Mammalian target of rapamycin complex 1 activation is required for the stimulation of human skeletal muscle protein synthesis by essential amino acids


Journal Title (Medline/Pubmed accepted abbreviation): J Nutr
Year: 2011
Volume: 141
Number:5
Page numbers: 856-862

Summary of background and research design

Increased availability of essential amino acids in the circulation results in stimulation of muscle protein synthesis in humans and other mammals. It is of interest to identify nutritional approaches that can utilize this effect to promote a net gain in muscle protein balance, particularly in clinical conditions (e.g. bed rest) that preclude use of exercise to stimulate muscle growth (or prevent wasting).

The mammalian target of rapamycin complex 1 (mTORC1) is a well-established signaling complex that integrates various signals and mediates activity of muscle protein synthesis via downstream effectors S6K1 and 4E-BP1, which promotes translation initiation and elongation activities, respectively. mTORC1 mediates the ability of essential amino acids to promote protein synthesis, although this has only been demonstrated indisputably in cell and animal models. Current data in humans is only correlational; as such mTORC1’s role in the human response has not yet been fully corroborated.

This study enrolled 3 young males and 5 young females (~25 yrs) in a randomized, cross-over trial with two test periods separated by 2-4 weeks. Both trials were identical, with the exception that during 1 trial participants consumed 16 mg of rapamycin, which directly inhibits mTORC1 activity. After an overnight fast, participants were constantly infused with stable isotope tracer amino acids for measuring protein synthesis. After 2 hours of initial tracer amino acid infusion, participants undergoing rapamycin treatment consumed the oral dose of rapamycin. 2 hours later, all participants consumed a 10-g solution of essential amino acids that were known to simulate protein synthesis in muscle. Blood and muscle samples were collected serially during the trial.


Summary of research findings
The rapamycin treatment significantly elevated blood rapamycin concentrations to a stable level prior to essential amino acid consumption and for the remainder of the trial. The essential amino acid consumption elicited an increase in muscle protein synthesis, while the rapamycin trial completely blocked this response. Cell signaling downstream of mTORC1 was activated with the essential amino acids, but blocked with rapamycin treatment.

Interpretation of findings/Key practice applications

The use of rapamycin to block signaling through mTORC1demonstrates that mTORC1 activity is required in humans for muscle protein synthetic activity to respond to essential amino acids. These findings support established work in animal skeletal muscle, and provide a foundation to develop evidence-based nutritional therapies or approaches to increase skeletal muscle size, or to counteract muscle wasting in clinical or pathological states. Finally, as rapamycin is used as a treatment for various clinical conditions (e.g. organ transplant patients), this study may reveal a mechanism by which these populations could potentially be resistant to stimulation of muscle protein anabolism by nutrients.
 
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