Activity of LKB1 and AMPK-related kinases in skeletal muscle: effects of contraction, phenformin, and AICAR
Abstract
Activation of AMP-activated protein kinase (AMPK) by exercise and metformin is beneficial for the treatment of type 2 diabetes. We recently found that, in cultured cells, the LKB1 tumor suppressor protein kinase activates AMPK in response to the metformin analog phenformin and the AMP mimetic drug 5-aminoimidazole-4-carboxamide-1-beta-D-ribofuranoside (AICAR). We have also reported that LKB1 activates 11 other AMPK-related kinases. The activity of LKB1 or the AMPK-related kinases has not previously been studied in a tissue with physiological relevance to diabetes. In this study, we have investigated whether contraction, phenformin, and AICAR influence LKB1 and AMPK-related kinase activity in rat skeletal muscle. Contraction in situ, induced via sciatic nerve stimulation, significantly increased AMPKalpha2 activity and phosphorylation in multiple muscle fiber types without affecting LKB1 activity. Treatment of isolated skeletal muscle with phenformin or AICAR stimulated the phosphorylation and activation of AMPKalpha1 and AMPKalpha2 without altering LKB1 activity. Contraction, phenformin, or AICAR did not significantly increase activities or expression of the AMPK-related kinases QSK, QIK, MARK2/3, and MARK4 in skeletal muscle. The results of this study suggest that muscle contraction, phenformin, or AICAR activates AMPK by a mechanism that does not involve direct activation of LKB1. They also suggest that the effects of excercise, phenformin, and AICAR on metabolic processes in muscle may be mediated through activation of AMPK rather than activation of LKB1 or the AMPK-related kinases.
Integrity signals
Registry
Cites
Statistics
Claims the paper makes
Claims other papers make about this one
Each is checked against this paper’s own text: does it say what the citing paper says it does?
When the AMP:ATP ratio increases, the probability of AMPK being in the AMP-bound state increases; this allosterically activates AMPK and makes AMPK a more efficient substrate for LKB1, phosphorylation by which leads to full activation of the kinase.
“When the AMP:ATP ratio increases the probability of AMPK being in the AMP bound state increases.This allosterically activates AMPK [13] and makes AMPK a more efficient substrate for its upstream kinase LKB1, phosphorylation by which leads to full activation of the kinase [14].”
From New strategies in sport nutrition to increase exercise performance (2016) · cites this paper as [14]
Cites
Role of AMP-Activated Protein Kinase in Mechanism of Metformin Action
Zhou, G., Myers, R., Li, Y., Chen, Y., Shen, X., Fenyk-Melody, J., Wu, M., Ventre, J., Doebber, T., Fujii, N., et al. (2001) · Journal of Clinical Investigation · doi:10.1172/jci13505 · Cited by 5,652 · see citing works
Shaw, R. J., Kosmatka, M., Bardeesy, N., Hurley, R. L., Witters, L. A., DePinho, R. A., & Cantley, L. C. (2004) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0308061100 · Cited by 1,797 · see citing works
Hawley, S. A., Boudeau, J., Reid, J. L., Mustard, K. J., Udd, L., Mäkelä, T. P., Alessi, D. R., & Hardie, D. G. (2003) · Journal of Biology · doi:10.1186/1475-4924-2-28 · Cited by 1,666 · see citing works
LKB1 is the upstream kinase in the AMP-activated protein kinase cascade
Woods, A., Johnstone, S. R., Dickerson, K., Leiper, F. C., Fryer, L. G. D., Neumann, D., Schlattner, U., Wallimann, T., Carlson, M., & Carling, D. (2003) · Current Biology · doi:10.1016/j.cub.2003.10.031 · Cited by 1,650 · see citing works
LKB1 is a master kinase that activates 13 kinases of the AMPK subfamily, including MARK/PAR‐1
Lizcano, J. M., Göransson, O., Toth, R., Deak, M., Morrice, N. A., Boudeau, J., Hawley, S. A., Udd, L., Mäkelä, T. P., Hardie, D. G., et al. (2004) · The EMBO Journal · doi:10.1038/sj.emboj.7600110 · Cited by 1,381 · see citing works
