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Increased Phosphorylation of Akt Substrate of 160 kDa (AS160) in Rat Skeletal Muscle in Response to Insulin or Contractile Activity
Abstract
In 3T3-L1 adipocytes, insulin-stimulated GLUT4 translocation requires phosphorylation of the protein designated Akt substrate of 160 kDa (AS160). Both insulin and contractions activate Akt in skeletal muscle. Therefore, we assessed the effects in skeletal muscle of each stimulus on phosphorylation of proteins, including AS160, on the Akt phosphomotif. Isolated rat epitrochlearis muscles were incubated with insulin (for time course and dose response), stimulated to contract, or incubated with 5-aminoimidazole-4-carboxamide-1-β-d-ribofuranoside (AICAR) and used to assess the following: serine-phosphorylation of Akt (P-Akt), immunoreactivity with an antibody recognizing the Akt phosphomotif (α-phospho-[Ser/Thr] Akt substrate [PAS]), and PAS immunoreactivity of samples immunoprecipitated with anti-AS160. P-Akt peaked at 5 min of insulin, and PAS immunoreactivity subsequently peaked for proteins of 250 kDa (10 min) and 160 kDa (15 min). P-Akt, PAS-160, and PAS-250 increased significantly with 0.6 nmol/l insulin. Contractile activity led to increased P-Akt and PAS immunoreactivity of proteins of 160 and 250 kDa. The 160-kDa protein was confirmed to be AS160 based on elevated PAS immunoreactivity in AS160 immunoprecipitates. Wortmannin inhibited insulin (120 nmol/l) and contraction effects on AS160 phosphorylation. Incubation with AICAR caused increased phosphorylation of AMP-activated protein kinase and AS160 but not Akt. Our working hypothesis is that phosphorylation of these putative Akt substrates is important for some of the insulin and contraction bioeffects.
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“AMPK rather than Akt has been proposed to be a possible candidate regulating TBC1D4 activity in response to exercise and muscle contractions given 1) Akt phosphorylation is not increased by exercise; 2) AICAR stimulates glucose uptake independently of insulin; 3) AICAR increases phosphorylation of TBC1D4 at PAS motifs in both rat [115] and mouse skeletal muscle [76]; and 4) glucose uptake is impa”
From AMPK and Exercise: Glucose Uptake and Insulin Sensitivity (2013) · cites this paper as [115]
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Insulin-stimulated Phosphorylation of a Rab GTPase-activating Protein Regulates GLUT4 Translocation
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BackgroundInfluentialHolland, W. L., & Summers, S. A. (2008) · Endocrine Reviews · doi:10.1210/er.2007-0025 · Cited by 604
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“In brief, AICAR treatment was shown to increase phosphorylation of AS160 at four sites, and that expression of an AS160 mutant (with all four phosphorylation sites mutated) reduced AICAR-induced glucose uptake (29).”
AMPK in skeletal muscle function and metabolism
Kjøbsted, R., Hingst, J. R., Fentz, J., Foretz, M., Sanz, M.-N., Pehmøller, C. K., Shum, M., Marette, A., Mounier, R., Treebak, J. T., et al. (2017) · The FASEB Journal · doi:10.1096/fj.201700442r · Cited by 517
“It has been proposed that phosphorylation of TBC1D4 may provide a mechanism for exercise-induced improvements in muscle insulin sensitivity.”
BackgroundInfluentialEmerging role for AS160/TBC1D4 and TBC1D1 in the regulation of GLUT4 traffic
Sakamoto, K., & Holman, G. D. (2008) · American Journal of Physiology-Endocrinology and Metabolism · doi:10.1152/ajpendo.90331.2008 · Cited by 481
“Moreover, both AS160 and TBC1D1 are phosphorylated at multiple sites by a variety of agonists that stimulate different protein kinases in intact cells (5, 8, 13, 25, 58, 59), indicating complex regulation and roles for these proteins.”
BackgroundThe Akt kinases: Isoform specificity in metabolism and cancer
Gonzalez, E., & McGraw, T. E. (2009) · Cell Cycle · doi:10.4161/cc.8.16.9335 · Cited by 485
Exercise training‐induced improvements in insulin action
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“AS160 is also phosphorylated in response to exercise in human skeletal muscle (Deshmukh et al. 2006, Frosig et al. 2007) and after in vitro contraction in rodent skeletal muscle (Bruss et al. 2005, Kramer et al. 2006).”
BackgroundInfluentialSano, H., Eguez, L., Teruel, M. N., Fukuda, M., Chuang, T. D., Chavez, J. A., Lienhard, G. E., & McGraw, T. E. (2007) · Cell Metabolism · doi:10.1016/j.cmet.2007.03.001 · Cited by 340
“…insulin action is best documented in studies of cultured model adipocytes, recent studies have shown that AS160 is a likely mediator of insulin action in rodents and humans as well (Bruss et al., 2005; Deshmukh et al., 2006; Karlsson et al., 2006; Kramer et al., 2006a, 2006b; Treebak et al., 2006).”
