Human Skeletal Muscle Protein Metabolism Responses to Amino Acid Nutrition

Abstract

Healthy individuals maintain remarkably constant skeletal muscle mass across much of adult life, suggesting the existence of robust homeostatic mechanisms. Muscle exists in dynamic equilibrium whereby the influx of amino acids (AAs) and the resulting increases in muscle protein synthesis (MPS) associated with the intake of dietary proteins cancel out the efflux of AAs from muscle protein breakdown that occurs between meals. Dysregulated proteostasis is evident with aging, especially beyond the sixth decade of life. Women and men aged 75 y lose muscle mass at a rate of ∼0.7% and 1%/y, respectively (sarcopenia), and lose strength 2- to 5-fold faster (dynapenia) as muscle "quality" decreases. Factors contributing to the disruption of an otherwise robust proteostatic system represent targets for potential therapies that promote healthy aging. Understanding age-related impairments in anabolic responses to AAs and identifying strategies to mitigate these factors constitute major areas of interest. Numerous studies have aimed to identify 1) the influence of distinct protein sources on absorption kinetics and muscle anabolism, 2) the latency and time course of MPS responses to protein/AAs, 3) the impacts of protein/AA intake on muscle microvascular recruitment, and 4) the role of certain AAs (e.g., leucine) as signaling molecules, which are able to trigger anabolic pathways in tissues. This review aims to discuss these 4 issues listed, to provide historical and modern perspectives of AAs as modulators of human skeletal muscle protein metabolism, to describe how advances in stable isotope/mass spectrometric approaches and instrumentation have underpinned these advances, and to highlight relevant differences between young adults and older individuals. Whenever possible, observations are based on human studies, with additional consideration of relevant nonhuman studies.

Keywords: aging; amino acids; leucine; metabolism; muscle.

FIGURE 1

Factors that may affect skeletal muscle protein metabolism in older individuals, shifting the dynamic equilibrium toward a net loss of muscle mass. AA, amino acid; EAA, essential amino acid; EEF2, eukaryotic elongation factor 2; EEF2K, eukaryotic elongation factor 2 kinase; EIF, eukaryotic initiation factor; MPB, muscle protein breakdown; MPS, muscle protein synthesis; mTOR, mechanistic target of rapamycin; mTORC1, mechanistic target of rapamycin complex 1; p70S6K1, ribosomal protein S6 kinase; PRAS40, proline-rich Akt substrate of 40 kDa; RPS6, ribosomal protein S6; 4EBP1, 4E-binding protein.