AMPK and the biochemistry of exercise: Implications for human health and disease

Biochemical Journal

Volumn 418, Issue 2, 2009, Pages 261-275

  Richter, Erik A ^a   Ruderman, Neil B ^b  

^a UNIVERSITY OF COPENHAGEN   (Denmark)

^b BOSTON UNIVERSITY MEDICAL CENTER   (United States)

Author keywords

AMP activated protein kinase (AMPK); Exercise; Metabolic syndrome; Muscle

Indexed keywords

ACTIVATING AGENTS; ADIPOSE TISSUE; ALZHEIMER'S DISEASE; AMP-ACTIVATED PROTEIN KINASE; AMP-ACTIVATED PROTEIN KINASE (AMPK); AMPK ACTIVITY; CHRONIC EFFECTS; EXERCISE; FATTY ACID OXIDATION; GLUCOSE UPTAKE; HUMAN HEALTH; LIPID SYNTHESIS; MAMMALIAN CELLS; METABOLIC SYNDROME; METABOLIC SYNDROMES; PHYSICAL ACTIVITY; SKELETAL MUSCLE; THERAPEUTIC BENEFITS; TYPE-2 DIABETES;

BIOCHEMISTRY; CHEMICAL ACTIVATION; ENZYME ACTIVITY; FATTY ACIDS; GLUCOSE; MAMMALS; METABOLISM; PHYSIOLOGICAL MODELS;

MUSCLE;

5 AMINO 4 IMIDAZOLECARBOXAMIDE RIBOSIDE; CALCIUM CALMODULIN DEPENDENT PROTEIN KINASE; GLYCOGEN; HIGH DENSITY LIPOPROTEIN; HYDROXYMETHYLGLUTARYL COENZYME A REDUCTASE KINASE; PROTEIN KINASE LKB1; SILENT INFORMATION REGULATOR PROTEIN; SILENT INFORMATION REGULATOR PROTEIN 1; TRANSFORMING GROWTH FACTOR BETA ACTIVATED KINASE 1; UNCLASSIFIED DRUG; BIOLOGICAL MARKER;

ADIPOSE TISSUE; ALZHEIMER DISEASE; BIOCHEMISTRY; CAPILLARY DENSITY; ENZYME ACTIVATION; ENZYME ACTIVITY; ENZYME REGULATION; EXERCISE INTENSITY; FATTY ACID OXIDATION; GLUCOSE TRANSPORT; GLYCOGEN ANALYSIS; HUMAN; HYPOTHALAMUS; IMMOBILIZATION; METABOLIC SYNDROME X; MUSCLE CONTRACTION; MUSCLE EXERCISE; NON INSULIN DEPENDENT DIABETES MELLITUS; NONHUMAN; PHENOTYPE; PRIORITY JOURNAL; PROTEIN EXPRESSION; PROTEIN SYNTHESIS; REVIEW; SEX DIFFERENCE; SKELETAL MUSCLE; TISSUE METABOLISM; ANIMAL; BIOLOGICAL MODEL; EXERCISE; GENERAL ASPECTS OF DISEASE; HEALTH; METABOLISM; MOTOR ACTIVITY; PHYSIOLOGY; TIME;

MAMMALIA; RODENTIA;

AMP-ACTIVATED PROTEIN KINASES; ANIMALS; BIOLOGICAL MARKERS; DISEASE; EXERCISE; HEALTH; HUMANS; MODELS, BIOLOGICAL; MOTOR ACTIVITY; MUSCLE CONTRACTION; MUSCLE, SKELETAL; TIME FACTORS;

EID: 61449106744     PISSN: 02646021     EISSN: 14708728     Source Type: Journal    
DOI: 10.1042/BJ20082055     Document Type: Review

References (222)

