Advances in the Role of Leucine-Sensing in the Regulation of Protein Synthesis in Aging Skeletal Muscle

Abstract

Skeletal muscle anabolic resistance (i.e., the decrease in muscle protein synthesis (MPS) in response to anabolic stimuli such as amino acids and exercise) has been identified as a major cause of age-related sarcopenia, to which blunted nutrition-sensing contributes. In recent years, it has been suggested that a leucine sensor may function as a rate-limiting factor in skeletal MPS via small-molecule GTPase. Leucine-sensing and response may therefore have important therapeutic potential in the steady regulation of protein metabolism in aging skeletal muscle. This paper systematically summarizes the three critical processes involved in the leucine-sensing and response process: (1) How the coincidence detector mammalian target of rapamycin complex 1 localizes on the surface of lysosome and how its crucial upstream regulators Rheb and RagB/RagD interact to modulate the leucine response; (2) how complexes such as Ragulator, GATOR, FLCN, and TSC control the nucleotide loading state of Rheb and RagB/RagD to modulate their functional activity; and (3) how the identified leucine sensor leucyl-tRNA synthetase (LARS) and stress response protein 2 (Sestrin2) participate in the leucine-sensing process and the activation of RagB/RagD. Finally, we discuss the potential mechanistic role of exercise and its interactions with leucine-sensing and anabolic responses.

Exercise May Promote Skeletal Muscle Hypertrophy via Enhancing Leucine-Sensing: Preliminary Evidence

“…ArS increases the risk of falls, disability and mortality in the elderly, affects both physical and mental health and quality of life, and is a direct contributor to rising healthcare costs in the elderly population (Xia et al, 2017a;Seol et al, 2020). Skeletal muscle anabolic resistance, the dampened muscle protein synthesis response to protein ingestion and mechanical tension, has currently been identified as a major cause of ArS, to which blunted nutrition-sensing contributes (Zhao et al, 2021). Moreover, age-related anabolic resistance was considered to be exacerbated during musculoskeletal disuse and reduced physical activity (Marshall et al, 2020).…”

“…Since the Michaelis constant (Km value) of LeuRS for leucine in the amino acids activation reaction and the dissociation constant (Kd value) of leucine for Sestrin2 are similar, whether LeuRS and Sestrin2 co-regulate mTORC1 collectively or separately (Pang and Martinis, 2009;Wolfson et al, 2016) requires further research (Lee et al, 2018). We recently proposed that exercise may effectively enhance the sensitivity of skeletal muscle tissues to amino acid stimulation (Zhao et al, 2021). Resistance exercise has been widely recognized as a potent intervention to maintain or increase skeletal muscle protein synthesis and hypertrophy.…”

“…Although not considered the most efficient intervention to stimulate a high magnitude of muscle hypertrophy, aerobic exercise can also attenuate the inhibition of muscle protein synthesis and deposition (Xia et al, 2016). However, to date there are no studies that have investigated the role of exercise on the LeuRS/Sestrin2-mTOR axis, and it's not clear which mode of training is most efficacious in regulating mTORC1 signaling and muscle hypertrophy mediated by LeuRS and/or Sestrin2 (Zhao et al, 2021). Thus, the preliminary evidence exploring these relationships are warranted, and the results will inspire more translational research on the topic.…”

Autophagy Deficiency by Atg4B Loss Leads to Metabolomic Alterations in Mice

“…For example, leucine positively regulates the activity of mammalian target of rapamycin (mTOR), key regulator of protein synthesis, among other processes [ 19 , 20 ]. Leucine also upregulates a variety of other important processes for cellular metabolism, such as glucose uptake, mitochondrial biogenesis, or fatty acid oxidation [ 21 , 22 ]. This amino-acid can be used to obtain Acetyl-CoA, which could be incorporated into the tricarboxylic acid (TCA) cycle and is also involved in autophagy regulation [ 23 ].…”

Pea Proteins Have Anabolic Effects Comparable to Milk Proteins on Whole Body Protein Retention and Muscle Protein Metabolism in Old Rats

“…The fact that pea protein provides well above the recommended leucine requirements points to it playing a potentially valuable role in combating the loss of skeletal muscle mass and function in older subjects. Leucine is an anabolic amino acid with proven effectiveness for the maintenance of muscle mass during aging [8]. Meeting the body's quantitative daily demand for EAA is vitally important; the quality of protein consumed by older people is an equally important factor, and is generally determined by its digestibility and utilizability by the body.…”