BackgroundSelf-citationSkeletal Muscle Glucose Uptake During Exercise: How is it Regulated?
Rose, A. J., & Richter, E. A. (2005) · Physiology · doi:10.1152/physiol.00012.2005 · Cited by 386
“However, both PKB and AS160 are unlikely to be involved in contraction-stimulated glucose uptake, as their activation/phosphorylation with contraction is inhibitable by the drug wortmannin (17, 114), whereas typically contraction-stimulated glucose transport in incubated muscle is not (see above).”
BackgroundExercise and type 2 diabetes: molecular mechanisms regulating glucose uptake in skeletal muscle
Stanford, K. I., & Goodyear, L. J. (2014) · AJP Advances in Physiology Education · doi:10.1152/advan.00080.2014 · Cited by 370
“It is phosphorylated on six different phospho-Akt-substrate (PAS) sites in response to both insulin and exercise in skeletal muscle (5, 43, 76).”
BackgroundSergi, D., Naumovski, N., Heilbronn, L. K., Abeywardena, M., O’Callaghan, N., Lionetti, L., & Luscombe-Marsh, N. (2019) · Frontiers in Physiology · doi:10.3389/fphys.2019.00532 · Cited by 347
Miyamoto, S., Murphy, A. N., & Brown, J. H. (2007) · Cell Death and Differentiation · doi:10.1038/sj.cdd.4402285 · Cited by 347
“This is, to our knowledge, the first experimental evidence that HK-II serves as a substrate for phosphorylation by Akt.”
MethodInfluentialInsulin in Central Nervous System: More than Just a Peripheral Hormone
Duarte, A. I., Moreira, P. I., & Oliveira, C. R. (2012) · Journal of Aging Research · doi:10.1155/2012/384017 · Cited by 337
“[30, 40, 46–48] and phosphorylated by protein kinase 3-”
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Contraction signaling to glucose transport in skeletal muscle
Jessen, N., & Goodyear, L. J. (2005) · Journal of Applied Physiology · doi:10.1152/japplphysiol.00175.2005 · Cited by 311
“However, similar to contraction-induced Akt activity, contraction-induced AS160 phosphorylation is inhibited by wortmannin (9).”
BackgroundEffect of Acute Exercise on AMPK Signaling in Skeletal Muscle of Subjects with Type 2 Diabetes
Sriwijitkamol, A., Coletta, D. K., Wajcberg, E., Balbontin, G. B., Reyna, S. M., Barrientes, J., Eagan, P. A., Jenkinson, C. P., Cersosimo, E., DeFronzo, R. A., et al. (2007) · Diabetes · doi:10.2337/db06-1119 · Cited by 304
“ACC, acetyl CoA carboxylase; AICAR, 5-aminoimidazole-4-carboxamide-1-D-ribofuranoside; AMPK, AMP-activated protein kinase; FFA, free fatty acid; IL, interleukin; NRF, nuclear respiratory factor; OGTT, oral glucose tolerance test; PAS, phospho-Akt substrate; PGC, peroxisome proliferator–activated receptor coactivator.”
BackgroundInfluentialKarlsson, H., Zierath, J. R., Kane, S., Krook, A., Lienhard, G. E., & Wallberg‐Henriksson, H. (2005) · Diabetes · doi:10.2337/diabetes.54.6.1692 · Cited by 299
“Furthermore, in rat epitrochlearis skeletal muscle, a 160-kDa protein, presumably AS160, is phosphorylated in a dosage-dependent manner by insulin during in vitro incubations (14,15).”
BackgroundSelf-citationAMPK and Exercise: Glucose Uptake and Insulin Sensitivity
O'Neill, H. M. (2013) · Diabetes & Metabolism Journal · doi:10.4093/dmj.2013.37.1.1 · Cited by 295
“In brief, evidence that TBC1D4 is involved in contraction-mediated glucose uptake came from the following studies: 1) Rat epitrochlearis muscle contracted in vitro in the absence of insulin increased TBC1D4 phosphorylation [115].”