1. Hardie, D. G. (2007) AMP-activated/SNF1 protein kinases: conserved guardians of cellular energy. Nat. Rev. Mol. Cell Biol. 8, 774-785
2. Kahn, B. B., Alquier, T., Carling, D. and Hardie, D. G. (2005) AMP-activated protein kinase: ancient energy gauge provides clues to modern understanding of metabolism. Cell Metab. 1, 15-25
3. Marsin, A. S., Bertrand, L., Rider, M. H., Deprez, J., Beauloye, C., Vincent, M. F., Van den Berghe, G., Carling, D. and Hue, L. (2000) Phosphorylation and activation of heart PFK-2 by AMPK has a role in the stimulation of glycolysis during ischaemia. Curr. Biol. 10, 1247-1255
4. Winder, W. W., Holmes, B. F., Rubink, D. S., Jensen, E. B., Chen, M. and Holloszy, J. O. (2000) Activation of AMP-activated protein kinase increases mitochondrial enzymes in skeletal muscle. J. Appl. Physiol. 88, 2219-2226
5. Jorgensen, S. B., Treebak, J. T., Viollet, B., Schjerling, P., Vaulont, S., Wojtaszewski, J. F. and Richter, E. A. (2007) Role of AMPKα2 in basal, training-, and AICAR-induced GLUT4, hexokinase II, and mitochondrial protein expression in mouse muscle. Am. J. Physiol. Endocrinol. Metab. 292, E331-E339
6. Ouchi, N., Shibata, R. and Walsh, K. (2005) AMP-activated protein kinase signaling stimulates VEGF expression and angiogenesis in skeletal muscle. Circ. Res. 96, 838-846
7. Williams, T. and Brenman, J. E. (2008) LKB1 and AMPK in cell polarity and division. Trends Cell Biol. 18, 193-198
8. Minokoshi, Y., Alquier, T., Furukawa, N., Kim, Y. B., Lee, A., Xue, B., Mu, J., Foufelle, F., Ferré, P., Birnbaum, M. J. et al. (2004) AMP-kinase regulates food intake by responding to hormonal and nutrient signals in the hypothalamus. Nature 428, 569-574
9. Hardie, D. G. (2008) Role of AMP-activated protein kinase in the metabolic syndrome and in heart disease. FEBS Lett. 582, 81-89
10. Ruderman, N. B. and Shulman, G. (2006) The metabolic syndrome. In Textbook of Endocrinology (Jamieson, J. and DeGroot, L., eds), pp. 1149-1166, Elsevier, Philadelphia
11. Luo, Z., Saha, A. K., Xiang, X. and Ruderman, N. B. (2005) AMPK, the metabolic syndrome and cancer. Trends Pharmacol. Sci. 26, 69-76
12. Song, X. M., Fiedler, M., Galuska, D., Ryder, J. W., Fernstrom, M., Chibalin, A. V., Wallberg-Henriksson, H. and Zierath, J. R. (2002) 5-Aminoimidazole-4-carboxamide ribonucleoside treatment improves glucose homeostasis in insulin-resistant diabetic (ob/ob) mice. Diabetologia 45, 56-65
13. Buhl, E. S., Jessen, N., Pold, R., Ledet, T., Flyvbjerg, A., Pedersen, S. B., Pedersen, O., Schmitz, O. and Lund, S. (2002) Long-term AICAR administration reduces metabolic disturbances and lowers blood pressure in rats displaying features of the insulin resistance syndrome. Diabetes 51, 2199-2206
14. Ruderman, N. and Prentki, M. (2004) AMP kinase and malonyl-CoA: targets for therapy of the metabolic syndrome. Nat. Rev. Drug Discov. 3, 340-351
15. Wojtaszewski, J. F., Nielsen, P., Hansen, B. F., Richter, E. A. and Kiens, B. (2000) Isoform-specific and exercise intensity-dependent activation of 5′-AMP-activated protein kinase in human skeletal muscle. J. Physiol. 528, 221-226
16. Chen, Z. P., Stephens, T. J., Murthy, S., Canny, B. J., Hargreaves, M., Witters, L. A., Kemp, B. E. and McConell, G. K. (2003) Effect of exercise intensity on skeletal muscle AMPK signaling in humans. Diabetes 52, 2205-2212
17. 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) Exercise induces isoform-specific increase in 5′AMP-activated protein kinase activity in human skeletal muscle. Biochem. Biophys. Res. Commun. 273, 1150-1155
18. Coven, D. L., Hu, X., Cong, L., Bergeron, R., Shulman, G. I., Hardie, D. G. and Young, L. H. (2003) Physiological role of AMP-activated protein kinase in the heart: graded activation during exercise. Am. J. Physiol. Endocrinol. Metab. 285, E629-E636
19. Park, H., Kaushik, V. K., Constant, S., Prentki, M., Przybytkowski, E., Ruderman, N. B. and Saha, A. K. (2002) Coordinate regulation of malonyl-CoA decarboxylase, sn-glycerol-3-phosphate acyltransferase, and acetyl-CoA carboxylase by AMP-activated protein kinase in rat tissues in response to exercise. J. Biol. Chem. 277, 32571-32577
20. Mikines, K., Sonne, B., Farrell, P., Tronier, B. and Galbo, H. (1988) Effect of physical exercise on sensitivity and responsiveness to insulin in humans. Am. J. Physiol. 254, E248-E259
21. Richter, E. A., Garetto, L. P., Goodman, M. N. and Ruderman, N. B. (1982) Muscle glucose metabolism following exercise in the rat. J. Clin. Invest. 69, 785-793
22. Richter, E. A., Mikines, K. J., Galbo, H. and Kiens, B. (1989) Effect of exercise on insulin action in human skeletal muscle. J. Appl. Physiol. 66, 876-885
23. Pilegaard, H., Ordway, G. A., Saltin, B. and Neufer, P. D. (2000) Transcriptional regulation of gene expression in human skeletal muscle during recovery from exercise. Am. J. Physiol. Endocrinol. Metab. 279, E806-E814
24. Vissing, K., McGee, S. L., Roepstorff, C., Schjerling, P., Hargreaves, M. and Kiens, B. (2008) Effect of sex differences on human MEF2 regulation during endurance exercise. Am. J. Physiol. Endocrinol. Metab. 294, E408-E415
25. Holloszy, J. O. and Coyle, E. F. (1984) Adaptations of skeletal muscle to endurance exercise and their metabolic consequences. J. Appl. Physiol. 56, 831-838
26. Blair, S. N., Kohl, III, H. W., Paffenbarger, Jr, R. S., Clark, D. G., Cooper, K. H. and Gibbons, L. W. (1989) Physical fitness and all-cause mortality: a prospective study of healthy men and women. JAMA, J. Am. Med. Assoc. 262, 2395-2401
27. Lees, S. J. and Booth, F. W. (2005) Physical inactivity is a disease. World Rev. Nutr. Diet. 95, 73-79
28. Xiao, B., Heath, R., Saiu, P., Leiper, F. C., Leone, P., Jing, C., Walker, P. A., Haire, L., Eccleston, J. F., Davis, C. T. et al. (2007) Structural basis for AMP binding to mammalian AMP-activated protein kinase. Nature 449, 496-500
29. Tullson, P. C., Bangsbo, J., Hellsten, Y. and Richter, E. A. (1995) IMP metabolism in human skeletal muscle after exhaustive exercise. J. Appl. Physiol. 78, 146-152
30. Hardie, D. G., Salt, I. P. and Davies, S. P. (2000) Analysis of the role of the AMP-activated protein kinase in the response to cellular stress. Methods Mol. Biol. 99, 63-74
31. Carling, D., Zammit, V. A. and Hardie, D. G. (1987) A common bicyclic protein kinase cascade inactivates the regulatory enzymes of fatty acid and cholesterol biosynthesis. FEBS Lett. 223, 217-222
32. Hardie, D. G., Scott, J. W., Pan, D. A. and Hudson, E. R. (2003) Management of cellular energy by the AMP-activated protein kinase system. FEBS Lett. 546, 113-120
33. Hancock, C. R., Janssen, E. and Terjung, R. L. (2006) Contraction-mediated phosphorylation of AMPK is lower in skeletal muscle of adenylate kinase-deficient mice. J. Appl. Physiol. 100, 406-413
34. Sanders, M. J., Grondin, P. O., Hegarty, B. D., Snowden, M. A. and Carling, D. (2007) Investigating the mechanism for AMP activation of the AMP-activated protein kinase cascade. Biochem. J. 403, 139-148
35. Suter, M., Riek, U., Tuerk, R., Schlattner, U., Wallimann, T. and Neumann, D. (2006) Dissecting the role of 5′-AMP for allosteric stimulation, activation, and deactivation of AMP-activated protein kinase. J. Biol. Chem. 281, 32207-32216
36. Hawley, S. A., Boudeau, J., Reid, J. L., Mustard, K. J., Udd, L., Makela, T. P., Alessi, D. R. and Hardie, D. G. (2003) Complexes between the LKB1 tumor suppressor, STRADα/β and MO25α/β are upstream kinases in the AMP-activated protein kinase cascade. J. Biol. 2, 28
