Adaptations Supporting Plasma Methionine on a Limited-Methionine, High-Cystine Diet Alter the Canine Plasma Metabolome Consistent with Interventions that Extend Life Span in Other Species

BACKGROUND: Using indicator amino acid oxidation methodology, the mean dietary requirement of adult dogs for methionine (Met) was estimated to be ∼66% of the current recommended allowance. Dogs fed a diet formulated to provide the estimated mean Met requirement for 32 wk maintained plasma Met, seemingly supported by betaine oxidation. OBJECTIVE: To gain a better understanding of the metabolic changes that were associated with supporting plasma Met when dogs were fed a limited Met diet over 32 wk, we analyzed plasma samples taken from that study using a data-driven metabolomics approach. METHODS: Labrador retrievers (20 females/13 males; mean age: 4.9 y; range: 2.0-7.9 y) were fed semi-purified, nutritionally complete diets. After 4 wk of feeding a control diet (DL-Met; 1.37 g/1000 kcal), 17 dogs remained on this diet and 16 were transitioned to a test diet formulated to the estimated mean Met requirement (0.55 g/1000 kcal), with dietary total sulfur amino acid maintained with additional l-cystine (Cys). Dogs were individually fed diets to maintain a stable body weight at an ideal body condition score for 32 wk. Plasma samples from fasted blood collected at baseline and 8 and 32 wk were analyzed using untargeted metabolic profiling. RESULTS: Analysis of metabolites (n = 593) confirmed our primary findings (increased Met, betaine, and dimethylglycine). Metabolite changes consistent with repartitioning choline to support Met cycling included reduced pools of lipids derived via phosphatidylethanolamine N-methyltransferase and enhanced fatty acid oxidation. Some changes were consistent with metabolomics studies reported in other species that used interventions known to extend life span (caloric- and Met-restricted diets or feeding strategy). CONCLUSIONS: Changes in the plasma metabolome were consistent with reported adaptations to support Met-dependent activities. We propose that feeding a limited-Met, high-Cys diet using the estimated mean Met requirement in adult Labrador retrievers alters regulation of the Met cycle, thereby altering metabolism, similar to interventions that extend life span.