Abstract
Methionine (Met) is considered the most toxic amino acid in mammals. Here, we investigated biochemical and behavioral impacts of ad libitum one-week feeding of high-Met diets on mice. Adult male mice were fed the standard rodent diet that contained 0.44% Met (1×) or a diet containing 16 graded Met doses (1.2×–13×). High-Met diets for one-week induced a dose-dependent decrease in body weight and an increase in serum Met levels with a 2.55 mM peak (versus basal 53 µM) on the 12×Met diet. Total homocysteine (Hcy) levels were also upregulated while concentrations of other amino acids were almost maintained in serum. Similarly, levels of Met and Hcy (but not the other amino acids) were highly elevated in the cerebrospinal fluids of mice on the 10×Met diet; the Met levels were much higher than Hcy and the others. In a series of behavioral tests, mice on the 10×Met diet displayed increased anxiety and decreased traveled distances in an open-field test, increased activity to escape from water soaking and tail hanging, and normal learning/memory activity in a Y-maze test, which were reflections of negative/positive symptoms and normal cognitive function, respectively. These results indicate that high-Met ad libitum feeding even for a week can induce bipolar disorder-like disease models in mice.
Highlights
Methionine (Met) is one of the nine essential amino acids in mammals but is the most toxic proteinogenic amino acid, whether expressed in terms of percentage of the diet or an increase over the nutritional requirement [1,2]
Met might be indirectly responsible for deleterious effects in human cases because no adverse symptoms are observed in hypermethioninemia patients due to innate Met adenosyltransferase (MAT) I/III deficiency (OMIM 250850) [10]
Our results demonstrate that one-week high-Met diets on mice drastically alter their circulatory/cerebrospinal fluid (CSF) amino acid profiles as well as their behavior
Summary
Methionine (Met) is one of the nine essential amino acids in mammals but is the most toxic proteinogenic amino acid, whether expressed in terms of percentage of the diet or an increase over the nutritional requirement [1,2]. Excessive Met in the diet causes various deleterious alterations in experimental animals, including the suppression of food intake and near-cessation of growth, schizophrenic symptoms, enlarged spleen/kidney/liver, and hemosiderosis/hemolytic anemia [2,3,4,5,6,7]. Met administration is known to exacerbate psychopathological symptoms among schizophrenic patients [8] and to induce hippocampal alteration associated with memory deficits, schizophrenia-like social deficits, and pre-pulse inhibition impairment in mice [5,6,9]; the molecular mechanisms for these. Met is metabolized by methionine adenosyltransferase (MAT) to S-adenosylmethionine (SAM), the most predominant methyl donor for hundreds of methyltransferases. The enhancement of methylation reactions could be associated with unique toxicity, especially via negative transcription regulation, because glycine supplementation often alleviates the Met toxicity
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