BackgroundResultInsulin action on glucose transporters through molecular switches, tracks and tethers
Zaid, H., Antonescu, C. N., Randhawa, V. K., & Klip, A. (2008) · Biochemical Journal · doi:10.1042/bj20080723 · Cited by 294
AS160 Regulates Insulin- and Contraction-stimulated Glucose Uptake in Mouse Skeletal Muscle
Kramer, H. F., Witczak, C. A., Taylor, E. B., FUJII, N. L., Hirshman, M. F., & Goodyear, L. J. (2006) · Journal of Biological Chemistry · doi:10.1074/jbc.m605461200 · Cited by 288
Regulation of Glucose Transporter Translocation in Health and Diabetes
Bogan, J. S. (2012) · Annual Review of Biochemistry · doi:10.1146/annurev-biochem-060109-094246 · Cited by 279
Treebak, J. T., Glund, S., Deshmukh, A. S., Klein, D. K., Long, Y. C., Jensen, T. E., Jørgensen, S. B., Viollet, B., Andersson, L., Neumann, D., et al. (2006) · Diabetes · doi:10.2337/db06-0175 · Cited by 289
“Insulin increases AS160 phosphorylation in a wortmanninsensitive manner in 3T3-L1 adipocytes (13) and skeletal muscle (14).”
BackgroundInfluentialMolecular Mechanism of Insulin Resistance in Obesity and Type 2 Diabetes
Choi, K., & Kim, Y. (2010) · The Korean Journal of Internal Medicine · doi:10.3904/kjim.2010.25.2.119 · Cited by 281
Taylor, E. B., An, D., Kramer, H. F., Yu, H., FUJII, N. L., Röckl, K. S. C., Bowles, N. P., Hirshman, M. F., Xie, J., Feener, E. P., et al. (2008) · Journal of Biological Chemistry · doi:10.1074/jbc.m708839200 · Cited by 268
Role of AMPK in skeletal muscle metabolic regulation and adaptation in relation to exercise
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“Interestingly, studies in rat muscle have shown that AS160 is phosphorylated both by AICAR and ex vivo contraction, suggesting that AS160 is involved in AMPK-dependent GLUT4 translocation (Bruss et al. 2005).”
BackgroundThong, F. S. L., Bilan, P. J., & Klip, A. (2007) · Diabetes · doi:10.2337/db06-0900 · Cited by 239
“Insulin increases AS160 phosphorylation in 3T3-L1 adipocytes (2) and skeletal muscle (8,9).”
BackgroundLeptin, resistin and visfatin: the missing link between endocrine metabolic disorders and immunity
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“Glucose uptake into the cells is stimulated by insulin and leptin activating the JAK2/IRS/PI3K/AKT signaling pathway [103] and triggering the translocation of the GLUT4 from the cytosol to the cell surface [104] Downregulation of PI3K and AKT indicates an insufficiency of insulin to maintain the normal signaling [105]…”
BackgroundO’Gorman, D. J., Karlsson, H. K. R., McQuaid, S., Yousif, O., Rahman, Y., Gasparro, D., Glund, S., Chibalin, A. V., Zierath, J. R., & Nolan, J. J. (2006) · Diabetologia · doi:10.1007/s00125-006-0457-3 · Cited by 226
“Interestingly, AS160 is also phosphorylated in response to muscle contraction, and as such may serve as a key intermediary in insulin-induced, as well as contraction-induced glucose transport [28].”
BackgroundTurning Signals On and Off: GLUT4 Traffic in the Insulin-Signaling Highway
Thong, F. S. L., Dugani, S. B., & Klip, A. (2005) · Physiology · doi:10.1152/physiol.00017.2005 · Cited by 227
“Indeed, muscle contraction/exercise, a potent stimulus of GLUT4 translocation from an intracellular compartment distinct from insulin and glucose uptake, was recently shown to increase Akt and AS160 phosphorylation in a wortmannin-dependent manner (17).”
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“ered protein that regulates insulin-stimulated GLUT4 translocation in 3T3-L1 adipocytes (38), L6 myotubes (39), and rat skeletal muscle (40).”
BackgroundAMP-activated protein kinase and the regulation of glucose transport
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“In the nonphosphorylated state, AS160 prevents the translocation of GLUT4 to the cell surface (26, 80), and when AS160 is phosphorylated by Akt on several phospho-motifs (12, 62) GLUT4 translocates.”
PI(3,4,5)P 3 Engagement Restricts Akt Activity to Cellular Membranes
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Rab8A and Rab13 are activated by insulin and regulate GLUT4 translocation in muscle cells
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Role of Akt substrate of 160 kDa in insulin-stimulated and contraction-stimulated glucose transport
Cartee, G. D., & Wojtaszewski, J. F. P. (2007) · Applied Physiology, Nutrition, and Metabolism · doi:10.1139/h07-026 · Cited by 184
“In light of the these facts, it was somewhat unexpected when the most distal insulin-signaling protein that has been linked to GLUT4 translocation in adipocytes, AS160, was found to become phosphorylated in skeletal muscle in response not only to insulin but also to contractile activity (Bruss et al. 2005).”
