5 research outputs found
S6 kinase deletion suppresses muscle growth adaptations to nutrient availability by activating AMP kinase
No full textS6 kinase (S6K) deletion in metazoans causes small cell size, insulin hypersensitivity, and metabolic adaptations; however, the underlying molecular mechanisms are unclear. Here we show that S6K-deficient skeletal muscle cells have increased AMP and inorganic phosphate levels relative to ATP and phosphocreatine, causing AMP-activated protein kinase (AMPK) upregulation. Energy stress and muscle cell atrophy are specifically triggered by the S6K1 deletion, independent of S6K2 activity. Two known AMPK-dependent functions, mitochondrial biogenesis and fatty acid beta-oxidation, are upregulated in S6K-deficient muscle cells, leading to a sharp depletion of lipid content, while glycogen stores are spared. Strikingly, AMPK inhibition in S6K-deficient cells restores cell growth and sensitivity to nutrient signals. These data indicate that S6K1 controls the energy state of the cell and the AMPK-dependent metabolic program, providing a mechanism for cell mass accumulation under high-calorie diet
Regulation of the mTOR/S6K pathway by cellular energy
Get PDFThe mammalian target of rapamycin (mTOR) signaling pathway integrates positive and negative signals that control cellular growth, metabolism and survival. mTOR exists in two different complexes, mTOR Complex1 and mTOR Complex2. mTOR Complex1, which is rapamycin-sensitive, phosphorylates ribosomal S6 kinase 1 (S6K1) and initiation factor 4E binding proteins (4E-BPs). mTOR Complex2, which is rapamycin-insensitive, phosphorylates and activates protein kinase B (PKB/Akt). Both mTOR complexes are stimulated by mitogens, but only mTOR Complex1 is under the control of nutrients and cellular energy status. With respect to cellular energy status, mTOR Complex1 signaling is sensitive to inhibition of both glycolytic flux and mitochondrial oxidative phosphorylation. In brief, energy deprivation affects mTOR Complex1 through two routes: an acute rapid response and a chronic long lasting response. Here we describe the mechanisms by which energy depletion influences mTOR Complex1 signaling, largely focusing on the acute response. Previous studies, mainly based on correlative evidence, argued that the acute energy deprivation response is mediated by adenosine mono phosphate-dependent protein kinase (AMPK) through the activation of the tumor suppressor, Tuberous Sclerosis Complex 1 and 2 (TSC1/2). We used specific knockout cell lines to address this issue and, unexpectedly, found that TSC1/2, recognized as a point of convergence for a number of specific signals, is dispensable for the regulation of mTOR Complex1 by acute energy depletion. Strikingly, neither the inhibitory acute nor the chronic energy-deprivation response towards mTOR Complex1 requires AMPK. Moreover, the upstream activator of AMPK, the serine/threonine protein kinase 11 (STK11/LKB1) is also dispensable for the acute energy depletion response to mTOR Complex1 signaling. The results demonstrate that acute energy depletion signals operate independently of the LKB1-AMPK-TSC2 axis on mTOR Complex1, revealing a novel autonomous energy-dependent mTOR Complex1 signaling pathway. Importantly, we find that metformin, a widely prescribed drug for the treatment of diabetes mellitus type II, which is thought to operate through the LKB1-AMPK-TSC2 axis, affects mTOR Complex1 signaling through this same autonomous energy-dependent pathway, independent of AMPK and TSC. The significance of these findings is underscored by recent clinical studies showing that patients using metformin have a lower incidence of tumor development
Central and peripheral determinants of fatigue in acute hypoxia