Corton, J. M., Gillespie, J. G., Hawley, S. A., & Hardie, D. G. (1995) · European Journal of Biochemistry · doi:10.1111/j.1432-1033.1995.tb20498.x · Cited by 1,232 · see citing works
The AMP-activated protein kinase cascade – a unifying system for energy control
Carling, D. (2003) · Trends in Biochemical Sciences · doi:10.1016/j.tibs.2003.11.005 · Cited by 1,112 · see citing works
Fryer, L. G. D., Patel, A. P., & Carling, D. (2002) · Journal of Biological Chemistry · doi:10.1074/jbc.m202489200 · Cited by 1,030 · see citing works
AMP-activated protein kinase, a metabolic master switch: possible roles in Type 2 diabetes
Winder, W. W., & Hardie, D. G. (1999) · American Journal of Physiology-Endocrinology and Metabolism · doi:10.1152/ajpendo.1999.277.1.e1 · Cited by 1,000 · see citing works
Mu, J., Brozinick, J. T., Valladares, O., Bucan, M., & Birnbaum, M. J. (2001) · Molecular Cell · doi:10.1016/s1097-2765(01)00251-9 · Cited by 924 · see citing works
Management of cellular energy by the AMP‐activated protein kinase system
Hardie, D. G., Scott, J. W., Pan, D. A., & Hudson, E. R. (2003) · FEBS Letters · doi:10.1016/s0014-5793(03)00560-x · Cited by 855 · see citing works
AMP‐activated protein kinase: the energy charge hypothesis revisited
Hardie, D. G., & Hawley, S. A. (2001) · BioEssays · doi:10.1002/bies.10009 · Cited by 784 · see citing works
Scott, J. W., Hawley, S. A., Green, K. A., Anis, M., Stewart, G., Scullion, G. A., Norman, D. G., & Hardie, D. G. (2004) · Journal of Clinical Investigation · doi:10.1172/jci19874 · Cited by 754 · see citing works
Self-citationHawley, S. A., Gadalla, A. E., Olsen, G. S., & Hardie, D. G. (2002) · Diabetes · doi:10.2337/diabetes.51.8.2420 · Cited by 696 · see citing works
Activation of yeast Snf1 and mammalian AMP-activated protein kinase by upstream kinases
Hong, S. P., Leiper, F. C., Woods, A., Carling, D., & Carlson, M. (2003) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1533136100 · Cited by 597 · see citing works
Jørgensen, S. B., Viollet, B., Andreelli, F., Frøsig, C., Birk, J. B., Schjerling, P., Vaulont, S., Richter, E. A., & Wojtaszewski, J. F. P. (2004) · Journal of Biological Chemistry · doi:10.1074/jbc.m306205200 · Cited by 553 · see citing works
Boudeau, J., Baas, A. F., Deák, M., MORRICE, N. A., Kieloch, A., Schutkowski, M., Prescott, A. R., Clevers, H. C., & Alessi, D. R. (2003) · The EMBO Journal · doi:10.1093/emboj/cdg490 · Cited by 456 · see citing works
Hayashi, T., Hirshman, M. F., Fujii, N., Habinowski, S. A., Witters, L. A., & Goodyear, L. J. (2000) · Diabetes · doi:10.2337/diabetes.49.4.527 · Cited by 447 · see citing works
Ca2+ and AMPK Both Mediate Stimulation of Glucose Transport by Muscle Contractions
Wright, D. C., Hucker, K. A., Holloszy, J. O., & Han, D. H. (2004) · Diabetes · doi:10.2337/diabetes.53.2.330 · Cited by 398 · see citing works
Effect of Exercise Intensity on Skeletal Muscle AMPK Signaling in Humans
Chen, Z.-P., Stephens, T. J., Murthy, S., Canny, B. J., Hargreaves, M., Witters, L. A., Kemp, B. E., & McConell, G. K. (2003) · Diabetes · doi:10.2337/diabetes.52.9.2205 · Cited by 369 · see citing works
Fujii, N., Hayashi, T., Hirshman, M. F., Smith, J. T., Habinowski, S. A., Kaijser, L., Mu, J., Ljungqvist, O., Birnbaum, M. J., Witters, L. A., et al. (2000) · Biochemical and Biophysical Research Communications · doi:10.1006/bbrc.2000.3073 · Cited by 351 · see citing works
Sapkota, G. P., Kieloch, A., Lizcano, J., Laín, S., Arthur, J. S., Williams, M. R., Morrice, N., Deák, M., & Alessi, D. (2001) · Journal of Biological Chemistry · doi:10.1074/jbc.m009953200 · Cited by 308 · see citing works
Vascular Abnormalities and Deregulation of VEGF in Lkb1 -Deficient Mice
Ylikorkala, A., Rossi, D. J., Korsisaari, N., Luukko, K., Alitalo, K. K., Henkemeyer, M. J., & Mäkelä, T. P. (2001) · Science · doi:10.1126/science.1062074 · Cited by 299 · see citing works
