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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    • "Mammalian target of rapamycin regulates its hypertrophic effects in SkM through the phosphorylation of downstream effectors such as P70S6 kinase 1 (S6K1) and eIF4E-binding protein1 (4E-BP1) (reviewed in Schiaffino et al., 2013). Their roles in SkM growth following contraction and mechanical load-induced hypertrophy, synergistic ablation, myotube hypertrophy and amino acid sensing are also well defined (Fujita et al., 2007; Drummond et al., 2009; Willett et al., 2009; Goodman et al., 2011; Miyazaki et al., 2011; Philp et al., 2011; Jacobs et al., 2013; Hamilton et al., 2014). In older people, mTOR becomes less responsive to contraction-induced activation (via resistance exercise), compared with young adults (Fry et al., 2011). "
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    ABSTRACT: Advancing age is associated with a progressive loss of skeletal muscle (SkM) mass and function. Given the worldwide aging demographics, this is a major contributor to morbidity, escalating socio-economic costs and ultimately mortality. Previously, it has been established that a decrease in regenerative capacity in addition to SkM loss with age coincides with suppression of insulin/insulin-like growth factor signalling pathways. However, genetic or pharmacological modulations of these highly conserved pathways have been observed to significantly enhance life and healthspan in various species, including mammals. This therefore provides a controversial paradigm in which reduced regenerative capacity of skeletal muscle tissue with age potentially promotes longevity of the organism. This paradox will be assessed and considered in the light of the following: (i) the genetic knockout, overexpression and pharmacological models that induce lifespan extension (e.g. IRS-1/s6K KO, mTOR inhibition) versus the important role of these signalling pathways in SkM growth and adaptation; (ii) the role of the sirtuins (SIRTs) in longevity versus their emerging role in SkM regeneration and survival under catabolic stress; (iii) the role of dietary restriction and its impact on longevity versus skeletal muscle mass regulation; (iv) the crosstalk between cellular energy metabolism (AMPK/TSC2/SIRT1) and survival (FOXO) versus growth and repair of SkM (e.g. AMPK vs. mTOR); and (v) the impact of protein feeding in combination with dietary restriction will be discussed as a potential intervention to maintain SkM mass while increasing longevity and enabling healthy aging. © 2015 The Authors. Aging Cell published by the Anatomical Society and John Wiley & Sons Ltd.
    Aging cell 04/2015; 14(4):511-23. DOI:10.1111/acel.12342 · 6.34 Impact Factor
    • "Indeed, inhibition of mTORC1 by rapamycin blocks both exerciseinduced (Drummond et al. 2009) and amino acid-induced (Dickinson et al. 2011) stimulation of muscle protein synthesis. However, in the elderly, both mTORC1 signaling and protein synthesis are refractory to the stimulatory effect of exercise (Fry et al. 2011). "
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    ABSTRACT: Ageing is associated with a loss of skeletal muscle performance, a condition referred to as sarcopenia. In part, the age-related reduction in performance is due to a selective loss of muscle fiber mass, but mass-independent effects have also been demonstrated. An important mass-independent determinant of muscle performance is the pattern of expression of isoforms of proteins that participate in muscle contraction (e.g., the troponins). In the present study, we tested the hypothesis that ageing impairs alternative splicing of the pre-mRNA encoding fast skeletal muscle troponin T (TNNT3) in human vastus lateralis muscle. Furthermore, we hypothesized that resistance exercise alone or in combination with consumption of essential amino acids would attenuate age-associated effects on TNNT3 alternative splicing. Our results indicate that ageing negatively affects the pattern of TNNT3 alternative splicing in a manner that correlates quantitatively with age-associated reductions in muscle performance. Interestingly, whereas vastus lateralis TNNT3 alternative splicing was unaffected by a bout of resistance exercise 24 h prior to muscle biopsy, ingestion of a mixture of essential amino acids after resistance exercise resulted in a significant shift in the pattern of TNNT3 splice form expression in both age groups to one predicted to promote greater muscle performance. We conclude that essential amino acid supplementation after resistance exercise may provide a means to reduce impairments in skeletal muscle quality during ageing in humans.
    Applied Physiology Nutrition and Metabolism 03/2015; 40(8):150323235940003. DOI:10.1139/apnm-2014-0568 · 2.34 Impact Factor
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    • "RPS6 is a downstream target of p70S6k with the potential to regulate protein synthesis (Goodman 2014) and is commonly used as an indirect marker of mTORC1 activation. Several studies have reported an upregulation of RPS6 phosphorylation following resistance exercise (Drummond et al. 2009; Hulmi et al. 2009, 2012; Apr o and Blomstrand 2010). However, the exact role of RPS6 in the regulation of protein synthesis remains to be determined. "
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    ABSTRACT: Resistance exercise stimulates an increase in muscle protein synthesis regulated by intracellular anabolic signaling molecules in a mammalian/mechanistic target of rapamycin (mTOR)-dependent pathway. The purpose of this study was to investigate acute anabolic signaling responses in experienced, resistance-trained men, and to examine the association between myosin heavy chain (MHC) isoform composition and the magnitude of anabolic signaling. Eight resistance-trained men (24.9 ± 4.3 years; 91.2 ± 12.4 kg; 176.7 ± 8.0 cm; 13.3 ± 3.9 body fat %) performed a whole body, high-volume resistance exercise protocol (REX) and a control protocol (CTL) in a balanced, randomized order. Participants were provided a standardized breakfast, recovery drink, and meal during each protocol. Fine needle muscle biopsies were completed at baseline (BL), 2 h (2H) and 6 h post-exercise (6H). BL biopsies were analyzed for MHC isoform composition. Phosphorylation of proteins specific to the Akt/mTOR signaling pathway and MHC mRNA expression was quantified. Phosphorylation of p70S6k was significantly greater in REX compared to CTL at 2H (P = 0.04). MHC mRNA expression and other targets in the Akt/mTOR pathway were not significantly influenced by REX. The percentage of type IIX isoform was inversely correlated (P < 0.05) with type I and type IIA MHC mRNA expression (r = −0.69 to −0.93). Maximal strength was also observed to be inversely correlated (P < 0.05) with Type I and Type IIA MHC mRNA expression (r = −0.75 to −0.77) and p70S6k phosphorylation (r = −0.75). Results indicate that activation of p70S6k occurs within 2-h following REX in experienced, resistance-trained men. Further, results also suggest that highly trained, stronger individuals have an attenuated acute anabolic response.
    01/2015; 3(1). DOI:10.14814/phy2.12268
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