BackgroundResultInfluentialSelf-citationGeraghty, K. M., Chen, S., Harthill, J. E., Ibrahim, A. F., Toth, R., Morrice, N. A., Vandermoere, F., Moorhead, G. B., Hardie, D. G., & MacKintosh, C. (2007) · Biochemical Journal · doi:10.1042/bj20070649 · Cited by 181
Francis, G. J., Martinez, J. A., Liu, W. Q., Xu, K., Ayer, A. B., Fine, J. M., Tuor, U. I., Glazner, G. W., Hanson, L. R., Frey, W. H., et al. (2008) · Brain · doi:10.1093/brain/awn288 · Cited by 175
RetractedInsulin receptor signals regulating GLUT4 translocation and actin dynamics.
Kanzaki, M. (2006) · Endocrine journal · doi:10.1507/endocrj.kr-65 · Cited by 181
“report also suggested involvement of AMP-kinase in the phosphorylation of AS160 in muscle in response to contractile activity [103].”
BackgroundMechanotransduction and the regulation of mTORC1 signaling in skeletal muscle
Hornberger, T. A. (2011) · The International Journal of Biochemistry & Cell Biology · doi:10.1016/j.biocel.2011.05.007 · Cited by 170
“…2005, Deshmukh et al., 2006, Haddad and Adams, 2006, Bodine et al., 2001, Carlson et al., 2001, Spangenburg and McBride, 2006, Lockhart et al., 2006, Bruss et al., 2005), and iii) constitutive activation of the PI3K→PKB pathway induces mTORC1 signaling and promotes skeletal muscle growth via a…”
BackgroundInsulin signaling and glucose transport in insulin resistant human skeletal muscle
Karlsson, H. K. R., & Zierath, J. R. (2007) · Cell Biochemistry and Biophysics · doi:10.1007/s12013-007-0030-9 · Cited by 159
“In addition, AS160 is phosphorylated in response to insulin in a dose-dependent fashion in rat skeletal muscle [46, 47 ].”
BackgroundChavez, J. A., Roach, W. G., Keller, S. R., Lane, W. S., & Lienhard, G. E. (2008) · Journal of Biological Chemistry · doi:10.1074/jbc.m708934200 · Cited by 165
Self-citationChen, S., Wasserman, D. H., MacKintosh, C., & Sakamoto, K. (2011) · Cell Metabolism · doi:10.1016/j.cmet.2010.12.005 · Cited by 161
Roles of TBC1D1 and TBC1D4 in insulin- and exercise-stimulated glucose transport of skeletal muscle
Cartee, G. D. (2014) · Diabetologia · doi:10.1007/s00125-014-3395-5 · Cited by 158
“In isolated rat epitrochlearis, a phosphatidylinositol 3-kinase (PI3K) inhibitor (wortmannin) prevented contraction-stimulated PAS-TBC1D4 without attenuating contraction-stimulated glucose transport, and an AMPK-inhibitor (compound C) reduced contraction-stimulated glucose transport without altering PAS-TBC1D4 [12, 62…”
BackgroundSelf-citationExercise and regulation of carbohydrate metabolism
Mul, J. D., Stanford, K. I., Hirshman, M. F., & Goodyear, L. J. (2015) · Progress in molecular biology and translational science · doi:10.1016/bs.pmbts.2015.07.020 · Cited by 151
“Akt-substrate (PAS) sites and both insulin and exercise increase AS160 PAS phosphorylation in skeletal muscle.(78,81,82) Prolonged exercise in humans and rats,(78) as well as AICAR, are also known to cause AS160 PAS phosphorylation.”
TBC1D1 Regulates Insulin- and Contraction-Induced Glucose Transport in Mouse Skeletal Muscle
An, D., Toyoda, T., Taylor, E. B., Yu, H., Fujii, N., Hirshman, M. F., & Goodyear, L. J. (2010) · Diabetes · doi:10.2337/db09-1266 · Cited by 147
“Insulin, exercise, and the AMPK activator 5 -aminoimidazole-4-carboxymide-1- -Dribofuranoside (AICAR) all cause phosphorylation of AS160 on PAS sites in skeletal muscle (5,7,10), and there is good evidence that phosphorylation of these sites inhibits AS160 activity, leading to trafficking of GLUT4 vesicles to the cell…”
BackgroundExercise-induced AMPK activity in skeletal muscle: Role in glucose uptake and insulin sensitivity
Friedrichsen, M., Mortensen, B., Pehmøller, C., Birk, J. B., & Wojtaszewski, J. F. P. (2013) · Molecular and Cellular Endocrinology · doi:10.1016/j.mce.2012.06.013 · Cited by 143
“Several studies have demonstrated TBC1D1 and TBC1D4 phosphorylation and 14-3-3- binding in response to AICAR and exercise/contraction in skeletal muscle of rodents (Funai and Cartee, 2009; Taylor et al., 2008; Treebak et al., 2006; Kramer et al., 2006a; Pehmoller et al., 2009; Bruss et al., 2005).”
