar to male mice and to what is seen in most male patients — and another with one functional copy of the gene, which represents the case in most female patients.
The data were then compared with those of each model’s corresponding controls, or unaffected mice with the same genetic background.
Results showed that each mouse model exhibited a unique, sex-specific metabolic signature, “despite similar food consumption and physical activity levels,” the researchers wrote.
The models showed striking differences in body composition, gas exchange, energy expenditure, fat and carbohydrate use, and mitochondria-related metabolite levels.
In the fragile X mouse model, both male and female mice with a complete loss of the FMR1 gene weighed significantly more and had significantly higher levels of three mitochondria-related metabolites, compared with their unaffected controls.
Several sex-based differences were observed among these mice, with only female mice showing lower gas exchange and caloric expenditure relative to their female controls. Sex-based differences in the levels of other metabolites were also observed.
In addition, female mice with one functional copy of the FMR1 gene showed similar metabolic signatures to unaffected females, supporting the compensatory effect of having at least one working gene copy and the milder symptoms observed in most fragile X female patients, compared with male patients.
“In line with sex-specific and model-specific alterations in body composition and metabolic [features], our metabolomic data suggest significant changes in mitochondrial metabolism” in these neurodevelopmental conditions, the researchers wrote.
The study provides “a basis for future studies aimed at understanding mechanisms underlying metabolic dysfunction in NDDs, and/or aimed at detecting changes in response to intervention,” they added.
The data also suggest that “personalized clinical interventions may be required to address unique NDD-associated metabolic abnormalities depending on both genetic cause and sex,” the team concluded.