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

Departments of Physical Therapy, University of Texas Medical Branch, Galveston, 77555-1144, USA.
The Journal of Physiology (Impact Factor: 5.04). 02/2009; 587(Pt 7):1535-46. DOI: 10.1113/jphysiol.2008.163816
Source: PubMed


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.

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Available from: Christopher S Fry, Oct 13, 2014
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    • "mediating responses to anabolic stimuli. Rapamycin abolishes the acute increase in muscle protein synthesis that occurs in the first few hours after resistance exercise (Drummond et al., 2009), indicating that this early upregulation of MPS is mTORC1-dependent. However, the effects of rapamycin on anabolic signaling and MPS at later stages of recovery from acute resistance exercise are unclear. "
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    ABSTRACT: This study aimed to determine i) the effect of acute resistance exercise on mechanisms of ribosome biogenesis, and ii) the impact of mammalian target of rapamycin on ribosome biogenesis, and muscle protein synthesis (MPS) and degradation. Female F344BN rats underwent unilateral electrical stimulation of the sciatic nerve to mimic resistance exercise in the tibialis anterior (TA) muscle. TA muscles were collected at intervals over the 36 h of exercise recovery (REx); separate groups of animals were administered rapamycin pre-exercise (REx+Rapamycin). Resistance exercise led to a prolonged (6 to 36 h) elevation (30-50%) of MPS that was fully blocked by rapamycin at 6 hours but only partially at 18 h. REx also altered pathways that regulate protein homeostasis and mRNA translation in a manner that was both rapamycin-sensitive (proteasome activity; phosphorylation of S6K1 and rpS6) and insensitive (phosphorylation of eEF2, ERK1/2 and UBF; gene expression of the myostatin target Mighty as well as c-Myc and its targets involved in ribosome biogenesis). The role of c-Myc was tested in vitro using the inhibitor 10058-F4, which, over time, decreased basal RNA and MPS in a dose-dependent manner (correlation of RNA and MPS, r(2) = 0.98), even though it had no effect on the acute stimulation of protein synthesis. In conclusion, acute resistance exercise stimulated rapamycin-sensitive and -insensitive mechanisms that regulate translation activity and capacity. This article is protected by copyright. All rights reserved.
    Full-text · Article · Nov 2015 · The Journal of Physiology
    • "In a recent issue of The Journal of Physiology Philp et al. (2015) have elegantly designed a study aiming to determine the effects of exercise with and without compromised mTOR activity via rapamycin treatment. The authors subjected mice to endurance exercise for 1 h and measured the rate of protein synthesis in myofibrillar and mitochondrial fractions at 30, 3 and 6 h post exercise, a considerable stretch in the time points compared to the human clinical study (Drummond et al. 2009), which measured protein synthesis up to "
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    • "As such, mTORC1 is the rapamycin-sensitive kinase involved in the regulation of MPS and skeletal muscle mass (Hornberger 2011). Signalling through the mTORC2 is complex and poorly understood, but does not appear to be inhibited by rapamycin and therefore is unlikely to contribute directly to cell growth (Drummond et al. 2009). In response to mechanical loading, activation of mTORC1 results in the phosphorylation of ribosomal S6 kinaseu 1 (p70S6K) and eukaryotic initiation factor 4E-binding protein-1 (4E-BP1) (Anthony et al. 2001; Burd et al. 2009). "
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    ABSTRACT: Skeletal muscle mass plays a vital role in locomotion, whole-body metabolic health, and is a positive predictor of longevity. It is well established the mammalian target of rapamycin (mTOR) is a central regulator of skeletal muscle protein turnover. The pursuit to find novel nutrient compounds or functional food sources that possess the ability to activate mTOR and promote skeletal muscle protein accretion has been on going. Over the last decade, a key role has been proposed for the phospholipid phosphatidic acid (PA) in mTOR activation. Mechanical load-induced (i.e., resistance exercise) intramuscular PA can directly bind to and activate mTOR. In addition, PA provided exogenously in cell culture heightens mTOR activity, albeit indirectly. Thus, endogenously generated PA and exogenous provision of PA appear to act through distinct mechanisms that converge on mTOR and, potentially, may amplify muscle protein synthesis. In support of this notion, limited evidence from humans suggests that resistance exercise training combined with oral supplemental PA enhances strength gains and muscle hypertrophy. However, the precise mechanisms underpinning the augmented muscle remodelling response with supplemental PA remain elusive. In this review, we will critically examine available evidence from cell cultures and animal and human experimental models to provide an overview of the mechanisms through which endogenous and exogenous PA may act to promote muscle anabolism, and discuss the potential for PA as a therapeutic tool to maintain or restore skeletal muscle mass in the context of ageing and disease.
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