Duarte, A. I., Rodrigues‐Santos, P., Oliveira, C. R., Santos, M. S., & Rego, A. C. (2008) · Biochimica et Biophysica Acta (BBA) - Molecular Cell Research · doi:10.1016/j.bbamcr.2008.02.016 · Cited by 148
Muscle cells engage Rab8A and myosin Vb in insulin-dependent GLUT4 translocation
Ishikura, S., & Klip, A. (2008) · American Journal of Physiology-Cell Physiology · doi:10.1152/ajpcell.00277.2008 · Cited by 139
“AS160 is phosphorylated in muscle and fat cells in response to insulin (2, 13).”
BackgroundTreebak, J. T., Birk, J. B., Rose, A. J., Kiens, B., Richter, E. A., & Wojtaszewski, J. F. P. (2006) · American Journal of Physiology-Endocrinology and Metabolism · doi:10.1152/ajpendo.00380.2006 · Cited by 133
“There is now evidence that AS160 may also be targeted by AMPK in skeletal muscle of rodents as 5-aminoimidazole-4-carboxamide-1-β-D-ribofuranoside (AICAR), an activator of AMPK, is able to induce phosphorylation of AS160 in epitrochlearis muscles from rats and extensor digitorum longus muscles from mice (3; 23; 40).”
BackgroundDeshmukh, A. S., Coffey, V. G., Zhong, Z., Chibalin, A., Hawley, J. A., & Zierath, J. R. (2006) · Diabetes · doi:10.2337/db05-1419 · Cited by 126
“Insulin and contraction activate Akt in skeletal muscle (11).”
BackgroundMethodInfluentialImprovement of insulin sensitivity by antagonism of the renin-angiotensin system
Henriksen, E. J. (2007) · American Journal of Physiology-Regulatory, Integrative and Comparative Physiology · doi:10.1152/ajpregu.00147.2007 · Cited by 127
“additional distal step important in the activation of glucose transport in muscle (7).”
BackgroundBergouignan, A., Latouche, C., Heywood, S., Grace, M. S., Reddy-Luthmoodoo, M., Natoli, A. K., Owen, N., Dunstan, D. W., & Kingwell, B. A. (2016) · Scientific Reports · doi:10.1038/srep32044 · Cited by 121
Potential role of TBC1D4 in enhanced post-exercise insulin action in human skeletal muscle
Treebak, J. T., Frøsig, C., Pehmøller, C., Chen, S., Maarbjerg, S. J., Brandt, N., MacKintosh, C., Zierath, J. R., Hardie, D. G., Kiens, B., et al. (2009) · Diabetologia · doi:10.1007/s00125-009-1294-y · Cited by 119
Funai, K., Schweitzer, G. G., Sharma, N., Kanzaki, M., & Cartee, G. D. (2009) · American Journal of Physiology-Endocrinology and Metabolism · doi:10.1152/ajpendo.00194.2009 · Cited by 119
Self-citationPrior exercise increases phosphorylation of Akt substrate of 160 kDa (AS160) in rat skeletal muscle
Arias, E. B., Kim, J., Funai, K., & Cartee, G. D. (2007) · American Journal of Physiology-Endocrinology and Metabolism · doi:10.1152/ajpendo.00602.2006 · Cited by 118
“AS160 was first recognized to be an Akt substrate, but incubation of isolated rat epitrochlearis muscle with the AMP activator 5-aminoimidazole-4-carboxamide-1- -D-ribofuranoside (AICAR) can also induce an increase in AS160 phosphorylation despite unchanged Akt phosphorylation, implicating AS160 as a substrate for AMP…”
BackgroundInfluentialSelf-citationSatoh, T. (2014) · International Journal of Molecular Sciences · doi:10.3390/ijms151018677 · Cited by 117
“Phosphorylation of AS160 occurs also in skeletal muscle cells upon insulin stimulation and contraction [26,27].”
BackgroundGLUT4 translocation: The last 200 nanometers
Watson, R. T., & Pessin, J. E. (2007) · Cellular Signalling · doi:10.1016/j.cellsig.2007.06.003 · Cited by 109
dos Santos, J. M., Moreli, M. L., Tewari, S., & Benite‐Ribeiro, S. A. (2015) · Metabolism · doi:10.1016/j.metabol.2015.09.013 · Cited by 108
“In fact, studies from the last three decades have demonstrated the benefits of exercise and muscle contraction on improving insulin sensitivity [33,40,41].”
Influence of Acute and Chronic Exercise on Glucose Uptake
Röhling, M., Herder, C., Stemper, T., & Müssig, K. (2016) · Journal of Diabetes Research · doi:10.1155/2016/2868652 · Cited by 114
“In line with these human studies, animal studies found that contraction-induced glucose uptake by electrical stimulation was also modulated by an increase in phosphorylation of AS160 and TBC1D1 proteins [57] (Tables 2 and 3).”