Elm1p Is One of Three Upstream Kinases for the Saccharomyces cerevisiae SNF1 Complex
Sutherland, C. M., Hawley, S. A., McCartney, R. R., Leech, A., Stark, M. J. R., Schmidt, M. C., & Hardie, D. G. (2003) · Current Biology · doi:10.1016/s0960-9822(03)00459-7 · Cited by 283 · see citing works
Sugden, C., Crawford, R. M., Halford, N. G., & Hardie, D. G. (1999) · The Plant Journal · doi:10.1046/j.1365-313x.1999.00532.x · Cited by 195 · see citing works
Contraction Regulation of Akt in Rat Skeletal Muscle
Sakamoto, K., Hirshman, M. F., Aschenbach, W. G., & Goodyear, L. J. (2002) · Journal of Biological Chemistry · doi:10.1074/jbc.m112410200 · Cited by 192 · see citing works
LKB1, a protein kinase regulating cell proliferation and polarity
Boudeau, J., Sapkota, G. P., & Alessi, D. R. (2003) · FEBS Letters · doi:10.1016/s0014-5793(03)00642-2 · Cited by 189 · see citing works
Trinczek, B., Brajenovic, M., Ebneth, A., & Drewes, G. (2004) · Journal of Biological Chemistry · doi:10.1074/jbc.m304528200 · Cited by 188 · see citing works
Metabolic and mitogenic signal transduction in human skeletal muscle after intense cycling exercise
Yu, M., Stepto, N. K., Chibalin, A., Fryer, L. G. D., Carling, D., Krook, A., Hawley, J. A., & Zierath, J. R. (2003) · The Journal of Physiology · doi:10.1113/jphysiol.2002.034223 · Cited by 160 · see citing works
Yeast Pak1 Kinase Associates with and Activates Snf1
Nath, N., McCartney, R. R., & Schmidt, M. C. (2003) · Molecular and Cellular Biology · doi:10.1128/mcb.23.11.3909-3917.2003 · Cited by 151 · see citing works
Discovery of PDKI, One of the Missing Links in Insulin Signal Transduction
Alessi, D. R. (2001) · Biochemical Society Transactions · doi:10.1042/bst0290001 · Cited by 128 · see citing works
Sapkota, G. P., Deák, M., Kieloch, A., MORRICE, N. A., Goodarzi, A. A., Smythe, C., Shiloh, Y., Lees‐Miller, S. P., & Alessi, D. R. (2002) · Biochemical Journal · doi:10.1042/bj20021284 · Cited by 123 · see citing works
Flagged first, then by citations
Cited by
Sorted by citations
Kahn, B. B., Alquier, T., Carling, D., & Hardie, D. G. (2005) · Cell Metabolism · doi:10.1016/j.cmet.2004.12.003 · Cited by 2,799 · see citing works
AMP-activated/SNF1 protein kinases: conserved guardians of cellular energy
Hardie, D. G. (2007) · Nature Reviews Molecular Cell Biology · doi:10.1038/nrm2249 · Cited by 2,207 · see citing works
AMP-activated protein kinase: an energy sensor that regulates all aspects of cell function
Hardie, D. G. (2011) · Genes & Development · doi:10.1101/gad.17420111 · Cited by 1,638 · see citing works
Exercise, GLUT4, and skeletal muscle glucose uptake
Richter, E. A., & Hargreaves, M. (2013) · Physiological Reviews · doi:10.1152/physrev.00038.2012 · Cited by 1,407 · see citing works
Foretz, M., Hébrard, S., Leclerc, J., Zarrinpashneh, E., Soty, M., Mithieux, G., Sakamoto, K., Andreelli, F., & Viollet, B. (2010) · Journal of Clinical Investigation · doi:10.1172/jci40671 · Cited by 1,181 · see citing works
The AMP-activated protein kinase pathway – new players upstream and downstream
Hardie, D. G. (2004) · Journal of Cell Science · doi:10.1242/jcs.01540 · Cited by 1,136 · see citing works
The LKB1 tumor suppressor negatively regulates mTOR signaling
Shaw, R. J., Bardeesy, N. M., Manning, B. D., Lopez, L. V., Kosmatka, M., DePinho, R. A., & Cantley, L. C. (2004) · Cancer Cell · doi:10.1016/j.ccr.2004.06.007 · Cited by 1,067 · see citing works
New insights into activation and function of the AMPK
Steinberg, G. R., & Hardie, D. G. (2022) · Nature Reviews Molecular Cell Biology · doi:10.1038/s41580-022-00547-x · Cited by 1,023 · see citing works
The CREB coactivator TORC2 is a key regulator of fasting glucose metabolism
Koo, S., Flechner, L., Qi, L., Zhang, X., Screaton, R. A., Jeffries, S., Hedrick, S. A., Xu, W., Boussouar, F., Brindle, P. K., et al. (2005) · Nature · doi:10.1038/nature03967 · Cited by 996 · see citing works
AMPK and SIRT1: a long-standing partnership?