37. Woods, A., Johnstone, S. R., Dickerson, K., Leiper, F. C., Fryer, L. G., Neumann, D., Schlattner, U., Wallimann, T., Carlson, M. and Carling, D. (2003) LKB1 is the upstream kinase in the AMP-activated protein kinase cascade. Curr. Biol. 13, 2004-2008
38. Sakamoto, K., Goransson, O., Hardie, D. G. and Alessi, D. R. (2004) Activity of LKB1 and AMPK-related kinases in skeletal muscle: effects of contraction, phenformin, and AICAR. Am. J. Physiol. Endocrinol. Metab. 287, E310-E317
39. Koh, 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) Skeletal muscle-selective knockout of LKB1 increases insulin sensitivity, improves glucose homeostasis, and decreases TRB3. Mol. Cell Biol. 26, 8217-8227
40. Thomson, D. M., Porter, B. B., Tall, J. H., Kim, H. J., Barrow, J. R. and Winder, W. W. (2007) Skeletal muscle and heart LKB1 deficiency causes decreased voluntary running and reduced muscle mitochondrial marker enzyme expression in mice. Am. J. Physiol. Endocrinol. Metab. 292, E196-E202
41. Hurst, D., Taylor, E. B., Cline, T. D., Greenwood, L. J., Compton, C. L., Lamb, J. D. and Winder, W. W. (2005) AMP-activated protein kinase kinase activity and phosphorylation of AMP-activated protein kinase in contracting muscle of sedentary and endurance-trained rats. Am. J. Physiol. Endocrinol. Metab. 289, E710-E715
42. Hawley, S. A., Pan, D. A., Mustard, K. J., Ross, L., Bain, J., Edelman, A. M., Frenguelli, B. G. and Hardie, D. G. (2005) Calmodulin-dependent protein kinase kinase-β is an alternative upstream kinase for AMP-activated protein kinase. Cell Metab. 2, 9-19
43. 2+/ calmodulin-dependent protein kinase kinase-β acts upstream of AMP-activated protein kinase in mammalian cells. Cell Metab. 2, 21-33
44. Jensen, T. E., Rose, A. J., Jorgensen, S. B., Brandt, N., Schjerling, P., Wojtaszewski, J. F. and Richter, E. A. (2007) Possible CaMKK-dependent regulation of AMPK phosphorylation and glucose uptake at the onset of mild tetanic skeletal muscle contraction. Am. J. Physiol. Endocrinol. Metab. 292, E1308-E1317
45. 2+/calmodulin-dependent protein kinase kinase-α regulates skeletal muscle glucose uptake independent of AMP-activated protein kinase and Akt activation. Diabetes 56, 1403-1409
46. 2+ release increases AMPK-dependent glucose uptake in rodent soleus muscle. Am. J. Physiol. Endocrinol. Metab. 293, E286-E292
47. Xie, M., Zhang, D., Dyck, J. R., Li, Y., Zhang, H., Morishima, M., Mann, D. L., Taffet, G. E., Baldini, A., Khoury, D. S. and Schneider, M. D. (2006) A pivotal role for endogenous TGF-β-activated kinase-1 in the LKB1/AMP-activated protein kinase energy-sensor pathway. Proc. Natl. Acad. Sci. U.S.A. 103, 17378-17383
48. Michan, S. and Sinclair, D. (2007) Sirtuins in mammals: insights into their biological function. Biochem. J. 404, 1-13
49. Lan, F., Cacicedo, J. M., Ruderman, N. and Ido, Y. (2008) SIRT1 modulation of the acetylation status, cytosolic localization and activity of LKB1: possible role in AMP-activated protein kinase activation. J. Biol. Chem. 283, 27628-27635
50. Suwa, M., Nakano, H., Radak, Z. and Kumagai, S. (2008) Endurance exercise increases the SIRT1 and peroxisome proliferator-activated receptor γ coactivator-1α protein expressions in rat skeletal muscle. Metab., Clin. Exp. 57, 986-998
51. Ferrara, N., Rinaldi, B., Corbi, G., Conti, V., Stiuso, P., Boccuti, S., Rengo, G., Rossi, F. and Filippelli, A. (2008) Exercise training promotes SIRT1 activity in aged rats. Rejuvenation Res. 11, 139-150
52. Civitarese, A. E., Carling, S., Heilbronn, L. K., Hulver, M. H., Ukropcova, B., Deutsch, W. A., Smith, S. R. and Ravussin, E. (2007) Calorie restriction increases muscle mitochondrial biogenesis in healthy humans. PLoS Med. 4, e76
53. Kelly, M., Keller, C., Avilucea, P. R., Keller, P., Luo, Z., Xiang, X., Giralt, M., Hidalgo, J., Saha, A. K., Pedersen, B. K. and Ruderman, N. B. (2004) AMPK activity is diminished in tissues of IL-6 knockout mice: the effect of exercise. Biochem. Biophys. Res. Commun. 320, 449-454
54. Ruderman, N. B., Keller, C., Richard, A. M., Saha, A. K., Luo, Z., Xiang, X., Giralt, M., Ritov, V. B., Menshikova, E. V., Kelley, D. E. et al. (2006) Interleukin-6 regulation of AMP-activated protein kinase: potential role in the systemic response to exercise and prevention of the metabolic syndrome. Diabetes 55 (Suppl. 2), S48-S54
55. MacDonald, C., Wojtaszewski, J. F., Pedersen, B. K., Kiens, B. and Richter, E. A. (2003) Interleukin-6 release from human skeletal muscle during exercise: relation to AMPK activity. J. Appl. Physiol. 95, 2273-2277
56. Musi, N., Hayashi, T., Fujii, N., Hirshman, M. F., Witters, L. A. and Goodyear, L. J. (2001) AMP-activated protein kinase activity and glucose uptake in rat skeletal muscle. Am. J. Physiol. Endocrinol. Metab. 280, E677-E684
57. Stephens, T. J., Chen, Z. P., Canny, B. J., Michell, B. J., Kemp, B. E. and McConell, G. K. (2002) Progressive increase in human skeletal muscle AMPKa2 activity and ACC phosphorylation during exercise. Am. J. Physiol. Endocrinol. Metab. 282, E688-E694
58. Wojtaszewski, J. F., MacDonald, C., Nielsen, J. N., Hellsten, Y., Hardie, D. G., Kemp, B. E., Kiens, B. and Richter, E. A. (2003) Regulation of 5′AMP-activated protein kinase activity and substrate utilization in exercising human skeletal muscle. Am. J. Physiol. Endocrinol. Metab. 284, E813-E822
59. Wojtaszewski, J. F., Mourtzakis, M., Hillig, T., Saltin, B. and Pilegaard, H. (2002) Dissociation of AMPK activity and ACCβ phosphorylation in human muscle during prolonged exercise. Biochem. Biophys. Res. Commun. 298, 309-316
60. Birk, J. B. and Wojtaszewski, J. F. (2006) Predominant α2/β2/ γ3 AMPK activation during exercise in human skeletal muscle. J. Physiol. 577, 1021-1032
61. Treebak, J. T., Birk, J. B., Rose, A. J., Kiens, B., Richter, E. A. and Wojtaszewski, J. F. (2007) AS160 phosphorylation is associated with activation of α2β2γ1, but not α2β2γ3-AMPK trimeric complex in skeletal muscle during exercise in humans. Am. J. Physiol. Endocrinol. Metab. 292, E715-E722
62. Kramer, H. F., Witczak, C. A., Fujii, N., Jessen, N., Taylor, E. B., Arnolds, D. E., Sakamoto, K., Hirshman, M. F. and Goodyear, L. J. (2006) Distinct signals regulate AS160 phosphorylation in response to insulin, AICAR, and contraction in mouse skeletal muscle. Diabetes 55, 2067-2076
63. Treebak, J. T., Glund, S., Deshmukh, A., Klein, D. K., Long, Y. C., Jensen, T. E., Jorgensen, S. B., Viollet, B., Andersson, L., Neumann, D. et al. (2006) AMPK-mediated AS160 phosphorylation in skeletal muscle is dependent on AMPK catalytic and regulatory subunits. Diabetes 55, 2051-2058
64. Derave, W., Ai, H., Ihlemann, J., Witters, L. A., Kristiansen, S., Richter, E. A. and Ploug, T. (2000) Dissociation of AMP-activated protein kinase activation and glucose transport in contracting slow-twitch muscle. Diabetes 49, 1281-1287
65. Steinberg, G. R., Watt, M. J., McGee, S. L., Chan, S., Hargreaves, M., Febbraio, M. A., Stapleton, D. and Kemp, B. E. (2006) Reduced glycogen availability is associated with increased AMPKα2 activity, nuclear AMPKα2 protein abundance, and GLUT4 mRNA expression in contracting human skeletal muscle. Appl. Physiol. Nutr. Metab. 31, 302-312
66. 565 phosphorylation in human skeletal muscle during exercise. J. Physiol. 560, 551-562