No full textThis thesis was submitted for the degree of Docter of Philosophy and awarded by Brunel University on 24th March 2011.Fatigue is defined as an exercise-induced decrease in maximal voluntary force produced by a muscle. Fatigue may arise from central and/or peripheral mechanisms. Supraspinal fatigue (a component of central fatigue) is defined as a suboptimal output from the motor cortex and measured using transcranial magnetic stimulation (TMS). Reductions in O2 supply (hypoxia) exacerbate fatigue and as the severity of hypoxia increases, central mechanisms of fatigue are thought to contribute more to exercise intolerance. In study 1, the feasibility of TMS to measure cortical voluntary activation and supraspinal fatigue of human knee-extensors was determined. TMS produced reliable measurements of cortical voluntary activation within- and between-days, and enabled the assessment of supraspinal fatigue. In study 2, the mechanisms of fatigue during single-limb exercise in normoxia (arterial O2 saturation [SaO2] ~98%), and mild to severe hypoxia (SaO2 93-80%) were determined. Hypoxia did not alter neuromuscular function or cortical voluntary activation of the knee-extensors at rest, despite large reductions in cerebral oxygenation. Maximal force declined by ~30% after single-limb exercise in all conditions, despite reduced exercise time in severe-hypoxia compared to normoxia (15.9 ± 5.4 vs. 24.7 ± 5.5 min; p < 0.05). Peripheral mechanisms of fatigue contributed more to the reduction in force generating capacity of the knee-extensors following single-limb exercise in normoxia and mild- to moderate-hypoxia, whereas supraspinal fatigue played a greater role in severe-hypoxia. In study 3, the effect of constant-load cycling exercise to the limit of tolerance in hypoxia (SaO2 ~80%) and normoxia was investigated. Time to the limit of tolerance was significantly shorter in hypoxia compared to normoxia (3.6 ± 1.3 vs. 8.1 ± 2.9 min; p < 0.001). The reductions in maximal voluntary force and knee-extensor twitch force at task-failure were not different in hypoxia compared to normoxia. However, the level of supraspinal fatigue was exacerbated in hypoxia, and occurred in parallel with reductions in cerebral oxygenation and O2 delivery. Supraspinal fatigue contributes to the decrease in whole-body exercise tolerance in hypoxia, presumably as a consequence of inadequate O2 delivery to the brain
Voltage-dependent anion channels: different isoforms for different functions
No full textThe Voltage-dependent anion channel (VDAC) is the most abundant protein of the outer
mitochondrial membrane (OMM) and mediates the flow of ions and metabolites between the
cytoplasm and the mitochondrial network. Here we reveal novel and unexpected roles of this
protein in the regulation of Ca2+ signaling, cell death and autophagy, throwing light on the
differential contribution of the three mammalian isoforms in these cellular processes. In particular,
we show that: i) VDAC is physically linked to the endoplasmic reticulum Ca2+ release channel
inositol-1,4,5-trisphosphate receptor (IP3R), through the molecular chaperone grp75 and the
functional coupling of these channel directly enhances Ca2+ accumulation in mitochondria; ii) the
different VDAC isoforms share common Ca2+ channelling properties in living cells but VDAC1 is
the only isotype selectively coupled to the ER Ca2+ releasing machinery, thus laying the foundations
for a preferential route specifically transmitting Ca2+-mediated cell death signals between the two
organelles; iii) VDAC2 is selectively required for the induction of the autophagic process through
the establishment of specific protein-protein interactions and the consequent assembly of
macromolecular complexes at the OMM level involved in nutrient sensing mediated by the
mammalian Target Of Rapamycin (mTOR) signaling pathway. These data highlight the pleiotropic
functions of VDAC and its role as central regulator of cell patho-physiology
Science and technology research and development in support to ITER and the Broader Approach at CEA
No full textIn parallel to the direct contribution to the procurement phase of ITER and Broader Approach, CEA has initiated research and development programmes, accompanied by experiments together with a significant modelling effort, aimed at ensuring robust operation, plasma performance, as well as mitigating the risks of the procurement phase. This overview reports the latest progress in both fusion science and technology including many areas, namely the mitigation of superconducting magnet quenches, disruption-generated runaway electrons, edge-localized modes (ELMs), the development of imaging surveillance, and heating and current drive systems for steady-state operation. The WEST (W Environment for Steady-state Tokamaks) project, turning Tore Supra into an actively cooled W-divertor platform