Ruderman, N. B., Julia Xu, X., Nelson, L., Cacicedo, J. M., Saha, A. K., Lan, F., & Ido, Y. (2010) · American Journal of Physiology-Endocrinology and Metabolism · doi:10.1152/ajpendo.00745.2009 · Cited by 903 · see citing works
AMP-Activated Protein Kinase – Development of the Energy Sensor Concept
Hardie, D. G., Hawley, S. A., & Scott, J. W. (2006) · The Journal of Physiology · doi:10.1113/jphysiol.2006.108944 · Cited by 813 · see citing works
LKB1-Dependent Signaling Pathways
Alessi, D. R., Sakamoto, K., & Bayascas, J. R. (2006) · Annual Review of Biochemistry · doi:10.1146/annurev.biochem.75.103004.142702 · Cited by 783 · see citing works
Glatz, J. F. C., Luiken, J. J. F. P., & Bonen, A. (2010) · Physiological Reviews · doi:10.1152/physrev.00003.2009 · Cited by 757 · see citing works
Investigating the mechanism for AMP activation of the AMP-activated protein kinase cascade
Sanders, M. J., Grondin, P., Hegarty, B. D., Snowden, M. A., & Carling, D. (2007) · Biochemical Journal · doi:10.1042/bj20061520 · Cited by 660 · see citing works
AMPK—Sensing Energy while Talking to Other Signaling Pathways
Hardie, D. G. (2014) · Cell Metabolism · doi:10.1016/j.cmet.2014.09.013 · Cited by 581 · see citing works
Deficiency of LKB1 in skeletal muscle prevents AMPK activation and glucose uptake during contraction
Sakamoto, K., McCarthy, A., Smith, D. P., Green, K. A., Hardie, D. G., Ashworth, A., & Alessi, D. R. (2005) · The EMBO Journal · doi:10.1038/sj.emboj.7600667 · Cited by 544 · see citing works
Gowans, G. J., Hawley, S. A., Ross, F. A., & Hardie, D. G. (2013) · Cell Metabolism · doi:10.1016/j.cmet.2013.08.019 · Cited by 531 · see citing works
AMPK: A Key Sensor of Fuel and Energy Status in Skeletal Muscle
Hardie, D. G., & Sakamoto, K. (2006) · Physiology · doi:10.1152/physiol.00044.2005 · Cited by 519 · see citing works
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 496 · see citing works
AMPK and the biochemistry of exercise: implications for human health and disease
Richter, E. A., & Ruderman, N. B. (2009) · Biochemical Journal · doi:10.1042/bj20082055 · Cited by 481 · see citing works
Viollet, B., Guigas, B., Leclerc, J., Hébrard, S., Lantier, L., Mounier, R., Andréelli, F., & Foretz, M. (2009) · Acta Physiologica · doi:10.1111/j.1748-1716.2009.01970.x · Cited by 486 · see citing works
AMPK: positive and negative regulation, and its role in whole-body energy homeostasis
Hardie, D. G. (2015) · Current Opinion in Cell Biology · doi:10.1016/j.ceb.2014.09.004 · Cited by 485 · see citing works
Self-citationAtherton, P. J., Babraj, J. A., Smith, K., Singh, J., Rennie, M. J., & Wackerhage, H. (2005) · The FASEB Journal · doi:10.1096/fj.04-2179fje · Cited by 475 · see citing works
Mechanism of Action of A-769662, a Valuable Tool for Activation of AMP-activated Protein Kinase
Göransson, O., McBride, A., Hawley, S. A., Ross, F. A., Shpiro, N., Foretz, M., Viollet, B., Hardie, D. G., & Sakamoto, K. (2007) · Journal of Biological Chemistry · doi:10.1074/jbc.m706536200 · Cited by 433 · see citing works
AMP-activated protein kinase and its downstream transcriptional pathways
Cantó, C., & Auwerx, J. (2010) · Cellular and Molecular Life Sciences · doi:10.1007/s00018-010-0454-z · Cited by 421 · see citing works
Steinberg, G. R., Michell, B. J., van Denderen, B. J. W., Watt, M. J., Carey, A. L., Fam, B. C., Andrikopoulos, S., Proietto, J., Görgün, C. Z., Carling, D., et al. (2006) · Cell Metabolism · doi:10.1016/j.cmet.2006.11.005 · Cited by 418 · see citing works
AMP-Activated Protein Kinase as a Drug Target
Hardie, D. G. (2006) · The Annual Review of Pharmacology and Toxicology · doi:10.1146/annurev.pharmtox.47.120505.105304 · Cited by 405 · see citing works
Important role of the LKB1-AMPK pathway in suppressing tumorigenesis in PTEN-deficient mice
Huang, X., Wullschleger, S., Shpiro, N., McGuire, V. A., Sakamoto, K., Woods, Y. L., Mcburnie, W., Fleming, S., & Alessi, D. R. (2008) · Biochemical Journal · doi:10.1042/bj20080557 · Cited by 396 · see citing works
AMPK alterations in cardiac physiology and pathology: enemy or ally?
Dyck, J. R. B., & Lopaschuk, G. D. (2006) · The Journal of Physiology · doi:10.1113/jphysiol.2006.109389 · Cited by 386 · see citing works
AMPK inhibition in health and disease
Viollet, B., Horman, S., Leclerc, J., Lantier, L., Foretz, M., Billaud, M., Giri, S., & Andreelli, F. (2010) · Critical Reviews in Biochemistry and Molecular Biology · doi:10.3109/10409238.2010.488215 · Cited by 383 · see citing works
AMP-activated protein kinase: new regulation, new roles?
