Nutritional and contractile regulation of human skeletal muscle protein synthesis and mTORC1 signaling

Abstract

In this review we discuss current findings in the human skeletal muscle literature describing the acute influence of nutrients (leucine-enriched essential amino acids in particular) and resistance exercise on muscle protein synthesis and mammalian target of rapamycin complex 1 (mTORC1) signaling. We show that essential amino acids and an acute bout of resistance exercise independently stimulate human skeletal muscle protein synthesis. It also appears that ingestion of essential amino acids following resistance exercise leads to an even larger increase in the rate of muscle protein synthesis compared with the independent effects of nutrients or muscle contraction. Until recently the cellular mechanisms responsible for controlling the rate of muscle protein synthesis in humans were unknown. In this review, we highlight new studies in humans that have clearly shown the mTORC1 signaling pathway is playing an important regulatory role in controlling muscle protein synthesis in response to nutrients and/or muscle contraction. We propose that essential amino acid ingestion shortly following a bout of resistance exercise is beneficial in promoting skeletal muscle growth and may be useful in counteracting muscle wasting in a variety of conditions such as aging, cancer cachexia, physical inactivity, and perhaps during rehabilitation following trauma or surgery.

Figures

Fig. 1.

A simplified schematic representation of the mammalian target of rapamycin complex 1 (mTORC1) signaling pathway driven by muscle contraction, insulin, essential amino acids (leucine), and/or energy. Proteins have been labeled to designate them as a positive (green) or negative (red) regulators of mTORC1 and muscle protein synthesis. AMPK, AMP-activated protein kinase; Akt, protein kinase B; TSC1, tuberous sclerosis complex 1; TSC2, tuberous sclerosis complex 2; REDD1/2, regulated in development and DNA damage responses; Rheb, Ras-homologue enriched in brain; TCTP, translationally controlled tumor protein; PAM, protein associated with Myc; Raptor, regulatory associated protein of mTOR; GβL, G protein β-subunit-like protein; MAP4K3, mitogen activated protein kinase kinase kinase kinase-3; hVps34, human vacuolar protein sorting-34; S6K1, p70 ribosomal S6 kinase 1; 4E-BP1, 4E binding protein 1; eEF2k, eukaryotic elongation factor 2 kinase; eEF2, eukaryotic elongation factor 2; rpS6, ribosomal protein S6; PRAS40, proline-rich Akt substrate-40.

Fig. 2.

A simplified schematic representation of the interaction between the mTORC1 and ERK1/2 signaling pathways following muscle contraction and/or insulin stimulation. mTORC1 pathway is indicated in blue, while the ERK1/2 pathway is in purple. MEK1/2, mitogen-activated protein kinase kinase-1/2; ERK1/2, extracellular signal-regulated kinase 1/2; MNK1, MAP kinase-interacting kinase 1; PI3K, phosphatidylinositol 3-kinase; RSK1, p90 ribosomal protein S6 kinase.

Fig. 3.

Effect of resistance exercise and the timing of nutrient (leucine-enriched essential amino acids + carbohydrates) ingestion on muscle protein synthesis in young human subjects. Data are presented as percent change in fractional synthetic rate (FSR) from baseline. Resistance Exercise, percent increase in FSR for 2-h period of postexercise recovery (n = 11; 7 men and 4 women) (Ref. 30); Nutrient Ingestion before Resistance Exercise, percent increase in FSR for 2 h period of postexercise recovery (nutrients ingested 1 h before exercise) [n = 11, 6 men (Ref. 43) and new data from 5 female subjects]; Nutrient Ingestion, percent increase in FSR 1 h following nutrient ingestion (n = 11; 6 men and 5 women) (Ref. 42); Nutrient Ingestion after Resistance Exercise, percent increase in FSR 1 h following nutrient ingestion when nutrients were ingested 1 h after resistance exercise (n = 6 men) (Ref. 30). *Significantly greater than baseline, P < 0.05. #Significantly greater than nutrient ingestion before resistance exercise, P < 0.05.