Administration of the mTORC1 inhibitor, rapamycin, to humans blocks the increase in skeletal muscle protein synthesis in response to resistance exercise or amino acid ingestion.
To determine whether rapamycin administration influences basal post-absorptive protein synthesis or breakdown in human skeletal muscle.
Six young (26±2 years) subjects were studied during two separate trials, in which each trial was divided into two consecutive 2 h basal periods. The trials were identical except during one trial a single oral dose (16 mg) of rapamycin was administered immediately prior to the second basal period. Muscle biopsies were obtained from the vastus lateralis at 0, 2, and 4 h to examine protein synthesis, mTORC1 signaling, and markers of autophagy (LC3B-I and LC3B-II protein) associated with each 2 h basal period.
During the Control trial, muscle protein synthesis, whole body protein breakdown (phenylalanine Ra), mTORC1 signaling, and markers of autophagy were similar between both basal periods (p>0.05). During the Rapamycin trial, these variables were similar to the Control trial (p>0.05) and were unaltered by rapamycin administration (p>0.05). Thus, post-absorptive muscle protein metabolism and mTORC1 signaling were not affected by rapamycin administration.
Short-term rapamycin administration may only impair protein synthesis in human skeletal muscle when combined with a stimulus such as resistance exercise or increased amino acid availability.
Abbreviations:CON (Control trial), 4E-BP1 (eukaryotic initiation factor 4E binding protein 1), FSR (fractional synthesis rate), LC3 (microtubule-associated protein 1 light chain 3), mTORC1 (mammalian target of rapamycin complex 1), Ra (rate of appearance), RAP (Rapamycin trial), S6K1 (ribosomal S6 kinase 1.)
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- Regulation of protein metabolism during stress.Curr Opin Gen Surg. 1993; : 72-77
- Aging muscle.Am J Clin Nutr. 2005; 81: 953-963
- Low relative skeletal muscle mass (sarcopenia) in older persons is associated with functional impairment and physical disability.J Am Geriatr Soc. 2002; 50: 889-896
- Pathogenesis of muscle wasting in cancer cachexia: targeted anabolic and anticatabolic therapies.Curr Opin Clin Nutr Metab Care. 2010; 13: 410-416
- Co-ingestion of protein and leucine stimulates muscle protein synthesis rates to the same extent in young and elderly lean men.Am J Clin Nutr. 2006; 84: 623-632
- Mixed muscle protein synthesis and breakdown after resistance exercise in humans.Am J Physiol. 1997; 273: E99-E107
- Age and aerobic exercise training effects on whole body and muscle protein metabolism.Am J Physiol Endocrinol Metab. 2004; 286: E92-E101
- Aging impairs contraction-induced human skeletal muscle mTORC1 signaling and protein synthesis.Skelet Muscle. 2011; 1: 11
- Essential amino acid sensing, signaling, and transport in the regulation of human muscle protein metabolism.Curr Opin Clin Nutr Metab Care. 2011; 14: 83-88
- Regulation of protein synthesis by amino acids in muscle of neonates.Front Biosci. 2011; 16: 1445-1460
- Nutritional and contractile regulation of human skeletal muscle protein synthesis and mTORC1 signaling.J Appl Physiol. 2009; 106: 1374-1384
- Akt/mTOR pathway is a crucial regulator of skeletal muscle hypertrophy and can prevent muscle atrophy in vivo.Nat Cell Biol. 2001; 3: 1014-1019
- Leucine stimulates translation initiation in skeletal muscle of postabsorptive rats via a rapamycin-sensitive pathway.J Nutr. 2000; 130: 2413-2419
- Resistance exercise increases muscle protein synthesis and translation of eukaryotic initiation factor 2Bepsilon mRNA in a mammalian target of rapamycin-dependent manner.J Biol Chem. 2005; 280: 7570-7580
- Leucine stimulates protein synthesis in skeletal muscle of neonatal pigs by enhancing mTORC1 activation.Am J Physiol Endocrinol Metab. 2008; 295: E868-E875
- Feeding stimulates protein synthesis in muscle and liver of neonatal pigs through an mTOR-dependent process.Am J Physiol Endocrinol Metab. 2000; 279: E1080-E1087
- The role of skeletal muscle mTOR in the regulation of mechanical load-induced growth.J Physiol. 2011; 589: 5485-5501
- Rapamycin administration in humans blocks the contraction-induced increase in skeletal muscle protein synthesis.J Physiol. 2009; 587: 1535-1546