Carling, D., Thornton, C., Woods, A., & Sanders, M. J. (2012) · Biochemical Journal · doi:10.1042/bj20120546 · Cited by 375 · see citing works
AMP-Activated Protein Kinase: A Target for Drugs both Ancient and Modern
Hardie, D. G., Ross, F. A., & Hawley, S. A. (2012) · Chemistry & Biology · doi:10.1016/j.chembiol.2012.08.019 · Cited by 373 · see citing works
Xie, M., Zhang, D., Dyck, J. R. B., Li, Y., Zhang, H., Morishima, M., Mann, D. L., Taffet, G. E., Baldini, A., Khoury, D. S., et al. (2006) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0604708103 · Cited by 344 · see citing works
Xue, B., & Kahn, B. B. (2006) · The Journal of Physiology · doi:10.1113/jphysiol.2006.113217 · Cited by 338 · see citing works
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 · see citing works
Effect 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 · see citing works
Srivastava, R. A. K., Pinkosky, S. L., Filippov, S. I., Hanselman, J. C., Cramer, C. T., & Newton, R. S. (2012) · Journal of Lipid Research · doi:10.1194/jlr.r025882 · Cited by 297 · see citing works
Exercise-induced histone modifications in human skeletal muscle
McGee, S. L., Fairlie, E., Garnham, A. P., & Hargreaves, M. (2009) · The Journal of Physiology · doi:10.1113/jphysiol.2009.181065 · Cited by 296 · see citing works
Activation and Signaling by the AMP-Activated Protein Kinase in Endothelial Cells
Fisslthaler, B., & Fleming, I. (2009) · Circulation Research · doi:10.1161/circresaha.109.201590 · Cited by 295 · see citing works
Predominant α2/β2/γ3 AMPK activation during exercise in human skeletal muscle
Birk, J. B., & Wojtaszewski, J. F. P. (2006) · The Journal of Physiology · doi:10.1113/jphysiol.2006.120972 · Cited by 293 · see citing works
The regulation of AMP-activated protein kinase by upstream kinases
Carling, D., Sanders, M. J., & Woods, A. (2008) · International Journal of Obesity · doi:10.1038/ijo.2008.124 · Cited by 286 · see citing works
Role of AMP-activated protein kinase in adipose tissue metabolism and inflammation
Bijland, S., Mancini, S. J., & Salt, I. P. (2013) · Clinical Science · doi:10.1042/cs20120536 · Cited by 283 · see citing works
AMPK: Regulating Energy Balance at the Cellular and Whole Body Levels
Hardie, D. G., & Ashford, M. L. J. (2014) · Physiology · doi:10.1152/physiol.00050.2013 · Cited by 280 · see citing works
Xie, Z., Dong, Y., Scholz, R., Neumann, D., & Zou, M.-H. (2008) · Circulation · doi:10.1161/circulationaha.107.744490 · Cited by 273 · see citing works
AMP-activated protein kinase: maintaining energy homeostasis at the cellular and whole-body levels
Hardie, D. G. (2014) · Annual Review of Nutrition · doi:10.1146/annurev-nutr-071812-161148 · Cited by 281 · see citing works
Role of AMPK in skeletal muscle metabolic regulation and adaptation in relation to exercise
Jørgensen, S. B., Richter, E. A., & Wojtaszewski, J. F. P. (2006) · The Journal of Physiology · doi:10.1113/jphysiol.2006.109942 · Cited by 261 · see citing works
Effect of Maternal Nutrient Restriction in Sheep on the Development of Fetal Skeletal Muscle1
Zhu, M.-J., Ford, S. P., Nathanielsz, P. W., & Du, . (2004) · Biology of Reproduction · doi:10.1095/biolreprod.104.034561 · Cited by 256 · see citing works
New roles for the LKB1→AMPK pathway
Hardie, D. G. (2005) · Current Opinion in Cell Biology · doi:10.1016/j.ceb.2005.01.006 · Cited by 255 · see citing works
Witczak, C. A., Sharoff, C. G., & Goodyear, L. J. (2008) · Cellular and Molecular Life Sciences · doi:10.1007/s00018-008-8244-6 · Cited by 250 · see citing works
Metformin Activates AMP Kinase through Inhibition of AMP Deaminase
Ouyang, J., Parakhia, R. A., & Ochs, R. S. (2010) · Journal of Biological Chemistry · doi:10.1074/jbc.m110.121806 · Cited by 246 · see citing works
The Regulation of Fat Metabolism during Aerobic Exercise
Muscella, A., Stefàno, E., Lunetti, P., Capobianco, L., & Marsigliante, S. (2020) · Biomolecules · doi:10.3390/biom10121699 · Cited by 237 · see citing works
Mechanisms of regulation of SNF1/AMPK/SnRK1 protein kinases
Crozet, P., Margalha, L., Confraria, A., Rodrigues, A., Martinho, C., Adamo, M., Elias, A., & Gonzalez, E. B. (2014) · Frontiers in Plant Science · doi:10.3389/fpls.2014.00190 · Cited by 234 · see citing works
AMP‐activated protein kinase: role in metabolism and therapeutic implications
Schimmack, G., DeFronzo, R. A., & Musi, N. (2006) · Diabetes Obesity and Metabolism · doi:10.1111/j.1463-1326.2005.00561.x · Cited by 229 · see citing works
New strategies in sport nutrition to increase exercise performance
Close, G. L., Hamilton, D. L., Philp, A., Burke, L. M., & Morton, J. P. (2016) · Free Radical Biology and Medicine · doi:10.1016/j.freeradbiomed.2016.01.016 · Cited by 221 · see citing works