67. Wojtaszewski, J. F., Jorgensen, S. B., Hellsten, Y., Hardie, D. G. and Richter, E. A. (2002) Glycogen-dependent effects of 5-aminoimidazole-4-carboxamide (AICA)-riboside on AMP-activated protein kinase and glycogen synthase activities in rat skeletal muscle. Diabetes 51, 284-292
68. Jorgensen, S. B., Nielsen, J. N., Birk, J. B., Olsen, G. S., Viollet, B., Andreelli, F., Schjerling, P., Vaulont, S., Hardie, D. G., Hansen, B. F. et al. (2004) The α-5′AMP-activated protein kinase is a site 2 glycogen synthase kinase in skeletal muscle and is responsive to glucose loading. Diabetes 53, 3074-3081
69. Hudson, E. R., Pan, D. A., James, J., Lucocq, J. M., Hawley, S. A., Green, K. A., Baba, O., Terashima, T. and Hardie, D. G. (2003) A novel domain in AMP-activated protein kinase causes glycogen storage bodies similar to those seen in hereditary cardiac arrhythmias. Curr. Biol. 13, 861-866
70. Polekhina, G., Gupta, A., Michell, B. J., Van Denderen, B. J., Murthy, S., Feil, S. C., Jennings, I. G., Campbell, D. J., Witters, L. A., Parker, M. W. et al. (2003) AMPKβ subunit targets metabolic stress sensing to glycogen. Cur. Biol. 13, 867-871
71. McBride, A., Ghilagaber, S., Nikolaev, A. and Hardie, D. G. (2009) The glycogen-binding domain on the AMPKβ subunit allows the kinase to act as a glycogen sensor. Cell Metab. 9, 23-34
72. Roepstorff, C., Thiele, M., Hillig, T., Pilegaard, H., Richter, E. A., Wojtaszewski, J. F. and Kiens, B. (2006) Higher skeletal muscle α2AMPK activation and lower energy charge and fat oxidation in men than in women during submaximal exercise. J. Physiol. 574, 125-138
73. Steffensen, C. H., Roepstorff, C., Madsen, M. and Kiens, B. (2002) Myocellular triacylglycerol breakdown in females but not in males during exercise. Am. J. Physiol. Endocrinol. Metab. 282, E634-E642
74. Merrill, G. F., Kurth, E. J., Hardie, D. G. and Winder, W. W. (1997) AICA riboside increases AMP-activated protein kinase, fatty acid oxidation, and glucose uptake in rat muscle. Am. J. Physiol. 273, E1107-E1112
75. Barnes, B. R., Marklund, S., Steiler, T. L., Walter, M., Hjalm, G., Amarger, V., Mahlapuu, M., Leng, Y., Johansson, C., Galuska, D. et al. (2004) The 5′-AMP-activated protein kinase γ 3 isoform has a key role in carbohydrate and lipid metabolism in glycolytic skeletal muscle. J. Biol. Chem. 279, 38441-38447
76. Jorgensen, S. B., Viollet, B., Andreelli, F., Frosig, C., Birk, J. B., Schjerling, P., Vaulont, S., Richter, E. A. and Wojtaszewski, J. F. (2004) Knockout of the α2 but not α1 5′-AMP-activated protein kinase isoform abolishes 5-aminoimidazole-4-carboxamide-1-β-4-ribofuranoside but not contraction-induced glucose uptake in skeletal muscle. J. Biol. Chem. 279, 1070-1079
77. Mu, J., Brozinick, Jr, J. T., Valladares, O., Bucan, M. and Birnbaum, M. J. (2001) A role for AMP-activated protein kinase in contraction- and hypoxia-regulated glucose transport in skeletal muscle. Mol. Cell 7, 1085-1094
78. Fujii, N., Hirshman, M. F., Kane, E. M., Ho, R. C., Peter, L. E., Seifert, M. M. and Goodyear, L. J. (2005) AMP-activated protein kinase α2 activity is not essential for contraction- and hyperosmolarity-induced glucose transport in skeletal muscle. J. Biol. Chem. 280, 39033-39041
79. Lefort, N., St.-Amand, E., Morasse, S., Côté, C. H. and Marette, A. (2008) The α-subunit of AMPK is essential for submaximal contraction-mediated glucose transport in skeletal muscle in vitro. Am. J. Physiol. Endocrinol. Metab. 295, E1447-E1454
80. Sakamoto, K., McCarthy, A., Smith, D., Green, K. A., Grahame, H. D., Ashworth, A. and Alessi, D. R. (2005) Deficiency of LKB1 in skeletal muscle prevents AMPK activation and glucose uptake during contraction. EMBO J. 24, 1810-1820
81. 2, in mouse skeletal muscle. PLoS ONE 3, e2102
82. Koh, H.-J., Fujii, N., Toyoda, T., Jung, M. M., Hirshman, M. F. and Goodyear, L. J. (2008) The AMPK-related protein kinase SNARK mediates contraction-stimulated glucose transport in mouse skeletal muscle. Diabetes 57, A91 (abstract)
83. Sano, H., Kane, S., Sano, E., Miinea, C. P., Asara, J. M., Lane, W. S., Garner, C. W. and Lienhard, G. E. (2003) Insulin-stimulated phosphorylation of a Rab GTPase-activating protein regulates GLUT4 translocation. J. Biol. Chem. 278, 14599-14602
84. Kramer, H. F., Witczak, C. A., Taylor, E. B., Fujii, N., Hirshman, M. F. and Goodyear, L. J. (2006) AS160 regulates insulin- and contraction-stimulated glucose uptake in mouse skeletal muscle. J. Biol. Chem. 281, 31478-31485
85. Deshmukh, A., Coffey, V. G., Zhong, Z., Chibalin, A. V., Hawley, J. A. and Zierath, J. R. (2006) Exercise-induced phosphorylation of the novel Akt substrates AS160 and filamin A in human skeletal muscle. Diabetes 55, 1776-1782
86. Funai, K. and Cartee, G. D. (2008) Contraction-stimulated glucose transport in rat skeletal muscle is sustained despite reversal of increased PAS-phosphorylation of AS160 and TBC1D1. J. Appl. Physiol. 105, 1788-1795
87. Geraghty, K. M., Chen, S., Harthill, J. E., Ibrahim, A. F., Toth, R., Morrice, N. A., Vandermoere, F., Moorhead, G. B., Hardie, D. G. and MacKintosh, C. (2007) Regulation of multisite phosphorylation and 14-3-3 binding of AS160 in response to IGF-1, EGF, PMA and AICAR. Biochem. J. 407, 231-241
88. Roach, W. G., Chavez, J. A., Miinea, C. P. and Lienhard, G. E. (2007) Substrate specificity and effect on GLUT4 translocation of the Rab GTPase-activating protein Tbc1d1. Biochem. J. 403, 353-358
89. Taylor, E. B., An, D., Kramer, H. F., Yu, H., Fujii, N. L., Roeckl, K. S., Bowles, N., Hirshman, M. F., Xie, J., Feener, E. P. and Goodyear, L. J. (2008) Discovery of TBC1D1 as an insulin-, AICAR-, and contraction-stimulated signaling nexus in mouse skeletal muscle. J. Biol. Chem. 283, 9787-9796
90. 2 -Aufname. Skand. Arch. Physiol. 81, 180-189
91. Rose, A. J. and Richter, E. A. (2005) Skeletal muscle glucose uptake during exercise: how is it regulated? Physiology 20, 260-270
92. van Loon, L. J., Greenhaff, P. L., Constantin-Teodosiu, D., Saris, W. H. and Wagenmakers, A. J. (2001) The effects of increasing exercise intensity on muscle fuel utilisation in humans. J. Physiol. 536, 295-304
93. Helge, J. W., Stallknecht, B., Richter, E. A., Galbo, H. and Kiens, B. (2007) Muscle metabolism during graded quadriceps exercise in man. J. Physiol. 581, 1247-1258
94. Winder, W. W., Arogyasami, J., Barton, R. J., Elayan, I. M. and Verhs, P. R. (1989) Muscle malonyl-CoA decreases during exercise. J. Appl. Physiol. 67, 2230-2233
95. Saha, A. K., Schwarsin, A. J., Roduit, R., Masse, F., Kaushik, V., Tornheim, K., Prentki, M. and Ruderman, N. B. (2000) Activation of malonyl-CoA decarboxylase in rat skeletal muscle by contraction and the AMP-activated protein kinase activator 5-aminoimidazole-4-carboxamide-1-β-D-ribofuranoside. J. Biol. Chem. 275, 24279-24283
96. Abu-Elheiga, L., Almarza-Ortega, D. B., Baldini, A. and Wakil, S. J. (1997) Human acetyl-CoA carboxylase 2: molecular cloning, characterization, chromosomal mapping, and evidence for two isoforms. J. Biol. Chem. 272, 10669-10677
97. McGarry, J. D. (2002) Banting Lecture 2001: dysregulation of fatty acid metabolism in the etiology of type 2 diabetes. Diabetes 51, 7-18
98. Odland, L. M., Heigenhauser, G. J. F., Lopaschuk, G. D. and Spriet, L. L. (1996) Human skeletal muscle malonyl-CoA at rest and during prolonged submaximal exercise. Am. J. Physiol. 270, E541-E544