ResultCurrent understanding of increased insulin sensitivity after exercise – emerging candidates
Maarbjerg, S. J., Sylow, L., & Richter, E. A. (2011) · Acta Physiologica · doi:10.1111/j.1748-1716.2011.02267.x · Cited by 104
“Increased TBC1D4 PAS/thr642 phosphorylation in response to insulin is well-conserved as it is observed in both human (Karlsson et al. 2005, Hojlund et al. 2008, Treebak et al. 2009), rat (Arias et al. 2004, Bruss et al. 2005) and mouse skeletal muscle (Taylor et al. 2008, Chen et al. 2011).”
BackgroundContraction regulates site-specific phosphorylation of TBC1D1 in skeletal muscle
Vichaiwong, K., Purohit, S., An, D., Toyoda, T., Jessen, N., Hirshman, M. F., & Goodyear, L. J. (2010) · Biochemical Journal · doi:10.1042/bj20101100 · Cited by 102
Getting the Akt Together: Guiding Intracellular Akt Activity by PI3K
Yudushkin, I. A. (2019) · Biomolecules · doi:10.3390/biom9020067 · Cited by 104
Rescue and regeneration of injured peripheral nerve axons by intrathecal insulin
Toth, C. C., Brussee, V., Martinez, J. A., McDonald, D. S., Cunningham, F. A., & Zochodne, D. W. (2006) · Neuroscience · doi:10.1016/j.neuroscience.2005.11.065 · Cited by 101
Cleasby, M. E., Reinten, T. A., Cooney, G. J., James, D. E., & Kraegen, E. W. (2006) · Molecular Endocrinology · doi:10.1210/me.2006-0154 · Cited by 101
Regulation of Carbohydrate Metabolism, Lipid Metabolism, and Protein Metabolism by AMPK
Angın, Y., Beauloye, C., Horman, S., & Bertrand, L. (2016) · Proceedings of the Fourth International Symposium on Polarization Phenomena in Nuclear Reactions · doi:10.1007/978-3-319-43589-3_2 · Cited by 100
Benton, C. R., Wright, D. C., & Bonen, A. (2008) · Applied Physiology, Nutrition, and Metabolism · doi:10.1139/h08-074 · Cited by 95
Peck, G. R., Ye, S., Pham, V., Fernando, R. N., Macaulay, S. L., Chai, S. Y., & Albiston, A. L. (2006) · Molecular Endocrinology · doi:10.1210/me.2005-0476 · Cited by 88
Thyfault, J. P., Cree, M. G., Zheng, D., Zwetsloot, J. J., Tapscott, E. B., Koves, T. R., Ilkayeva, O., Wolfe, R. R., Muoio, D. M., & Dohm, G. L. (2007) · American Journal of Physiology-Cell Physiology · doi:10.1152/ajpcell.00311.2006 · Cited by 87
“Contraction and insulin induced AS160 phosphorylation independently, and the combined treatments acted synergistically (5).”
BackgroundGupte, A. A., Bomhoff, G. L., & Geiger, P. C. (2008) · Journal of Applied Physiology · doi:10.1152/japplphysiol.00148.2008 · Cited by 88
“Akt substrate of 160 kDa (AS160) is a Rab GTPase-activating protein previously shown to be activated by insulin and muscle contraction, the latter most likely via AMPK (8, 27).”
BackgroundDivergent cell signaling after short-term intensified endurance training in human skeletal muscle
Benziane, B., Burton, T. J., Scanlan, B., Galuska, D., Canny, B. J., Chibalin, A. V., Zierath, J. R., & Stepto, N. K. (2008) · American Journal of Physiology-Endocrinology and Metabolism · doi:10.1152/ajpendo.90428.2008 · Cited by 119
Jensen, T. E., Wojtaszewski, J. F. P., & Richter, E. A. (2009) · Acta Physiologica · doi:10.1111/j.1748-1716.2009.01979.x · Cited by 78
“For more in-depth discussion of structural features of AMPK, see Towler & Hardie (2007), Carling et al. (2008) and Bright et al.”
BackgroundGeneral aspects of muscle glucose uptake
Alvim, R. D. O., CHEUHEN, M. R., MACHADO, S. R., de Sousa, A. G. P., & SANTOS, P. C. J. L. (2015) · Anais da Academia Brasileira de Ciências · doi:10.1590/0001-3765201520140225 · Cited by 92
“In addition, previous studies have reported increased AS160 phosphorylation with in vitro contractions in rat epitrochlearis muscles (Bruss et al. 2005).”