LKB1 and AMPK Family Signaling: The Intimate Link Between Cell Polarity and Energy Metabolism
Jansen, M., ten Klooster, J. P., Offerhaus, G. J. A., & Clevers, H. C. (2009) · Physiological Reviews · doi:10.1152/physrev.00026.2008 · Cited by 220 · see citing works
Deficiency of LKB1 in heart prevents ischemia-mediated activation of AMPKα2 but not AMPKα1
Sakamoto, K., Zarrinpashneh, E., Budas, G. R., Pouleur, A., Dutta, A., Prescott, A. R., Vanoverschelde, J., Ashworth, A., Jovanović, A., Alessi, D. R., et al. (2005) · American Journal of Physiology-Endocrinology and Metabolism · doi:10.1152/ajpendo.00443.2005 · Cited by 221 · see citing works
Jensen, T. E., Rose, A. J., Jørgensen, S. B., Brandt, N., Schjerling, P., Wojtaszewski, J. F. P., & Richter, E. A. (2007) · American Journal of Physiology-Endocrinology and Metabolism · doi:10.1152/ajpendo.00456.2006 · Cited by 214 · see citing works
Role of AMP‐activated protein kinase in the metabolic syndrome and in heart disease
Hardie, D. G. (2007) · FEBS Letters · doi:10.1016/j.febslet.2007.11.018 · Cited by 214 · see citing works
Zhou, L., Deepa, S. S., Etzler, J. C., Ryu, J., Mao, X., Fang, Q., Liu, D. D., Torres, J. M., Jia, W., Lechleiter, J. D., et al. (2009) · Journal of Biological Chemistry · doi:10.1074/jbc.m109.028357 · Cited by 212 · see citing works
Dual Role of Interleukin-6 in Regulating Insulin Sensitivity in Murine Skeletal Muscle
Nieto-Vazquez, I., Fernández-Veledo, S., de Alvaro, C., & Lorenzo, M. (2008) · Diabetes · doi:10.2337/db07-1062 · Cited by 209 · see citing works
RetractedKoh, H.-J., Arnolds, D. E., Fujii, N., Tran, T. T., Rogers, M. J., Jessen, N., Li, Y., Liew, C. W., Ho, R. C., Hirshman, M. F., et al. (2006) · Molecular and Cellular Biology · doi:10.1128/mcb.00979-06 · Cited by 202 · see citing works
Limitations in anti-obesity drug development: the critical role of hunger-promoting neurons
Dietrich, M. O., & Horváth, T. L. (2012) · Nature Reviews Drug Discovery · doi:10.1038/nrd3739 · Cited by 202 · see citing works
Chen, M. B., McAinch, A. J., Macaulay, S. L., Castelli, L. A., O’Brien, P. E., Dixon, J. B., Cameron‐Smith, D., Kemp, B. E., & Steinberg, G. R. (2005) · The Journal of Clinical Endocrinology & Metabolism · doi:10.1210/jc.2004-1980 · Cited by 200 · see citing works
The regulation and function of mammalian AMPK‐related kinases
Bright, N. J., Thornton, C., & Carling, D. (2009) · Acta Physiologica · doi:10.1111/j.1748-1716.2009.01971.x · Cited by 200 · see citing works
Koopman, R., Zorenc, A. H. G., Gransier, R. J. J., Cameron-Smith, D., & van Loon, L. J. C. (2006) · American Journal of Physiology-Endocrinology and Metabolism · doi:10.1152/ajpendo.00530.2005 · Cited by 196 · see citing works
Harthill, J. E., Meek, S. E. M., MORRICE, N. A., Peggie, M. W., Borch, J., Wong, B. H. C., & MacKintosh, C. (2006) · The Plant Journal · doi:10.1111/j.1365-313x.2006.02780.x · Cited by 182 · see citing works
AMP-activated protein kinase phosphorylates transcription factors of the CREB family
Thomson, D. M., Herway, S. T., Fillmore, N., Kim, H., Brown, J. D., Barrow, J. R., & Winder, W. W. (2007) · Journal of Applied Physiology · doi:10.1152/japplphysiol.00900.2007 · Cited by 183 · see citing works
The orphan nuclear receptor Nur77 regulates LKB1 localization and activates AMPK
Zhan, Y.-Y., Chen, Y., Zhang, Q., Zhuang, J.-J., Tian, M., Chen, H.-Z., Zhang, L.-R., Zhang, H.-K., He, J.-P., Wang, W.-J., et al. (2012) · Nature Chemical Biology · doi:10.1038/nchembio.1069 · Cited by 180 · see citing works
Ducommun, S., Deak, M., Sumpton, D., Ford, R. J., Núñez Galindo, A., Kussmann, M., Viollet, B., Steinberg, G. R., Foretz, M., Dayon, L., et al. (2015) · Cellular Signalling · doi:10.1016/j.cellsig.2015.02.008 · Cited by 167 · see citing works
Self-citationRegulation of AMP-activated protein kinase by natural and synthetic activators
Hardie, D. G. (2015) · Acta Pharmaceutica Sinica B · doi:10.1016/j.apsb.2015.06.002 · Cited by 176 · see citing works
Han, S., & Roman, J. (2006) · Molecular Cancer Therapeutics · doi:10.1158/1535-7163.mct-05-0347 · Cited by 171 · see citing works
AMP-Activated Protein Kinase: A Key Stress Signaling Pathway in the Heart
Young, L. H., Li, J., Baron, S. J., & Russell, R. R. (2005) · Trends in Cardiovascular Medicine · doi:10.1016/j.tcm.2005.04.005 · Cited by 166 · see citing works
The LKB1-salt-inducible kinase pathway functions as a key gluconeogenic suppressor in the liver
Patel, K. A., Foretz, M., Marion, A., Campbell, D. G., Gourlay, R., Boudaba, N., Tournier, E., Titchenell, P. M., Peggie, M. W., Deák, M., et al. (2014) · Nature Communications · doi:10.1038/ncomms5535 · Cited by 162 · see citing works
Molecular Pathways: Is AMPK a Friend or a Foe in Cancer?
