Rapamycin administration in humans blocks the contraction‐induced increase in skeletal muscle protein synthesis

Abstract

Muscle protein synthesis and mTORC1 signalling are concurrently stimulated following muscle contraction in humans. In an effort to determine whether mTORC1 signalling is essential for regulating muscle protein synthesis in humans, we treated subjects with a potent mTORC1 inhibitor (rapamycin) prior to performing a series of high-intensity muscle contractions. Here we show that rapamycin treatment blocks the early (1-2 h) acute contraction-induced increase (∼40%) in human muscle protein synthesis. In addition, several downstream components of the mTORC1 signalling pathway were also blunted or blocked by rapamycin. For instance, S6K1 phosphorylation (Thr421/Ser424) was increased post-exercise 6-fold in the control group while being unchanged with rapamycin treatment. Furthermore, eEF2 phosphorylation (Thr56) was reduced by ∼25% post-exercise in the control group but phosphorylation following rapamycin treatment was unaltered, indicating that translation elongation was inhibited. Rapamycin administration prior to exercise also reduced the ability of raptor to associate with mTORC1 during post-exercise recovery. Surprisingly, rapamycin treatment prior to resistance exercise completely blocked the contraction-induced increase in the phosphorylation of ERK1/2 (Thr202/Tyr204) and blunted the increase in MNK1 (Thr197/202) phosphorylation. However, the phosphorylation of a known target of MNK1, eIF4E (Ser208), was similar in both groups (P > 0.05) which is consistent with the notion that rapamycin does not directly inhibit MAPK signalling. We conclude that mTORC1 signalling is, in part, playing a key role in regulating the contraction-induced stimulation of muscle protein synthesis in humans, while dual activation of mTORC1 and ERK1/2 stimulation may be required for full stimulation of human skeletal muscle protein synthesis.

New strategies in sport nutrition to increase exercise performance

“…mTORC1 is well defined as essential to loading induced muscle growth in rodents [89] and stimulus induced increases in MPS in humans [90,91]. Activation of mTORC1 is required for increases in protein synthesis with amino acids [90] and resistance exercise [91].…”

“…However, when insulin is infused to supra-physiological levels mTORC1 is potently activated without a concomitant increase in muscle protein synthesis [99]. So while the data are clear that mTORC1 is required for load-induced growth [89], resistance exercise [91] and feeding [90], it is still very unclear if manipulating mTORC1 above what occurs physiologically will lead to enhanced muscle growth.…”

Physiological stimuli necessary for muscle hypertrophy

“…Muscle protein synthesis can be enhanced by exercise stimuli through the following mechanisms: 1) exposure to exercise stimuli increasing the phosphorylation of the mechanistic target of rapamycin (mTOR), 2) increase in phosphorylation of the downstream targets of mTOR, i.e. eukaryotic translation initiation factor 4E binding protein 1 (4E-BP1) and ribosomal protein S6 kinase 1(S6K1), and 3) enhancement of mRNA translation (creation of proteins) [10][11][12][13][14][15] . Numerous attempts have been made to uncover ideal training conditions for muscle hypertrophy.…”

Functional phosphatome requirement for protein homeostasis, networked mitochondria, and sarcomere structure in C. elegans muscle

“…Our connectivity analysis of the kinome and phosphatome with respect to protein degradation suggests that LET‐92 is a central node and that it appears to be a modulator of muscle protein degradation with knockdown producing mpk‐1 ‐dependent autophagic degradation. These results, coupled with the fact that ERK is known to be expressed and active in human skeletal muscle,34 raise the question of if Raf‐MAPK is a central modulator of autophagic degradation, with a significant number of kinases and phosphatases providing modulatory signals for this central pathway. This also raises the question of if Raf‐MAPK is not just a central player in controlling protein synthesis but also of autophagy, perhaps acting to either modulate or complement a similar role of mTor.…”