BackgroundNesfatin-1 in Human and Murine Cardiomyocytes: Synthesis, Secretion, and Mobilization of GLUT-4
Feijóo‐Bandín, S., Rodríguez‐Penas, D., García‐Rúa, V., Mosquera‐Leal, A., Otero, M. F., Pereira, E., Rubio, J. A., Martínez, I., Seoane, L. M., Gualillo, O., et al. (2013) · Endocrinology · doi:10.1210/en.2013-1497 · Cited by 78
Stöckli, J., Davey, J. R., Hohnen-Behrens, C., Xu, A., James, D. E., & Ramm, G. (2008) · Molecular Endocrinology · doi:10.1210/me.2008-0111 · Cited by 78
Exercise and Insulin: Convergence or Divergence at AS160 and TBC1D1?
Cartee, G. D., & Funai, K. (2009) · Exercise and Sport Sciences Reviews · doi:10.1097/jes.0b013e3181b7b7c5 · Cited by 77
“The PI3K inhibitor wortmannin eliminates insulin stimulation of both PAS-AS160 and glucose transport in isolated rat epitrochlearis muscle (4,11).”
BackgroundInfluentialSelf-citationFunai, K., & Cartee, G. D. (2009) · Diabetes · doi:10.2337/db08-1477 · Cited by 76
“In skeletal muscle, insulin or contraction results in elevated PAS-AS160 (18,19), and AS160 phosphorylation appears to regulate glucose transport (20).”
BackgroundResultInfluentialSelf-citationThe Rab-GTPase-activating protein TBC1D1 regulates skeletal muscle glucose metabolism
Szekeres, F. L. M., Chadt, A., Tom, R. Z., Deshmukh, A. S., Chibalin, A., Björnholm, M., Al‐Hasani, H., & Zierath, J. R. (2012) · American Journal of Physiology-Endocrinology and Metabolism · doi:10.1152/ajpendo.00605.2011 · Cited by 77
Maris, M., Overbergh, L., Gysemans, C. A., Waget, A., Cardozo, A. K., Verdrengh, E., da Cunha, J. P. M. C. M., Gotoh, T., Cnop, M., Eizirik, D. L., et al. (2012) · Diabetologia · doi:10.1007/s00125-011-2427-7 · Cited by 74
“Finally, Chop mice have no ectopic fat deposition in muscle and a preserved AKT serine phosphorylation on insulin stimulation, which could contribute to preserving peripheral insulin sensitivity in these mice [47].”
BackgroundIntranasal Insulin Ameliorates Experimental Diabetic Neuropathy
Francis, G. J., Martinez, J., Liu, W., Nguyen, T. M., Ayer, A. B., Fine, J. M., Zochodne, D. W., Hanson, L. R., Frey, W. H., & Toth, C. C. (2009) · Diabetes · doi:10.2337/db08-1287 · Cited by 72
RetractedSignalling mechanisms in skeletal muscle: role in substrate selection and muscle adaptation
Hawley, J. A., Hargreaves, M., & Zierath, J. R. (2006) · Essays in Biochemistry · doi:10.1042/bse0420001 · Cited by 70
“AS160 is phosphorylated in rat skeletal muscle in response to contraction [30] and also in human skeletal muscle in response to exercise [31].”
BackgroundLiu, Y., Lai, Y., Hill, E. V., Tyteca, D., Carpentier, S., Ingvaldsen, A., Vertommen, D., Lantier, L., Foretz, M., Dequiedt, F., et al. (2013) · Biochemical Journal · doi:10.1042/bj20130644 · Cited by 67
Tang, S., Tabet, F., Cochran, B. J., Torres, L., Wu, B. J., Barter, P. J., & Rye, K. (2019) · Scientific Reports · doi:10.1038/s41598-018-38014-3 · Cited by 70
Loss of HIF-1α impairs GLUT4 translocation and glucose uptake by the skeletal muscle cells
Sakagami, H., Makino, Y., Mizumoto, K., Isoe, T., Takeda, Y., Watanabe, J., Fujita, Y., Takiyama, Y., Abiko, A., & Haneda, M. (2014) · American Journal of Physiology-Endocrinology and Metabolism · doi:10.1152/ajpendo.00597.2012 · Cited by 65
Substrate Trapping Proteomics Reveals Targets of the βTrCP2/FBXW11 Ubiquitin Ligase
Kim, T. Y., Siesser, P. F., Rossman, K. L., Goldfarb, D., MacKinnon, K. M., Yan, F., Yi, X., MacCoss, M. J., Moon, R. T., Der, C. J., et al. (2014) · Molecular and Cellular Biology · doi:10.1128/mcb.00857-14 · Cited by 64
Funai, K., Schweitzer, G. G., Castorena, C. M., Kanzaki, M., & Cartee, G. D. (2010) · American Journal of Physiology-Endocrinology and Metabolism · doi:10.1152/ajpendo.00758.2009 · Cited by 63
“ately after contraction by isolated epitrochlearis muscles (4, 14) but whether this phosphorylation persists for hours after contraction remains to be determined.”