Hardie, D. G. (2015) · Clinical Cancer Research · doi:10.1158/1078-0432.ccr-14-3300 · Cited by 160 · see citing works
Targeting AMPK: A new therapeutic opportunity in breast cancer
Hadad, S. M., Fleming, S., & Thompson, A. M. (2008) · Critical Reviews in Oncology/Hematology · doi:10.1016/j.critrevonc.2008.01.007 · Cited by 154 · see citing works
López, M., Lelliott, C. J., Tovar, S. A., Kimber, W. L., Gallego, R., Virtue, S., Blount, M., Vazquez, M. J., Finer, N., Powles, T. J., et al. (2006) · Diabetes · doi:10.2337/db05-1356 · Cited by 151 · see citing works
AMPK: a cellular energy sensor primarily regulated by AMP
Gowans, G. J., & Hardie, D. G. (2014) · Biochemical Society Transactions · doi:10.1042/bst20130244 · Cited by 149 · see citing works
Dando, I., Donadelli, M., Costanzo, C., Pozza, E. D., D’Alessandro, A., Zolla, L., & Palmieri, M. (2013) · Cell Death and Disease · doi:10.1038/cddis.2013.151 · Cited by 147 · see citing works
Thomson, D. M., Porter, B. B., Tall, J. H., Kim, H.-J., Barrow, J. R., & Winder, W. W. (2007) · American Journal of Physiology-Endocrinology and Metabolism · doi:10.1152/ajpendo.00366.2006 · Cited by 146 · see citing works
Cellular energy sensing and signaling by AMP-activated protein kinase
Winder, W. W., & Thomson, D. M. (2007) · Cell Biochemistry and Biophysics · doi:10.1007/s12013-007-0008-7 · Cited by 141 · see citing works
Exercise-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 · see citing works
Fogarty, S., Hawley, S. A., Green, K. A., Saner, N., Mustard, K. J., & Hardie, D. G. (2009) · Biochemical Journal · doi:10.1042/bj20091372 · Cited by 140 · see citing works
Exploiting the anti-inflammatory effects of AMP-activated protein kinase activation
Salt, I. P., & Palmer, T. M. (2012) · Expert Opinion on Investigational Drugs · doi:10.1517/13543784.2012.696609 · Cited by 138 · see citing works
McConell, G. K., Lee, R. S., Chen, Z., Stepto, N. K., Huynh, N., Stephens, T. J., Canny, B. J., & Kemp, B. E. (2005) · The Journal of Physiology · doi:10.1113/jphysiol.2005.089839 · Cited by 140 · see citing works
King, T. D., Song, L., & Jope, R. S. (2006) · Biochemical Pharmacology · doi:10.1016/j.bcp.2006.03.005 · Cited by 137 · see citing works
The strange case of AMPK and cancer: Dr Jekyll or Mr Hyde?