- Mammalian target of rapamycin complex 1 activation is required for the stimulation of human skeletal muscle protein synthesis by essential amino acids.J Nutr. 2011; 141: 856-862
- Involvement of the rapamycin-sensitive pathway in the insulin regulation of muscle protein synthesis in streptozotocin-diabetic rats.J Endocrinol. 1999; 160: 137-145
- Autophagy and related mechanisms of lysosome-mediated protein degradation.Trends Cell Biol. 1994; 4: 139-143
- Relieving autophagy and 4EBP1 from rapamycin resistance.Mol Cell Biol. 2011; 31: 2867-2876
- A novel mTOR activating protein protects dopamine neurons against oxidative stress by repressing autophagy related cell death.J Neurochem. 2010; 112: 366-376
- Phosphorylation of ribosomal protein S6 is inhibitory for autophagy in isolated rat hepatocytes.J Biol Chem. 1995; 270: 2320-2326
- Leucine limitation induces autophagy and activation of lysosome-dependent proteolysis in C2C12 myotubes through a mammalian target of rapamycin-independent signaling pathway.J Biol Chem. 2000; 275: 29900-29906
- Excess leucine intake enhances muscle anabolic signaling but not net protein anabolism in young men and women.J Nutr. 2010; 140: 1970-1976
- Muscle electrolytes in man.Scand J Med Sci Sports. 1962; 68: 1-110
- Leucine-enriched essential amino acid and carbohydrate ingestion following resistance exercise enhances mTOR signaling and protein synthesis in human muscle.Am J Physiol Endocrinol Metab. 2008; 294: E392-E400
- Sequential muscle biopsies during a 6-h tracer infusion do not affect human mixed muscle protein synthesis and muscle phenylalanine kinetics.Am J Physiol Endocrinol Metab. 2008; 295: E959-E963
- Resistance exercise increases AMPK activity and reduces 4E-BP1 phosphorylation and protein synthesis in human skeletal muscle.J Physiol. 2006; 576: 613-624
- The determination of low d5-phenylalanine enrichment (0.002-0.09 atom percent excess), after conversion to phenylethylamine, in relation to protein turnover studies by gas chromatography/electron ionization mass spectrometry.Rapid Commun Mass Spectrom. 1992; 6: 421-424
- Measurement of very low stable isotope enrichments by gas chromatography/mass spectrometry: application to measurement of muscle protein synthesis.Metabolism. 1997; 46: 943-948
- Isotopic tracers in metabolic research: principles and practice of kinetic analysis. 2nd ed. John Wiley & Sons, Inc., Hoboken2005
- LC3, a mammalian homologue of yeast Apg8p, is localized in autophagosome membranes after processing.EMBO J. 2000; 19: 5720-5728
- How to interpret LC3 immunoblotting.Autophagy. 2007; 3: 542-545
- Guidelines for the use and interpretation of assays for monitoring autophagy in higher eukaryotes.Autophagy. 2008; 4: 151-175
- Sirolimus (rapamycin): from the soil of Easter Island to a bright future.J Am Acad Dermatol. 2007; 57: 1046-1050
- Sirolimus experience in heart transplantation.Transplant Proc. 2006; 38: 2547-2549
- Sirolimus for Kaposi's sarcoma in renal-transplant recipients.N Engl J Med. 2005; 352: 1317-1323
- FoxO3 controls autophagy in skeletal muscle in vivo.Cell Metab. 2007; 6: 458-471
- FoxO3 coordinately activates protein degradation by the autophagic/lysosomal and proteasomal pathways in atrophying muscle cells.Cell Metab. 2007; 6: 472-483
- Phosphorylation of mammalian target of rapamycin (mTOR) at Ser-2448 is mediated by p70S6 kinase.J Biol Chem. 2005; 280: 25485-25490
- The Rag GTPases bind raptor and mediate amino acid signaling to mTORC1.Science. 2008; 320: 1496-1501
- Blocking eukaryotic initiation factor 4F complex formation does not inhibit the mTORC1-dependent activation of protein synthesis in cardiomyocytes.Am J Physiol Heart Circ Physiol. 2009; 296: H505-H514
- Inhibition of mTORC1 leads to MAPK pathway activation through a PI3K-dependent feedback loop in human cancer.J Clin Invest. 2008; 118: 3065-3074
- Target of rapamycin inhibitors (sirolimus and everolimus) for primary immunosuppression of kidney transplant recipients: a systematic review and meta-analysis of randomized trials.Transplantation. 2006; 81: 1234-1248
Published online: September 10, 2012
Accepted: July 11, 2012
Received: February 23, 2012
This trial was registered at clinicaltrials.gov as NCT00891696.
© 2013 Elsevier Inc. Published by Elsevier Inc. All rights reserved.