Amino acids are components of proteins that also exist free-form in the body; their functions can be divided into (1) nutritional, (2) sensory, and (3) biological regulatory roles. The skeletal muscle, which is the largest organ in the human body, representing ~40% of the total body weight, plays important roles in exercise, energy expenditure, and glucose/amino acid usage—processes that are modulated by various amino acids and their metabolites. In this review, we address the metabolism and function of amino acids in the skeletal muscle. The expression of PGC1α, a transcriptional coactivator, is increased in the skeletal muscle during exercise. PGC1α activates branched-chain amino acid (BCAA) metabolism and is used for energy in the tricarboxylic acid (TCA) cycle. Leucine, a BCAA, and its metabolite, β-hydroxy-β-methylbutyrate (HMB), both activate mammalian target of rapamycin complex 1 (mTORC1) and increase protein synthesis, but the mechanisms of activation appear to be different. The metabolite of valine (another BCAA), β-aminoisobutyric acid (BAIBA), is increased by exercise, is secreted by the skeletal muscle, and acts on other tissues, such as white adipose tissue, to increase energy expenditure. In addition, several amino acid-related molecules reportedly activate skeletal muscle function. Oral 5-aminolevulinic acid (ALA) supplementation can protect against mild hyperglycemia and help prevent type 2 diabetes. β-alanine levels are decreased in the skeletal muscles of aged mice. β-alanine supplementation increased the physical performance and improved the executive function induced by endurance exercise in middle-aged individuals. Further studies focusing on the effects of amino acids and their metabolites on skeletal muscle function will provide data essential for the production of food supplements for older adults, athletes, and individuals with metabolic diseases.

Leucine (Leu) regulates protein synthesis and degradation via activation of mammalian target of rapamycin complex 1 (mTORC1). Glutamine (Gln) synergistically promotes mTORC1 activation with Leu via glutaminolysis and Leu absorption via an antiporter. However, Gln has also been shown to inhibit mTORC1 activity. To resolve this paradox, we aimed to elucidate the effects of Gln on Leu-mediated mTORC1 activation. We administered Leu, Gln, tryptophan, Leu + Gln, or Leu + tryptophan to mice after 24-h fasting. The mice were then administered puromycin to evaluate protein synthesis and the gastrocnemius muscle was harvested 30 min later. Phosphorylated eukaryotic initiation factor 4E-binding protein 1, 70-kDa ribosomal protein S6 kinase 1, and Unc-51 like kinase 1 levels were the highest in the Leu + Gln group and significantly increased compared with those in the control group; however, Gln alone did not increase the levels of phosphorylated proteins. No difference in glutamate dehydrogenase activity was observed between the groups. Leu concentrations in the gastrocnemius muscle were similar in the Leu-intake groups. Our study highlights a novel mechanism underlying the promotive effect of Gln on Leu-mediated mTORC1 activation, providing insights into the pathway through which amino acids regulate muscle protein metabolism.

Extending healthy lifespans is an important public health goal in societies with a long life expectancy. Late-onset hypogonadism (LOH), a condition associated with an age-related decrease in testosterone level, contributes to the onset of various diseases. Previously, we demonstrated that the oral ingestion of bean sprouts rich in the HASPIN inhibitor coumestrol increased blood testosterone levels in mice. In the present study, we showed that the oral ingestion of bean sprouts also led to increased blood testosterone levels in humans. These results suggested that bean sprouts, which are rich in coumestrol, have potential as a dietary intervention for the treatment of LOH.

1) Background: Coumestrol is a bioactive compound that inhibits HASPIN activity and prevents tau and H3 phosphorylation. Oral ingestion of CBSs increases blood testosterone levels, which decline with age causing late-onset hypogonadism. Oral ingestion of coumestrol-rich bean sprouts (CBSs) has been shown to suppress the onset of Alzheimer’s disease in 5xFAD mice and the onset of colon cancer in APC^min/+ mice. 2) Methods: We investigated the effect of oral ingestion of CBSs on the progression of aging in male senescence-accelerated prone 1 (SAMP1) mice allowed voluntary exercise or no exercise. The SAMP1 mice were divided into two groups fed either a standard diet or a diet including bean sprouts from 12 to 18 weeks of age. Each group was divided into two groups with voluntary exercise or no exercise. 3) Results: Voluntary exercise accelerated aging-related declines in blood testosterone levels, nerve growth factor levels, and spatial working memory, and oral ingestion of CBSs suppressed these age-related phenotypes, regardless of exercise. 4) Conclusion: Ingestion of CBSs prevented aging-related phenotypes in the experimental mice. A detailed analysis of the molecular mechanisms of coumestrol will be useful for understanding aging and preventing age-related diseases such as cancer, Alzheimer’s disease, and LOH.