Vara‐Ciruelos, D., Russell, F. M., & Hardie, D. G. (2019) · Open Biology · doi:10.1098/rsob.190099 · Cited by 136 · see citing works
Fuel economy in food‐deprived skeletal muscle: signaling pathways and regulatory mechanisms
de Lange, P., Moreno, M., Silvestri, E., Lombardi, A., Goglia, F., & Lanni, A. (2007) · The FASEB Journal · doi:10.1096/fj.07-8527rev · Cited by 133 · see citing works
Sukhodub, A., Jovanović, S., Du, Q., Budas, G. R., Clelland, A. K., Shen, M., Sakamoto, K., Tian, R., & Jovanović, A. (2006) · Journal of Cellular Physiology · doi:10.1002/jcp.20862 · Cited by 136 · see citing works
Important role for AMPKαl in limiting skeletal muscle cell hypertrophy
Mounier, R., Lantier, L., Leclerc, J., Sotiropoulos, A., Pende, M., Daegelen, D., Sakamoto, K., Foretz, M., & Viollet, B. (2009) · The FASEB Journal · doi:10.1096/fj.08-119057 · Cited by 133 · see citing works
Thomson, D. M., & Gordon, S. E. (2005) · Journal of Applied Physiology · doi:10.1152/japplphysiol.00811.2004 · Cited by 131 · see citing works
Gruzman, A., Babai-Shani, G., & Sasson, S. (2009) · The Review of Diabetic Studies · doi:10.1900/rds.2009.6.13 · Cited by 128 · see citing works
Mechanism of Action of Compound-13: An α1-Selective Small Molecule Activator of AMPK
Hunter, R. W., Foretz, M., Bultot, L., Fullerton, M. D., Deák, M., Ross, F. A., Hawley, S. A., Shpiro, N., Viollet, B., Barron, D., et al. (2014) · Chemistry & Biology · doi:10.1016/j.chembiol.2014.05.014 · Cited by 125 · see citing works
AICAR induces phosphorylation of AMPK in an ATM-dependent, LKB1-independent manner
Sun, Y., Connors, K. E., & Yang, D.-Q. (2007) · Molecular and Cellular Biochemistry · doi:10.1007/s11010-007-9575-6 · Cited by 122 · see citing works
Histone modifications and exercise adaptations
McGee, S. L., & Hargreaves, M. (2011) · Journal of Applied Physiology · doi:10.1152/japplphysiol.00979.2010 · Cited by 120 · see citing works
14-3-3 cooperates with LKB1 to regulate the activity and localization of QSK and SIK
Al-Hakim, A., Göransson, O., Deák, M., Toth, R. L., Campbell, D. G., MORRICE, N. A., Prescott, A. R., & Alessi, D. R. (2005) · Journal of Cell Science · doi:10.1242/jcs.02670 · Cited by 119 · see citing works
AMP‐ACTIVATED PROTEIN KINASE ACTIVATION AS A STRATEGY FOR PROTECTING VASCULAR ENDOTHELIAL FUNCTION
Zou, M., & Wu, Y. (2007) · Clinical and Experimental Pharmacology and Physiology · doi:10.1111/j.1440-1681.2007.04851.x · Cited by 115 · see citing works
Insulin promotes glycogen synthesis in the absence of GSK3 phosphorylation in skeletal muscle
Bouskila, M., Hirshman, M. F., Jensen, J., Goodyear, L. J., & Sakamoto, K. (2007) · American Journal of Physiology-Endocrinology and Metabolism · doi:10.1152/ajpendo.00481.2007 · Cited by 113 · see citing works
Lan, F., Weikel, K., Cacicedo, J., & Ido, Y. (2017) · Nutrients · doi:10.3390/nu9070751 · Cited by 112 · see citing works
Shen, Q. W., Zhu, M. J., Tong, J., Ren, J. T., & Du, . (2007) · American Journal of Physiology-Cell Physiology · doi:10.1152/ajpcell.00115.2007 · Cited by 111 · see citing works
Neither LKB1 Nor AMPK Are the Direct Targets of Metformin
Hardie, D. G. (2006) · Gastroenterology · doi:10.1053/j.gastro.2006.07.032 · Cited by 111 · see citing works
- Authors
- Sakamoto, K., Göransson, O., Hardie, D. G., & Alessi, D. R.
- Affiliations
- University of Dundee (GB)
- Venue
- American Journal of Physiology-Endocrinology and Metabolism
- Publisher
- American Physiological Society
- Published
- 2004-08
- Volume
- 287
- Issue
- 2
- Pages
- E310-E317
- ISSN
- 0193-1849 (ISSN-L)
- 1522-1555
- OpenAlex
- W2050427373
- Cited by
- 299
- References
- 32
- Citations by year
- 2025: 6 · 2024: 2 · 2023: 2 · 2022: 6 · 2021: 6 · 2020: 7 · 2019: 7 · 2018: 8 · 2017: 11 · 2016: 13 · 2015: 13 · 2014: 24 · 2013: 14 · 2012: 20
- FWCI
- 10.06
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- American Journal of Physiology-Endocrinology and Metabolism (publishedVersion)
- PubMed (publishedVersion)
- Discovery Research Portal (University of Dundee) (publishedVersion)
- Lund University Publications (Lund University) (submittedVersion)
- Funders
- University of Bristol
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Metabolism, Diabetes, and Cancer
- Health Sciences › Medicine › Physiology › Adipose Tissue and Metabolism
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Muscle Physiology and Disorders
- Keywords
- LKB1, AMPK, AMPK-related kinases, skeletal muscle, muscle contraction, phenformin, AICAR, AMPKα1, AMPKα2, MARK kinases, physical activity, type 2 diabetes, muscle fiber type, sciatic nerve stimulation
- MeSH terms
- AMP-Activated Protein Kinase Kinases, Aminoimidazole Carboxamide, Animals, Cells, Cultured, Enzyme Activation, Fibroblasts, HeLa Cells, Humans, Hypoglycemic Agents, Isoenzymes, Male, Multienzyme Complexes, Muscle Contraction, Organ Culture Techniques, Phenformin, Physical Conditioning, Animal, Ribonucleotides, Rats, Wistar, Protein Serine-Threonine Kinases, Mice, Knockout, Muscle, Skeletal, Mice, Rats, AMP-Activated Protein Kinases
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
Are you an author, or do you see a problem with this page? Request a review