99. Odland, L. M., Howlett, R. A., Heigenhauser, G. J., Hultman, E. and Spriet, L. L. (1998) Skeletal muscle malonyl-CoA content at the onset of exercise at varying power outputs in humans. Am. J. Physiol. 274, E1080-E1085
100. Dean, D., Daugaard, J. R., Young, M. E., Saha, A., Vavvas, D., Asp, S., Kiens, B., Kim, K. H., Witters, L., Richter, E. A. and Ruderman, N. (2000) Exercise diminishes the activity of acetyl-CoA carboxylase in human muscle. Diabetes 49, 1295-1300
101. Roepstorff, C., Halberg, N., Hillig, T., Saha, A. K., Ruderman, N. B., Wojtaszewski, J. F., Richter, E. A. and Kiens, B. (2005) Malonyl-CoA and carnitine in regulation of fat oxidation in human skeletal muscle during exercise. Am. J. Physiol. Endocrinol. Metab. 288, E133-E142
102. Kuhl, J. E., Ruderman, N. B., Musi, N., Goodyear, L. J., Patti, M. E., Crunkhorn, S., Dronamraju, D., Thorell, A., Nygren, J., Ljungkvist, O. et al. (2006) Exercise training decreases the concentration of malonyl-CoA and increases the expression and activity of malonyl-CoA decarboxylase in human muscle. Am. J. Physiol. Endocrinol. Metab. 290, E1296-E1303
103. Dzamko, N. L., Schertzer, J. D., Ryall, J., Steel, R., Macaulay, S. L., Wee, S., Chen, Z. P., Michell, B. J., Oakhill, J. S., Watt, M. J. et al. (2008) AMPK independent pathways regulate skeletal muscle fatty acid oxidation. J. Physiol. 586, 5819-5831
104. Raney, M. A. and Turcotte, L. P. (2007) Evidence for the regulation of contraction-induced fatty acid oxidation via extracellular signal-regulated kinase 1/2 activation independent of changes in fatty acid uptake. Metabolism 56, 1192-1200
105. 2+-dependent signaling pathways regulating FA uptake and oxidation in contracting rodent muscle. J. Appl. Physiol. 104, 1366-1373
106. Sahlin, K. (1990) Muscle carnitine metabolism during incremental dynamic exercise in humans. Acta Physiol. Scand. 138, 259-262
107. Muoio, D. M., Seefeld, K., Witters, L. A. and Coleman, R. A. (1999) AMP-activated kinase reciprocally regulates triacylglycerol synthesis and fatty acid oxidation in liver and muscle: evidence that sn-glycerol-3-phosphate acyltransferase is a novel target. Biochem. J. 338, 783-791
108. Habets, D. D., Coumans, W. A., Voshol, P. J., den Boer, M. A., Febbraio, M., Bonen, A., Glatz, J. F. and Luiken, J. J. (2007) AMPK-mediated increase in myocardial long-chain fatty acid uptake critically depends on sarcolemmal CD36. Biochem. Biophys. Res. Commun. 355, 204-210
109. Bonen, A., Han, X. X., Habets, D. D., Febbraio, M., Glatz, J. F. and Luiken, J. J. (2007) A null mutation in skeletal muscle FAT/CD36 reveals its essential role in insulin- and AICAR-stimulated fatty acid metabolism. Am. J. Physiol. Endocrinol. Metab. 292, E1740-E1749
110. Rennie, M. J. (2005) Why muscle stops building when it's working. J. Physiol. 569, 3
111. Bylund-Fellenius, A. C., Ojamaa, K. M., Flaim, K. E., Li, J. B., Wassner, S. J. and Jefferson, L. S. (1984) Protein synthesis versus energy state in contracting muscles of perfused rat hindlimb. Am. J. Physiol. 246, E297-E305
112. Dreyer, H. C., Fujita, S., Cadenas, J. G., Chinkes, D. L., Volpi, E. and Rasmussen, B. B. (2006) Resistance exercise increases AMPK activity and reduces 4E-BP1 phosphorylation and protein synthesis in human skeletal muscle. J. Physiol. 576, 613-624
113. Horman, S., Browne, G., Krause, U., Patel, J., Vertommen, D., Bertrand, L., Lavoinne, A., Hue, L., Proud, C. and Rider, M. (2002) Activation of AMP-activated protein kinase leads to the phosphorylation of elongation factor 2 and an inhibition of protein synthesis. Curr. Biol. 12, 1419-1423
114. Horman, S., Beauloye, C., Vertommen, D., Vanoverschelde, J. L., Hue, L. and Rider, M. H. (2003) Myocardial ischemia and increased heart work modulate the phosphorylation state of eukaryotic elongation factor-2. J. Biol. Chem. 278, 41970-41976
115. Rose, A. J., Broholm, C., Kiillerich, K., Finn, S. G., Proud, C. G., Rider, M. H., Richter, E. A. and Kiens, B. (2005) Exercise rapidly increases eukaryotic elongation factor 2 phosphorylation in skeletal muscle of men. J. Physiol. 569, 223-228
116. Deldicque, L., Atherton, P., Patel, R., Theisen, D., Nielens, H., Rennie, M. J. and Francaux, M. (2008) Decrease in Akt/PKB signalling in human skeletal muscle by resistance exercise. Eur. J. Appl. Physiol. 104, 57-65
117. Rose, A. J., Bisiani, B., Kiens, B. and Richter, E. A. (2008) Skeletal muscle eEF2 and 4EBP1 phosphorylation during endurance exercise is dependent on intensity and muscle fiber type. Am. J. Physiol. Regul. Integr. Comp. Physiol., doi:10.1152/ajpregu.90806.2008
118. Rennie, M. J. and Tipton, K. D. (2000) Protein and amino acid metabolism during and after exercise and the effects of nutrition. Annu. Rev. Nutr. 20, 457-483
119. Biolo, G., Williams, B. D., Fleming, R. Y. and Wolfe, R. R. (1999) Insulin action on muscle protein kinetics and amino acid transport during recovery after resistance exercise. Diabetes 48, 949-957
120. Zorzano, A., Balon, T., Garetto, L., Goodman, M. and Ruderman, N. (1985) Muscle α-aminoisobutyric acid transport after exercise: enhanced stimulation by insulin. Am. J. Physiol. 248, E546-E552
121. Frosig, C., Sajan, M. P., Maarbjerg, S. J., Brandt, N., Roepstorff, C., Wojtaszewski, J. F., Kiens, B., Farese, R. V. and Richter, E. A. (2007) Exercise improves phosphatidylinositol-3,4,5-trisphosphate responsiveness of atypical protein kinase C and interacts with insulin signalling to peptide elongation in human skeletal muscle. J. Physiol. 582, 1289-1301
122. Mu, J., Barton, E. R. and Birnbaum, M. J. (2003) Selective suppression of AMP-activated protein kinase in skeletal muscle: update on 'lazy mice'. Biochem. Soc. Trans. 31, 236-241
123. Fujii, N., Seifert, M. M., Kane, E. M., Peter, L. E., Ho, R. C., Winstead, S., Hirshman, M. F. and Goodyear, L. J. (2007) Role of AMP-activated protein kinase in exercise capacity, whole body glucose homeostasis, and glucose transport in skeletal muscle: insight from analysis of a transgenic mouse model. Diabetes Res. Clin. Pract. 77, (Suppl. 1), S92-S98
124. Jorgensen, S. B., Richter, E. A. and Wojtaszewski, J. F. (2006) Role of AMPK in skeletal muscle metabolic regulation and adaptation in relation to exercise. J. Physiol. 574, 17-31
125. Jorgensen, S. B., Wojtaszewski, J. F., Viollet, B., Andreelli, F., Birk, J. B., Hellsten, Y., Schjerling, P., Vaulont, S., Neufer, P. D., Richter, E. A. and Pilegaard, H. (2005) Effects of α-AMPK knockout on exercise-induced gene activation in mouse skeletal muscle. FASEB J. 19, 1146-1148
126. Klein, D., Pilegaard, H., Treebak, J. T., Jensen, T. E., Viollet, B., Schjerling, P. and Wojtaszewski, J. F. (2007) Lack of α2 5′AMP activated protein kinase enhances pyruvate dehydrogenase activity during exercise. Am. J. Physiol. Endocrinol. Metab. 293, E1242-E1249
127. Musi, N., Hirshman, M. F., Arad, M., Xing, Y., Fujii, N., Pomerleau, J., Ahmad, F., Berul, C. I., Seidman, J. G., Tian, R. and Goodyear, L. J. (2005) Functional role of AMP-activated protein kinase in the heart during exercise. FEBS Lett. 579, 2045-2050
128. Galbo, H. (1995) Integrated endocrine responses and exercise. In Endocrinology, 3rd edn (DeGroot, L. J., ed.), pp. 2692-2701, W.B. Saunders, Philadelphia
129. Viollet, B., Foretz, M., Guigas, B., Horman, S., Dentin, R., Bertrand, L., Hue, L. and Andreelli, F. (2006) Activation of AMP-activated protein kinase in the liver: a new strategy for the management of metabolic hepatic disorders. J. Physiol. 574, 41-53