BackgroundSelf-citationRole of Akt2 in contraction-stimulated cell signaling and glucose uptake in skeletal muscle
Sakamoto, K., Arnolds, D. E., Fujii, N., Kramer, H. F., Hirshman, M. F., & Goodyear, L. J. (2006) · American Journal of Physiology-Endocrinology and Metabolism · doi:10.1152/ajpendo.00204.2006 · Cited by 63
“While these pathways are likely to converge before GLUT4 translocation, potentially at the level of AS160 (3), our findings make clear that Akt2 is necessary for the stimulation of glucose uptake in skeletal muscle by insulin, but not exercise.”
BackgroundResultAMPK activators – potential therapeutics for metabolic and other diseases
Zhou, G., Sebhat, I. K., & Zhang, B. B. (2009) · Acta Physiologica · doi:10.1111/j.1748-1716.2009.01967.x · Cited by 63
“Acutely, AMPK activation increases glucose uptake via Glut4 surface membrane translocation initiated by phosphorylation of a 160-kDa AKT substrate (AS160) (Bruss et al. 2005, Eguez et al. 2005).”
BackgroundAKT ISOFORMS-AS160-GLUT4: The defining axis of insulin resistance
Sharma, M., & Dey, C. S. (2021) · Reviews in Endocrine and Metabolic Disorders · doi:10.1007/s11154-021-09652-2 · Cited by 81
“[51] detected AS160 phosphorylation post insulin stimulation in L6 skeletal muscle cells [49–51].”
BackgroundTunduguru, R., Chiu, T. T., Ramalingam, L., Elmendorf, J. S., Klip, A., & Thurmond, D. C. (2014) · Biochemical Pharmacology · doi:10.1016/j.bcp.2014.08.033 · Cited by 61
“Under normal insulin-sensitive conditions, circulating insulin binds to the insulin receptor present on the extracellular surface of the skeletal muscle cell to initiate an intracellular signaling cascade which bifurcates downstream of phosphatidylinositol 3-kinase (PI3K) into at least two parallel pathways that lead…”
Richter, E. A., Bilan, P. J., & Klip, A. (2025) · Physiological Reviews · doi:10.1152/physrev.00033.2024 · Cited by 64
Akt/protein kinase B in skeletal muscle physiology and pathology
Wu, M., Falasca, M., & Blough, E. R. (2010) · Journal of Cellular Physiology · doi:10.1002/jcp.22353 · Cited by 60
“Similarly, Akt is rapidly activated by muscle contraction suggesting that it may play a role in contraction-induced muscle glucose uptake and protein synthesis (Atherton et al., 2005; Bruss et al., 2005; Arias et al., 2007; Katta et al., 2009b; Wu et al., 2009b).”
Background
Metadata
- Authors
- Bruss, M. D., Arias, E. B., Lienhard, G. E., & Cartee, G. D.
- Affiliations
- University of Wisconsin–Madison (US)
- University of Michigan (US)
- Dartmouth College (US)
- Venue
- Diabetes
- Publisher
- American Diabetes Association
- Published
- 2005-01-01
- Volume
- 54
- Issue
- 1
- Pages
- 41-50
- ISSN
- 0012-1797 (ISSN-L)
- 1939-327X
- OpenAlex
- W2148321229
- Cited by
- 273
- References
- 30
- Citations by year
- 2025: 2 · 2023: 1 · 2022: 14 · 2021: 9 · 2020: 5 · 2019: 10 · 2018: 11 · 2017: 7 · 2016: 7 · 2015: 16 · 2014: 16 · 2013: 11 · 2012: 20
- FWCI
- 9.97
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Diabetes (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Institutes of Health
- National Institute on Aging (AG 10026)
- National Institute of Diabetes and Digestive and Kidney Diseases (R01DK025336, DK-25336, R56DK042816)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Metabolism, Diabetes, and Cancer
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › PI3K/AKT/mTOR signaling in cancer
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Muscle Physiology and Disorders
- Keywords
- AS160, Akt phosphorylation, skeletal muscle, insulin signaling, muscle contraction, GLUT4 translocation, AMPK, wortmannin, epitrochlearis muscle
- MeSH terms
- Aminoimidazole Carboxamide, Animals, Insulin, Kinetics, Male, Muscle Contraction, Muscle Proteins, Phosphorylation, Proto-Oncogene Proteins, Ribonucleotides, Rats, Wistar, Protein Serine-Threonine Kinases, Muscle, Skeletal, Proto-Oncogene Proteins c-akt, Rats
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