open to the ITER partners and industries, is presented. © 2013 IAEA, Vienna.Stambaugh R, 1999, NUCL FUSION, V39, P2391, DOI 10.1088-0029-5515-39-12-304; [Anonymous], 2012, PLASMA PHYS; Aumeunier MH, 2011, IEEE T PLASMA SCI, V39, P3014, DOI 10.1109-TPS.2011.2155678; Aumeunier MH, 2012, REV SCI INSTRUM, V83, DOI 10.1063-1.4733532; Bayetti P., 2012, P 24 IAEA FUS EN C S; Becoulet M, 2012, NUCL FUSION, V52, DOI 10.1088-0029-5515-52-5-054003; Becoulet M., 2013, P 24 IAEA FUS EN C S; Bernard JM, 2013, FUSION ENG DES, V88, P950, DOI 10.1016-j.fusengdes.2013.01.040; Bucalossi J, 2011, FUSION ENG DES, V86, P684, DOI 10.1016-j.fusengdes.2011.01.114; Coatanea M, 2010, IEEE T APPL SUPERCON, V20, P427, DOI 10.1109-TASC.2009.2039705; Coatanea M, 2011, FUSION ENG DES, V86, P1418, DOI 10.1016-j.fusengdes.2011.01.105; Colas L, 2013, J NUCL MATER, V438, pS330, DOI 10.1016-j.jnucmat.2013.01.061; Colas L, 2012, PHYS PLASMAS, V19, DOI 10.1063-1.4750046; Corre Y, 2012, NUCL FUSION, V52, DOI 10.1088-0029-5515-52-10-103010; Courtois X., 2012, P 24 IAEA FUS EN C S; Dachicourt R, 2013, J NUCL MATER, V438, pS334, DOI 10.1016-j.jnucmat.2013.01.062; Decker J, 2011, NUCL FUSION, V51, DOI 10.1088-0029-5515-51-7-073025; Delpech L, 2011, AIP CONF PROC, V1406, DOI 10.1063-1.3664949; Dodeul L., 2013, FUSION ENG IN PRESS, DOI [10.1016-j.fusengdes.2013.01.015, DOI 10.1016-J.FUSENGDES.2013.01.015]; Duchateau J.L., 2012, P 24 IAEA FUS EN C S; Dumont RJ, 2013, NUCL FUSION, V53, DOI 10.1088-0029-5515-53-1-013002; Ekedahl A., 2011, P 19 TOP C RF POW PL, V1406, P399; Ekedahl A, 2010, NUCL FUSION, V50, DOI 10.1088-0029-5515-50-11-112002; Ferlay F., 2013, FUSION ENG IN PRESS, DOI [10.1016-j.fusengdes.2013.01.044, DOI 10.1016-J.FUSENGDES.2013.01.044]; Firdaouss M, 2009, J NUCL MATER, V390-91, P947, DOI 10.1016-j.jnucmat.2009.01.243; Garbet X., 2012, P 24 IAEA FUS EN C S; Giruzzi G., 2012, P 24 IAEA FUS EN C S; Grosman A., 2012, P 27 S FUS TECH LIEG; Gunn JP, 2013, J NUCL MATER, V438, pS184, DOI 10.1016-j.jnucmat.2013.01.055; Hillairet J., 2012, P 24 IAEA FUS EN C S; Hillairet J, 2012, FUSION ENG DES, V87, P275, DOI 10.1016-j.fusengdes.2012.01.007; Hillairet J, 2010, NUCL FUSION, V50, DOI 10.1088-0029-5515-50-12-125010; Hoang GT, 2009, NUCL FUSION, V49, DOI 10.1088-0029-5515-49-7-075001; Huysmans GTA, 2009, PLASMA PHYS CONTR F, V51, DOI 10.1088-0741-3335-51-12-124012; Ide S., 2012, P 24 IAEA FUS EN C S; Jacquot J., 2012, P 39 EPS C 16 INT C; Joanny M, 2012, REV SCI INSTRUM, V83, DOI 10.1063-1.4731004; Kazarian F, 2009, FUSION ENG DES, V84, P1006, DOI 10.1016-j.fusengdes.2009.03.014; Kubic M, 2013, J NUCL MATER, V438, pS509, DOI 10.1016-j.jnucmat.2013.01.105; Lamalle P, 2013, FUSION ENG DES, V88, P517, DOI 10.1016-j.fusengdes.2012.11.027; Larroque S., 2012, P 27 S FUS TECHN LIE; Litaudon X., 2012, P 24 IAEA FUS EN C S; Lotte P, 2010, REV SCI INSTRUM, V81, DOI 10.1063-1.3474653; Lutjens H, 2010, J COMPUT PHYS, V229, P8130, DOI 10.1016-j.jcp.2010.07.013; Missirlian M., 2012, P 27 S FUS TECHN LIE; Monier-Garbet P., 2012, P 24 IAEA FUS EN C S; Nardon E, 2010, NUCL FUSION, V50, DOI 10.1088-0029-5515-50-3-034002; Nicolas T, 2012, PHYS PLASMAS, V19, DOI 10.1063-1.4766893; Nicollet S, 2011, FUSION ENG DES, V86, P1497, DOI 10.1016-j.fusengdes.2011.03.102; PERKINS FW, 1989, NUCL FUSION, V29, P583, DOI 10.1088-0029-5515-29-4-004; Peysson Y, 2011, PLASMA PHYS CONTR F, V53, DOI 10.1088-0741-3335-53-12-124028; Pitts RA, 2011, J NUCL MATER, V415, pS957, DOI 10.1016-j.jnucmat.2011.01.114; Pitts RA, 2013, J NUCL MATER, V438, pS48, DOI 10.1016-j.jnucmat.2013.01.008; Preynas M, 2011, NUCL FUSION, V51, DOI 10.1088-0029-5515-51-2-023001; Reichle R., 2009, P 1 INT C ADV NUCL I, DOI [10.1109-ANIMMA.2009.5503692, DOI 10.1109-ANIMMA.2009.5503692]; Sabot R., 2010, P 37 EPS C PLASM PHY; Saint-Laurent F., 2011, P 38 EPS C STRASB FR; Saint-Laurent F., 2012, P 24 IAEA FUS EN C S; Salasca S, 2009, FUSION ENG DES, V84, P1689, DOI 10.1016-j.fusengdes.2008.12.088; Saoutic B, 2011, NUCL FUSION, V51, DOI 10.1088-0029-5515-51-9-094014; Sarazin Y., 2012, P 24 IAEA FUS EN C S; Strugarek A., 2013, PLASMA PHYS IN PRESS; Travere J.M., 2011, P 2 INT C ADV NUCL I, DOI [10.1109-ANIMMA.2011.6172871, DOI 10.1109-ANIMMA.2011.6172871]; Travere J.M., 2012, P 24 IAEA FUS EN C S; Zarzoso D, 2013, PHYS REV LETT, V110, DOI 10.1103-PhysRevLett.110.1250020