130. Daval, M., Foufelle, F. and Ferré, P. (2006) Functions of AMP-activated protein kinase in adipose tissue. J. Physiol. 574, 55-62
131. Carlson, C. L. and Winder, W. W. (1999) Liver AMP-activated protein kinase and acetyl-CoA carboxylase during and after exercise. J. Appl. Physiol. 86, 669-674
132. Kelly, M., Keller, C., Avilucea, P. R., Keller, P., Luo, Z., Xiang, X., Giralt, M., Hidalgo, J., Saha, A. K., Pedersen, B. K. and Ruderman, N. B. (2004) AMPK activity is diminished in tissues of IL-6 knockout mice: the effect of exercise. Biochem. Biophys. Res. Commun. 320, 449-454
133. Koh, H. J., Hirshman, M. F., He, H., Li, Y., Manabe, Y., Balschi, J. A. and Goodyear, L. J. (2007) Adrenaline is a critical mediator of acute exercise-induced AMP-activated protein kinase activation in adipocytes. Biochem. J. 403, 473-481
134. Gauthier, M. S., Miyoshi, H., Souza, S. C., Cacicedo, J. M., Saha, A. K., Greenberg, A. S. and Ruderman, N. B. (2008) AMP-activated protein kinase is activated as a consequence of lipolysis in the adipocyte: potential mechanism and physiological relevance. J. Biol. Chem. 283, 16514-16524
135. Greenberg, A. S. and Obin, M. S. (2006) Obesity and the role of adipose tissue in inflammation and metabolism. Am. J. Clin. Nutr. 83, 461S-465S
136. Kristensen, J. M., Johnsen, A. B., Birk, J. B., Nielsen, J. N., Jensen, B. R., Hellsten, Y., Richter, E. A. and Wojtaszewski, J. F. (2007) Absence of humoral mediated 5′AMP-activated protein kinase activation in human skeletal muscle and adipose tissue during exercise. J. Physiol. 585, 897-909
137. Watt, M. J., Holmes, A. G., Pinnamaneni, S. K., Garnham, A. P., Steinberg, G. R., Kemp, B. E. and Febbraio, M. A. (2006) Regulation of HSL serine phosphorylation in skeletal muscle and adipose tissue. Am. J. Physiol. Endocrinol. Metab. 290, E500-E508
138. Takekoshi, K., Fukuhara, M., Quin, Z., Nissato, S., Isobe, K., Kawakami, Y. and Ohmori, H. (2006) Long-term exercise stimulates adenosine monophosphate-activated protein kinase activity and subunit expression in rat visceral adipose tissue and liver. Metab., Clin. Exp. 55, 1122-1128
139. Febbraio, M. A. and Pedersen, B. K. (2002) Muscle-derived interleukin-6: mechanisms for activation and possible biological roles. FASEB J. 16, 1335-1347
140. van Hall, G., Steensberg, A., Sacchetti, M., Fischer, C., Keller, C., Schjerling, P., Hiscock, N., Møller, K., Saltin, B., Febbraio, M. A. and Pedersen, B. K. (2003) Interleukin-6 stimulates lipolysis and fat oxidation in humans. J. Clin. Endocrinol. Metab. 88, 3005-3010
141. Martin, T. L., Alquier, T., Asakura, K., Furukawa, N., Preitner, F. and Kahn, B. B. (2006) Diet-induced obesity alters AMP kinase activity in hypothalamus and skeletal muscle J. Biol. Chem. 281, 18933-18941
142. Kola, B., Hubina, E., Tucci, S. A., Kirkham, T. C., Garcia, E. A., Mitchell, S. E., Williams, L. M., Hawley, S. A., Hardie, D. G., Grossman, A. B. and Korbonits, M. (2005) Cannabinoids and ghrelin have both central and peripheral metabolic and cardiac effects via AMP-activated protein kinase. J. Biol. Chem. 280, 25196-25201
143. Andersson, U., Filipsson, K., Abbott, C. R., Woods, A., Smith, K., Bloom, S. R., Carling, D. and Small, C. J. (2004) AMP-activated protein kinase plays a role in the control of food intake. J. Biol. Chem. 279, 12005-12008
144. Andersson, U., Treebak, J. T., Nielsen, J. N., Smith, K. L., Abbott, C. R., Small, C. J., Carling, D. and Richter, E. A. (2005) Exercise in rats does not alter hypothalamic AMP-activated protein kinase activity. Biochem. Biophys. Res. Commun. 329, 719-725
145. Flores, M. B., Fernandes, M. F., Ropelle, E. R., Faria, M. C., Ueno, M., Velloso, L. A., Saad, M. J. and Carvalheira, J. B. (2006) Exercise improves insulin and leptin sensitivity in hypothalamus of Wistar rats. Diabetes 55, 2554-2561
146. Park, S., Jang, J. S., Jun, D. W. and Hong, S. M. (2005) Exercise enhances insulin and leptin signaling in the cerebral cortex and hypothalamus during dexamethasone-induced stress in diabetic rats. Neuroendocrinology 82, 282-293
147. Holmes, B. F., Kurth-Kraczek, E. J. and Winder, W. W. (1999) Chronic activation of 5′-AMP-activated protein kinase increases GLUT-4, hexokinase and glycogen in muscle. J. Appl. Physiol. 87, 1990-1995
148. Zong, H., Ren, J. M., Young, L. H., Pypaert, M., Mu, J., Birnbaum, M. J. and Shulman, G. I. (2002) AMP kinase is required for mitochondrial biogenesis in skeletal muscle in response to chronic energy deprivation. Proc. Natl. Acad. Sci. U.S.A. 99, 15983-15987
149. Rockl, K. S., Hirshman, M. F., Brandauer, J., Fujii, N., Witters, L. A. and Goodyear, L. J. (2007) Skeletal muscle adaptation to exercise training: AMP-activated protein kinase mediates muscle fiber type shift. Diabetes 56, 2062-2069
150. Putman, C. T., Kiricsi, M., Pearcey, J., MacLean, I. M., Bamford, J. A., Murdoch, G. K., Dixon, W. T. and Pette, D. (2003) AMPK activation increases uncoupling protein-3 expression and mitochondrial enzyme activities in rat muscle without fibre type transitions. J. Physiol. 551, 169-178
151. Schiaffino, S., Sandri, M. and Murgia, M. (2007) Activity-dependent signaling pathways controlling muscle diversity and plasticity. Physiology 22, 269-278
152. Nielsen, J. N., Mustard, K. J., Graham, D. A., Yu, H., MacDonald, C. S., Pilegaard, H., Goodyear, L. J., Hardie, D. G., Richter, E. A. and Wojtaszewski, J. F. (2002) 5′AMP-activated protein kinase activity and subunit expression in exercise-trained human skeletal muscle. J. Appl. Physiol. 94, 631-641
153. Frosig, C., Jorgensen, S. B., Hardie, D. G., Richter, E. A. and Wojtaszewski, J. F. (2004) 5′-AMP-activated protein kinase activity and protein expression are regulated by endurance training in human skeletal muscle. Am. J. Physiol. Endocrinol. Metab. 286, E411-E417
154. Fisher, J. S., Gao, J., Han, D. H., Holloszy, J. O. and Nolte, L. A. (2002) Activation of AMP kinase enhances sensitivity of muscle glucose transport to insulin. Am. J. Physiol. Endocrinol. Metab. 282, E18-E23
155. Iglesias, M. A., Ye, J. M., Frangioudakis, G., Saha, A. K., Tomas, E., Ruderman, N. B., Cooney, G. J. and Kraegen, E. W. (2002) AICAR administration causes an apparent enhancement of muscle and liver insulin action in insulin-resistant high-fat-fed rats. Diabetes 51, 2886-2894
156. Blair, S. N., Kohl, III, H. W., Barlow, C. E., Paffenbarger, R. S., Gibbons, L. W. and Macera, C. A. (1995) Changes in physical fitness and all-cause mortality. JAMA, J. Am. Med. Assoc. 273, 1093-1098
157. Thompson, A. M., Church, T. S., Janssen, I., Katzmarzyk, P. T., Earnest, C. P. and Blair, S. N. (2008) Cardiorespiratory fitness as a predictor of cancer mortality among men with pre-diabetes and diabetes. Diabetes Care 31, 764-769
158. Mikines, K. J., Richter, E. A., Dela, F. and Galbo, H. (1991) Seven days of bed rest decrease insulin action on glucose uptake in leg and whole body. J. Appl. Physiol. 70, 1245-1254
159. Dolkas, C. B. and Greenleaf, J. E. (1977) Insulin and glucose responses during bed rest with isotonic and isometric exercise. J. Appl. Physiol. 43, 1033-1038
160. Lipman, R., Schnure, J., Bradley, E. and Lecocq, F. (1970) Impairment of peripheral glucose utilization in normal subjects by prolonged bed rest. J. Lab. Clin. Med. 76, 221-230
