Amino Acids in Health and Disease: The Good, the Bad, and the Ugly

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TL;DR

This Special Issue editorial summarizes 10 original articles and 4 reviews on amino acid metabolism beyond protein synthesis, covering methionine toxicity, nitric oxide pathways, and branched-chain amino acids in metabolic disease. Key findings include that high methionine intake induces anxiety-like behavior in mice, nitrate supplementation alters amino acid homeostasis, and essential amino acids with exercise protect against dexamethasone-induced muscle loss. The collection underscores amino acids as fundamental signaling molecules with clinical relevance across cardiology, neurology, endocrinology, and gastroenterology.

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**Background:** This editorial introduces the Special Issue 'Amino Acid Metabolism and Regulation in Health and Disease 2.0,' which collected 10 original articles and 4 comprehensive reviews submitted between May 2021 and October 2022. The issue aims to highlight novel findings in amino acid metabolism beyond their roles as protein constituents and nitrogen sources, focusing on health and disease implications.

**Methods:** The editorial summarizes each contribution thematically. Original articles employed diverse methodologies: dose-response feeding studies in eels (0–10 g/kg methionine) and mice (×1–×13 standard methionine); GC-MS analytical chemistry for novel metabolite detection; clinical measurements of Arg/NOS pathway metabolites in 130 children with atopic dermatitis and/or asthma; a randomized supplementation trial of NaNO₃ (0.14 mmol/kg/day) vs. NaCl in 17 healthy volunteers; pig feeding studies with very low protein diets supplemented with valine and isoleucine; rat models of takotsubo cardiomyopathy with homoarginine administration; and a mouse study combining essential amino acids with resistance exercise training during dexamethasone treatment.

**Key Results:** Methionine supplementation in eels increased lipid deposition in a dose-dependent manner. In mice, a 10× methionine diet for one week induced anxiety-like behavior (increased open-field test anxiety, decreased traveled distances, increased escape activity) while maintaining normal Y-maze learning/memory, resembling bipolar disorder symptoms. The GC-MS method successfully detected 1,3-thiasinane-4-carboxylic acid (TCA) for the first time in human urine. In children with atopic diseases, the Arg/NOS pathway was activated with higher plasma nitrate and nitrite independent of disease severity. NaNO₃ supplementation increased plasma nitrate (×7.4), nitrite (×1.67), and homoarginine (×1.32), while decreasing tyrosine (×0.864), phenylalanine (×0.923), tryptophan (×0.921), and malondialdehyde (×0.890). In pigs, combined valine and isoleucine supplementation to very low protein diets improved food intake, gut development, and hepatic IGF-1 expression. Homoarginine administration in rat cardiomyopathy models showed lysine and arginine as major metabolites, with kidneys and heart playing major metabolic roles. Essential amino acids plus resistance exercise training synergistically protected against dexamethasone-induced muscle loss and completely restored impaired insulin sensitivity in mice.

**Clinical Implications:** The findings suggest multiple translational applications: high methionine diets may provide a rapid, inexpensive model for bipolar disorder research relevant to hypermethioninemia and homocysteinemia patients; TCA in urine may serve as a novel biomarker; nitrate supplementation shows both positive (increased homoarginine) and negative (decreased aromatic amino acids) effects relevant to muscle strengthening; valine/isoleucine supplementation could improve growth performance in protein-restricted animal feeds; and combined essential amino acid supplementation with resistance exercise may counteract corticosteroid-induced muscle wasting and insulin resistance. The four reviews highlight therapeutic targets including GCPII inhibitors for neuroprotection, siRNA therapy for primary hyperoxaluria, and dietary BCAA modulation for metabolic diseases.