Interaction between the AMP-activated protein kinase and mTOR signaling pathways
ABSTRACT The AMP-activated protein kinase (AMPK) has been referred to as an "energy sensor" because it binds to and is regulated by both AMP and ATP. The binding of AMP to AMPK allows it to be phosphorylated by upstream kinases, resulting in its activation. In contrast, the binding of ATP prevents its activation. AMPK regulates a multitude of metabolic processes that cumulatively function to maintain cellular energy homeostasis through repression of a number of energy-consuming processes with simultaneous enhancement of energy-producing processes. One downstream AMPK target that has been recently identified is the mammalian target of rapamycin (mTOR), a positive effector of cell growth and division. The focus of the present review is to briefly summarize current knowledge concerning the regulation of mTOR signaling by AMPK.
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- "Previous studies suggest that metformin suppresses mTOR, a central regulator of protein synthesis and cell growth . We found an increase in gene expression of mTOR in PBMCs of metformin-treated participants, which was not parallelled by an increase in mTOR protein. "
ABSTRACT: Prediabetes increases cardiovascular risk and is associated with excess mortality. In preclinical models, metformin has been shown to exert anti-ageing effects. In this study, we sought to assess whether metformin modulates putative effector longevity programs in prediabetic subjects. In a randomized, single-blind, placebo-controlled trial, 38 prediabetic subjects received metformin (1500 mg/day) or placebo for 2 months. At baseline and after treatment, we collected anthropometric and metabolic parameters. Gene and protein levels of SIRT1, mTOR, p53, p66Shc, SIRT1 activity, AMPK activation, telomere length, and SIRT1 promoter chromatin accessibility were determined in peripheral blood mononuclear cells (PBMCs). Plasma N-glycans, non-invasive surrogate markers of ageing, were also analysed. Compared to baseline, metformin significantly improved metabolic parameters and insulin sensitivity, increased SIRT1 gene/protein expression and SIRT1 promoter chromatin accessibility, elevated mTOR gene expression with concomitant reduction in p70S6K phosphorylation in subjects' PBMCs, and modified the plasma N-glycan profile. Compared to placebo, metformin increased SIRT1 protein expression and reduced p70S6K phosphorylation (a proxy of mTOR activity). Plasma N-glycans were also favourably modified by metformin compared to placebo. In individuals with prediabetes, metformin ameliorated effector pathways that have been shown to regulate longevity in animal models. CLINICALTRIALS. NCT01765946 - January 2013. Copyright © 2015 Elsevier B.V. All rights reserved.Nutrition Metabolism and Cardiovascular Diseases 03/2015; 25(7). DOI:10.1016/j.numecd.2015.03.007 · 3.88 Impact Factor
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- "Endurance training adaptations which signal through the adenosine monophosphate-activated kinase (AMPK)/peroxisome-proliferator-activated receptor c coactivator 1a (PGC-1a) pathway (Kimball 2006) inhibit the mTOR pathway and decrease protein synthesis (Coffey et al. 2006). Cortisol and other glucocorticoids inhibit p70 S6k phosphorylation, a downstream event in mTOR signaling (Shah et al. 2000a, b, 2002). "
ABSTRACT: Our aim was to examine the effect of betaine supplementation on selected circulating hormonal measures and Akt muscle signaling proteins after an acute exercise session. Twelve trained men (age 19.7 ± 1.23 years) underwent 2 weeks of supplementation with either betaine (B) (1.25 g BID) or placebo (P). Following a 2-week washout period, subjects underwent supplementation with the other treatment (B or P). Before and after each 2-week period, subjects performed an acute exercise session (AES). Circulating GH, IGF-1, cortisol, and insulin were measured. Vastus lateralis samples were analyzed for signaling proteins (Akt, p70 S6k, AMPK). B (vs. P) supplementation approached a significant increase in GH (mean ± SD (Area under the curve, AUC), B: 40.72 ± 6.14, P: 38.28 ± 5.54, p = 0.060) and significantly increased IGF-1 (mean ± SD (AUC), B: 106.19 ± 13.45, P: 95.10 ± 14.23, p = 0.010), but significantly decreased cortisol (mean ± SD (AUC), B: 1,079.18 ± 110.02, P: 1,228.53 ± 130.32, p = 0.007). There was no difference in insulin (AUC). B increased resting Total muscle Akt (p = 0.003). B potentiated phosphorylation (relative to P) of Akt (Ser(473)) and p70 S6 k (Thr(389)) (p = 0.016 and p = 0.005, respectively). Phosphorylation of AMPK (Thr(172)) decreased during both treatments (both p = 0.001). Betaine (vs. placebo) supplementation enhanced both the anabolic endocrine profile and the corresponding anabolic signaling environment, suggesting increased protein synthesis.Arbeitsphysiologie 09/2012; 113(3). DOI:10.1007/s00421-012-2492-8 · 2.30 Impact Factor
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- "In contrast, AMP-dependent protein kinase (AMPK) deficient mice results in muscle hypertrophy due to enhanced mTORC1 activity (Lantier et al., 2010; Mounier et al., 2009). Since Fyn null mice have increased skeletal muscle AMPK activity, and AMPK is an established inhibitor of mTORC1-dependent signaling (Kimball, 2006; Shackelford and Shaw, 2009), we anticipated that increased Fyn expression would inhibit AMPK and thereby result in mTORC1 activation. In turn, increased Fyn expression would be expected to drive muscle hypertrophy, opposite to the observed muscle atrophy phenotype. "
ABSTRACT: Skeletal muscle atrophy induced by aging (sarcopenia), inactivity, and prolonged fasting states (starvation) is predominantly restricted to glycolytic type II muscle fibers and typical spares oxidative type I fibers. However, the mechanisms accounting for muscle fiber-type specificity of atrophy have remained enigmatic. In the current study, although the Fyn tyrosine kinase activated the mTORC1 signaling complex, it also induced marked atrophy of glycolytic fibers with relatively less effect on oxidative muscle fibers. This was due to inhibition of macroautophagy via an mTORC1-independent but STAT3-dependent reduction in Vps34 protein levels and decreased Vps34/p150/Beclin1/Atg14 complex 1. Physiologically, in the fed state endogenous Fyn kinase activity was increased in glycolytic but not oxidative skeletal muscle. In parallel, Y705-STAT3 phosphorylation increased with decreased Vps34 protein levels. Moreover, fed/starved regulation of Y705-STAT3 phosphorylation and Vps34 protein levels was prevented in skeletal muscle of Fyn null mice. These data demonstrate a Fyn/STAT3/Vps34 pathway that is responsible for fiber-type-specific regulation of macroautophagy and skeletal muscle atrophy.Cell Reports 05/2012; 1(5):557-69. DOI:10.1016/j.celrep.2012.03.014 · 7.21 Impact Factor