161. Jager, S., Handschin, C., St-Pierre, J. and Spiegelman, B. M. (2007) AMP-activated protein kinase (AMPK) action in skeletal muscle via direct phosphorylation of PGC-1α. Proc. Natl. Acad. Sci. U.S.A. 104, 12017-12022
162. Olsen, R. H., Krogh-Madsen, R., Thomsen, C., Booth, F. W. and Pedersen, B. K. (2008) Metabolic responses to reduced daily steps in healthy nonexercising men. JAMA, J. Am. Med. Assoc. 299, 1261-1263
163. Grundy, S. M. (2006) Does the metabolic syndrome exist? Diabetes Care 29, 1689-1692
164. Dishman, R. K., Berthoud, H. R., Booth, F. W., Cotman, C. W., Edgerton, V. R., Fleshner, M. R., Gandevia, S. C., Gomez-Pinilla, F., Greenwood, B. N., Hillman, C. H. et al. (2006) Neurobiology of exercise. Obesity 14, 345-356
165. Manson, J. E., Nathan, D. M., Krolewski, A. S., Stampfer, M. J., Willett, W. C. and Hennekens, C. H. (1992) A prospective study of exercise and incidence of diabetes among US male physicians. JAMA, J. Am. Med. Assoc. 268, 63-67
166. Hu, F. B., Sigal, R. J., Rich-Edwards, J. W., Colditz, G. A., Solomon, C. G., Willett, W. C., Speizer, F. E. and Manson, J. E. (1999) Walking compared with vigorous physical activity and risk of type 2 diabetes in women: a prospective study. JAMA, J. Am. Med. Assoc. 282, 1433-1439
167. Ruderman, N. B., Saha, A. K., Vavvas, D., Kurowski, T., Laybutt, D. R., Schmitz-Peiffer, C., Biden, T. and Kraegen, E. W. (1998) Malonyl CoA as a metabolic switch and a regulator of insulin sensitivity. Adv. Exp. Med. Biol. 441, 263-270
168. Wojtaszewski, J. F. and Richter, E. A. (2006) Effects of acute exercise and training on insulin action and sensitivity: focus on molecular mechanisms in muscle. Essays Biochem. 42, 31-46
169. Wojtaszewski, J. F., Nielsen, J. N. and Richter, E. A. (2002) Effect of acute exercise on insulin signaling and action in humans. J. Appl. Physiol. 93, 384-392
170. Tuomilehto, J., Lindstrom, J., Eriksson, J. G., Valle, T. T., Hamalainen, H., Ilanne-Parikka, P., Keinanen-Kiukaanniemi, S., Laakso, M., Louheranta, A., Rastas, M. et al. (2001) Prevention of type 2 diabetes mellitus by changes in lifestyle among subjects with impaired glucose tolerance. N. Engl. J. Med. 344, 1343-1350
171. Knowler, W. C., Barrett-Connor, E., Fowler, S. E., Hamman, R. F., Lachin, J. M., Walker, E. A. and Nathan, D. M. (2002) Reduction in the incidence of type 2 diabetes with lifestyle intervention or metformin. N. Engl. J. Med. 346, 393-403
172. Pan, X. R., Li, G. W., Hu, Y. H., Wang, J. X., Yang, W. Y., An, Z. X., Hu, Z. X., Lin, J., Xiao, J. Z., Cao, H. B. et al. (1997) Effects of diet and exercise in preventing NIDDM in people with impaired glucose tolerance: the Da Qing IGT and Diabetes Study. Diabetes Care 20, 537-544
173. Musi, N., Hirshman, M. F., Nygren, J., Svanfeldt, M., Bavenholm, P., Rooyackers, O., Zhou, G., Williamson, J. M., Ljunqvist, O., Efendic, S. et al. (2002) Metformin increases AMP-activated protein kinase activity in skeletal muscle of subjects with type 2 diabetes. Diabetes 51, 2074-2081
174. Bandyopadhyay, G. K., Yu, J. G., Ofrecio, J. and Olefsky, J. M. (2006) Increased malonyl-CoA levels in muscle from obese and type 2 diabetic subjects lead to decreased fatty acid oxidation and increased lipogenesis; thiazolidinedione treatment reverses these defects. Diabetes 55, 2277-2285
175. Gerstein, H. C., Yusuf, S., Bosch, J., Pogue, J., Sheridan, P., Dinccag, N., Hanefeld, M., Hoogwerf, B., Laakso, M., Mohan, V. et al. (2006) Effect of rosiglitazone on the frequency of diabetes in patients with impaired glucose tolerance or impaired fasting glucose: a randomised controlled trial. Lancet 368, 1096-1105
176. Orchard, T. J., Temprosa, M., Goldberg, R., Haffner, S., Ratner, R., Marcovina, S. and Fowler, S. (2005) The effect of metformin and intensive lifestyle intervention on the metabolic syndrome: the Diabetes Prevention Program randomized trial. Ann. Intern. Med. 142, 611-619
177. UK Prospective Diabetes Study (UKPDS) Group (1998) Effect of intensive blood-glucose control with metformin on complications in overweight patients with type 2 diabetes (UKPDS 34). Lancet 352, 854-865
178. Bowker, S. L., Majumdar, S. R., Veugelers, P. and Johnson, J. A. (2006) Increased cancer-related mortality for patients with type 2 diabetes who use sulfonylureas or insulin. Diabetes Care 29, 254-258
179. Evans, J. M., Donnelly, L. A., Emslie-Smith, A. M., Alessi, D. R. and Morris, A. D. (2005) Metformin and reduced risk of cancer in diabetic patients. Br. Med. J. 330, 1304-1305
180. Rogers, C. J., Colbert, L. H., Greiner, J. W., Perkins, S. N. and Hursting, S. D. (2008) Physical activity and cancer prevention: pathways and targets for intervention. Sports Med. 38, 271-296
181. Hojlund, K., Mustard, K. J., Staehr, P., Hardie, D. G., Beck-Nielsen, H., Richter, E. A. and Wojtaszewski, J. F. (2004) AMPK activity and isoform protein expression are similar in muscle of obese subjects with and without type 2 diabetes. Am. J. Physiol. Endocrinol. Metab. 286, E239-E244
182. Steinberg, G. R., Smith, A. C., Van Denderen, B. J., Chen, Z., Murthy, S., Campbell, D. J., Heigenhauser, G. J., Dyck, D. J. and Kemp, B. E. (2004) AMP-activated protein kinase is not down-regulated in human skeletal muscle of obese females. J. Clin. Endocrinol. Metab. 89, 4575-4580
183. Koistinen, H. A., Galuska, D., Chibalin, A. V., Yang, J., Zierath, J. R., Holman, G. D. and Wallberg-Henriksson, H. (2003) 5-Amino-imidazole carboxamide riboside increases glucose transport and cell-surface GLUT4 content in skeletal muscle from subjects with type 2 diabetes. Diabetes 52, 1066-1072
184. 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) Effect of acute exercise on AMPK signaling in skeletal muscle of subjects with type 2 diabetes: a time-course and dose-response study. Diabetes 56, 836-848
185. De Filippis, E., Alvarez, G., Berria, R., Cusi, K., Everman, S., Meyer, C. and Mandarino, L. J. (2008) Insulin-resistant muscle is exercise resistant: evidence for reduced response of nuclear-encoded mitochondrial genes to exercise. Am. J. Physiol. Endocrinol. Metab. 294, 607-614
186. Kubota, N., Terauchi, Y., Kubota, T., Kumagai, H., Itoh, S., Satoh, H., Yano, W., Ogata, H., Tokuyama, K., Takamoto, I. et al. (2006) Pioglitazone ameliorates insulin resistance and diabetes by both adiponectin-dependent and -independent pathways. J. Biol. Chem. 281, 8748-8755
187. Nawrocki, A. R., Rajala, M. W., Tomas, E., Pajvani, U. B., Saha, A. K., Trumbauer, M. E., Pang, Z., Chen, A. S., Ruderman, N. B., Chen, H. et al. (2006) Mice lacking adiponectin show decreased hepatic insulin sensitivity and reduced responsiveness to peroxisome proliferator-activated receptor γ agonists. J. Biol. Chem. 281, 2654-2660
188. Becker-Zimmermann, K., Berger, M., Berchtold, P., Gries, F. A., Herberg, L. and Schwenen, M. (1982) Treadmill training improves intravenous glucose tolerance and insulin sensitivity in fatty Zucker rats. Diabetologia 22, 468-474
189. Unger, R. H. (2002) Lipotoxic diseases. Annu. Rev. Med. 53, 319-336
190. Yu, X., McCorkle, S., Wang, M., Lee, Y., Li, J., Saha, A. K., Unger, R. H. and Ruderman, N. B. (2004) Leptinomimetic effects of the AMP kinase activator AICAR in leptin-resistant rats: prevention of diabetes and ectopic lipid deposition. Diabetologia 47, 2012-2021
191. Pold, R., Jensen, L. S., Jessen, N., Buhl, E. S., Schmitz, O., Flyvbjerg, A., Fujii, N., Goodyear, L. J., Gotfredsen, C. F., Brand, C. L. and Lund, S. (2005) Long-term AICAR administration and exercise prevents diabetes in ZDF rats. Diabetes 54, 928-934
