title: 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 ( approximately 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 approximately 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.
authors.affiliation: Departments of Physical Therapy, University of Texas Medical Branch, Galveston, 77555-1144, USA.
authors.forename: Micah J
authors.initials: MJ
authors.lastname: Drummond
authors.forename: Christopher S
authors.initials: CS
authors.lastname: Fry
authors.forename: Erin L
authors.initials: EL
authors.lastname: Glynn
authors.forename: Hans C
authors.initials: HC
authors.lastname: Dreyer
authors.forename: Shaheen
authors.initials: S
authors.lastname: Dhanani
authors.forename: Kyle L
authors.initials: KL
authors.lastname: Timmerman
authors.forename: Elena
authors.initials: E
authors.lastname: Volpi
authors.forename: Blake B
authors.initials: BB
authors.lastname: Rasmussen
mesh_terms: D000284:Administration, Oral; D000328:Adult; D000596:Amino Acids / Q000097:blood; D015444:Exercise; D006801:Humans; D006854:Hydrocortisone / Q000097:blood; D007328:Insulin / Q000097:blood; D047908:Intracellular Signaling Peptides and Proteins / Q000378:metabolism; D008297:Male; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism; D048052:Mitogen-Activated Protein Kinase 3 / Q000378:metabolism; D009119:Muscle Contraction; D009124:Muscle Proteins / Q000096:biosynthesis*; D018482:Muscle, Skeletal / Q000187:drug effects* / Q000201:enzymology / Q000378:metabolism; D020652:Peptide Elongation Factor 2 / Q000378:metabolism; D010766:Phosphorylation; D014176:Protein Biosynthesis / Q000187:drug effects*; D047428:Protein Kinase Inhibitors / Q000008:administration & dosage* / Q000097:blood; D011494:Protein Kinases / Q000378:metabolism*; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D019893:Ribosomal Protein S6 Kinases / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects*; D020123:Sirolimus / Q000008:administration & dosage* / Q000097:blood; D058570:TOR Serine-Threonine Kinases; D013997:Time Factors
chemical_list: D000596:Amino Acids; D007328:Insulin; D047908:Intracellular Signaling Peptides and Proteins; D009124:Muscle Proteins; D020652:Peptide Elongation Factor 2; D047428:Protein Kinase Inhibitors; D011494:Protein Kinases; C491395:MKNK1 protein, human; C546842:MTOR protein, human; D017346:Protein Serine-Threonine Kinases; D019893:Ribosomal Protein S6 Kinases; D058570:TOR Serine-Threonine Kinases; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D020123:Sirolimus; D006854:Hydrocortisone