192. Wallenius, V., Wallenius, K., Ahren, B., Rudling, M., Carlsten, H., Dickson, S. L., Ohlsson, C. and Jansson, J. O. (2002) Interleukin-6-deficient mice develop mature-onset obesity. Nat. Med. 8, 75-79
193. Faldt, J., Wernstedt, I., Fitzgerald, S. M., Wallenius, K., Bergstrom, G. and Jansson, J. O. (2004) Reduced exercise endurance in interleukin-6-deficient mice. Endocrinology 145, 2680-2686
194. Viollet, B., Andreelli, F., Jorgensen, S. B., Perrin, C., Geloen, A., Flamez, D., Mu, J., Lenzner, C., Baud, O., Bennoun, M. et al. (2003) The AMP-activated protein kinase α2 catalytic subunit controls whole-body insulin sensitivity. J. Clin. Invest. 111 b, 91-98
195. Villena, J. A., Viollet, B., Andreelli, F., Kahn, A., Vaulont, S. and Sul, H. S. (2004) Induced adiposity and adipocyte hypertrophy in mice lacking the AMP-activated protein kinase-α2 subunit. Diabetes 53, 2242-2249
196. Fujii, N., Ho, R. C., Manabe, Y., Jessen, N., Toyoda, T., Holland, W. L., Summers, S. A., Hirshman, M. F. and Goodyear, L. J. (2008) Ablation of AMP-activated protein kinase α2 activity exacerbates insulin resistance induced by high-fat feeding of mice. Diabetes 57, 2958-2966
197. Kern, P. A., Simsolo, R. B. and Fournier, M. (1999) Effect of weight loss on muscle fiber type, fiber size, capillarity, and succinate dehydrogenase activity in humans. J. Clin. Endocrinol. Metab. 84, 4185-4190
198. Prior, B. M., Yang, H. T. and Terjung, R. L. (2004) What makes vessels grow with exercise training? J. Appl. Physiol. 97, 1119-1128
199. Frisbee, J. C., Samora, J. B., Peterson, J. and Bryner, R. (2006) Exercise training blunts microvascular rarefaction in the metabolic syndrome. Am. J. Physiol. Heart Circ. Physiol. 291, H2483-H2492
200. Ouchi, N., Kobayashi, H., Kihara, S., Kumada, M., Sato, K., Inoue, T., Funahashi, T. and Walsh, K. (2004) Adiponectin stimulates angiogenesis by promoting cross-talk between AMP-activated protein kinase and Akt signaling in endothelial cells. J. Biol. Chem. 279, 1304-1309
201. Kivela, R., Silvennoinen, M., Touvra, A. M., Lehti, T. M., Kainulainen, H. and Vihko, V. (2006) Effects of experimental type 1 diabetes and exercise training on angiogenic gene expression and capillarization in skeletal muscle. FASEB J. 20, 1570-1572
202. Reihill, J. A., Ewart, M. A., Hardie, D. G. and Salt, I. P. (2007) AMP-activated protein kinase mediates VEGF-stimulated endothelial NO production. Biochem. Biophys. Res. Commun. 354, 1084-1088
203. Kojda, G., Cheng, Y. C., Burchfield, J. and Harrison, D. G. (2001) Dysfunctional regulation of endothelial nitric oxide synthase (eNOS) expression in response to exercise in mice lacking one eNOS gene. Circulation 103, 2839-2844
204. Chen, Z. P., Mitchelhill, K. I., Michell, B. J., Stapleton, D., Rodriguez-Crespo, I., Witters, L. A., Power, D. A., Ortiz de Montellano, P. R. and Kemp, B. E. (1999) AMP-activated protein kinase phosphorylation of endothelial NO synthase. FEBS Lett. 443, 285-289
205. Morrow, V. A., Foufelle, F., Connell, J. M., Petrie, J. R., Gould, G. W. and Salt, I. P. (2003) Direct activation of AMP-activated protein kinase stimulates nitric-oxide synthesis in human aortic endothelial cells. J. Biol. Chem. 278, 31629-31639
206. Mattagajasingh, I., Kim, C. S., Naqvi, A., Yamamori, T., Hoffman, T. A., Jung, S. B., DeRicco, J., Kasuno, K. and Irani, K. (2007) SIRT1 promotes endothelium-dependent vascular relaxation by activating endothelial nitric oxide synthase. Proc. Natl. Acad. Sci. U.S.A. 104, 14855-14860
207. Potente, M., Ghaeni, L., Baldessari, D., Mostoslavsky, R., Rossig, L., Dequiedt, F., Haendeler, J., Mione, M., Dejana, E., Alt, F. W. et al. (2007) SIRT1 controls endothelial angiogenic functions during vascular growth. Genes Dev. 21, 2644-2658
208. Kramer, A. F. and Erickson, K. I. (2007) Capitalizing on cortical plasticity: influence of physical activity on cognition and brain function. Trends Cogn. Sci. 11, 342-348
209. Lautenschlager, N. T., Cox, K. L., Flicker, L., Foster, J. K., van Bockxmeer, F. M., Xiao, J., Greenop, K. R. and Almeida, O. P. (2008) Effect of physical activity on cognitive function in older adults at risk for Alzheimer disease: a randomized trial. JAMA, J. Am. Med. Assoc. 300, 1027-1037
210. Pereira, A. C., Huddleston, D. E., Brickman, A. M., Sosunov, A. A., Hen, R., McKhann, G. M., Sloan, R., Gage, F. H., Brown, T. R. and Small, S. A. (2007) An in vivo correlate of exercise-induced neurogenesis in the adult dentate gyrus. Proc. Natl. Acad. Sci. U.S.A. 104, 5638-5643
211. Boveris, A. and Navarro, A. (2008) Systemic and mitochondrial adaptive responses to moderate exercise in rodents. Free Radical Biol. Med. 44, 224-229
212. Parachikova, A., Nichol, K. E. and Cotman, C. W. (2008) Short-term exercise in aged Tg2576 mice alters neuroinflammation and improves cognition. Neurobiol. Dis. 30, 121-129
213. Dagon, Y., Avraham, Y., Magen, I., Gertler, A., Ben-Hur, T. and Berry, E. M. (2005) Nutritional status, cognition, and survival: a new role for leptin and AMP kinase. J. Biol. Chem. 280, 42142-42148
214. Anekonda, T. S. and Reddy, P. H. (2006) Neuronal protection by sirtuins in Alzheimer's disease. J. Neurochem. 96, 305-313
215. Kim, D., Nguyen, M. D., Dobbin, M. M., Fischer, A., Sananbenesi, F., Rodgers, J. T., Delalle, I., Baur, J. A., Sui, G., Armour, S. M. et al. (2007) SIRT1 deacetylase protects against neurodegeneration in models for Alzheimer's disease and amyotrophic lateral sclerosis. EMBO J. 26, 3169-3179
216. Qin, W., Yang, T., Ho, L., Zhao, Z., Wang, J., Chen, L., Zhao, W., Thiyagarajan, M., MacGrogan, D., Rodgers, J. T. et al. (2006) Neuronal SIRT1 activation as a novel mechanism underlying the prevention of Alzheimer disease amyloid neuropathology by calorie restriction. J. Biol. Chem. 281, 21745-21754
217. Hou, X., Xu, S., Maitland-Toolan, K. A., Sato, K., Jiang, B., Ido, Y., Lan, F., Walsh, K., Wierzbicki, M., Verbeuren, T. J. et al. (2008) SIRT1 regulates hepatocyte lipid metabolism through activating AMP-activated protein kinase. J. Biol. Chem. 283, 20015-20026
218. Zang, M., Xu, S., Maitland-Toolan, K. A., Zuccollo, A., Hou, X., Jiang, B., Wierzbicki, M., Verbeuren, T. J. and Cohen, R. A. (2006) Polyphenols stimulate AMP-activated protein kinase, lower lipids, and inhibit accelerated atherosclerosis in diabetic LDL receptor-deficient mice. Diabetes 55, 2180-2191
219. Baur, J. A., Pearson, K. J., Price, N. L., Jamieson, H. A., Lerin, C., Kalra, A., Prabhu, V. V., Allard, J. S., Lopez-Lluch, G., Lewis, K. et al. (2006) Resveratrol improves health and survival of mice on a high-calorie diet. Nature 444, 337-342
220. Dasgupta, B. and Milbrandt, J. (2007) Resveratrol stimulates AMP kinase activity in neurons. Proc. Natl. Acad. Sci. U.S.A. 104, 7217-7222
221. Suzuki, K. and Koike, T. (2007) Resveratrol abolishes resistance to axonal degeneration in slow Wallerian degeneration (WldS) mice: activation of SIRT2, an NAD-dependent tubulin deacetylase. Biochem. Biophys. Res. Commun. 359, 665-671
222. Kraegen, E. W., Saha, A. K., Preston, E., Wilks, D., Hoy, A. J., Cooney, G. J. and Ruderman, N. B. (2005) Increased malonyl-CoA and diacylglycerol content and reduced AMPK activity accompany insulin resistance induced by glucose infusion in muscle and liver of rats. Am. J. Physiol. Endocrinol. Metab. 290, E471-E479