Divergent effects of exercise on metabolic and mitogenic signaling pathways in human skeletal muscle

^a Department of Physiology and Pharmacology, Karolinska Institute, Stockholm, SE-114 86, Sweden; the
^b Department of Human Biology, University College of Physical Education and Sports, Stockholm, SE 114 86, Sweden; the
^c Department of Clinical Physiology, Karolinska Hospital, SE 171 76, Sweden;
^d Department of Molecular Medicine, Karolinska Hospital, SE 171 76, Sweden; and the
^e Department of Molecular Pharmacology, Stanford University School of Medicine, Stanford, California, 94305-5332, USA

The molecular signaling mechanisms by which muscle contractions lead to changes in glucose metabolism and gene expression remain largely undefined. We assessed whether exercise activates MAP kinase proteins (ERK1/2, SEK1, and p38 MAP kinase) as well as Akt and PYK2 in skeletal muscle from healthy volunteers obtained during and after one-leg cycle ergometry at ~70% VO_2max. Exercise led to a marked increase in ERK1/2 phosphorylation, which rapidly decreased to resting levels upon recovery. Exercise increased phosphorylation of SEK1 and p38 MAP kinase to a lesser extent than ERK1/2. In contrast to ERK1/2, p38 MAP kinase phosphorylation was increased in nonexercised muscle upon cessation of exercise. Phosphorylation of the transcription factor CREB was increased in nonexercised muscle upon cessation of exercise. Exercise did not activate Akt or increase tyrosine phosphorylation of PYK2. Thus, exercise has divergent effects on parallel MAP kinase pathways, of which only p38 demonstrated a systemic response. However, our data do not support a role of Akt or PYK2 in exercise/contraction-induced signaling in human skeletal. Activation of the different MAP kinase pathways by physical exercise appears to be important in the regulation of transcriptional events in skeletal muscle.—Widegren, U., Jiang, X.-J., Krook, A., Chibalin, A. V., Björnholm, M., Tally, M., Roth, R. A., Henriksson, J., Wallberg-Henriksson, H., Zierath, J. R. Divergent effects of exercise on metabolic and mitogenic signaling pathways in human skeletal muscle. FASEB J. 12, 1379–1389 (1998)

Key Words: insulin action • mitogen-activated protein kinase • Akt kinase • calcium-dependent tyrosine kinase

This article has been cited by other articles:

				A. Granlund, O. Kotova, B. Benziane, D. Galuska, M. Jensen-Waern, A. V. Chibalin, and B. Essén-Gustavsson Effects of exercise on muscle glycogen synthesis signalling and enzyme activities in pigs carrying the PRKAG3 mutation Exp Physiol, April 1, 2010; 95(4): 541 - 549. [Abstract] [Full Text] [PDF]

				L. Holm, G. van Hall, A. J. Rose, B. F. Miller, S. Doessing, E. A. Richter, and M. Kjaer Contraction intensity and feeding affect collagen and myofibrillar protein synthesis rates differently in human skeletal muscle Am J Physiol Endocrinol Metab, February 1, 2010; 298(2): E257 - E269. [Abstract] [Full Text] [PDF]

				T. Nedachi, H. Hatakeyama, T. Kono, M. Sato, and M. Kanzaki Characterization of contraction-inducible CXC chemokines and their roles in C2C12 myocytes Am J Physiol Endocrinol Metab, October 1, 2009; 297(4): E866 - E878. [Abstract] [Full Text] [PDF]

				V. G. Coffey, H. Pilegaard, A. P. Garnham, B. J. O'Brien, and J. A. Hawley Consecutive bouts of diverse contractile activity alter acute responses in human skeletal muscle J Appl Physiol, April 1, 2009; 106(4): 1187 - 1197. [Abstract] [Full Text] [PDF]

				A. Wiik, Y. Hellsten, P. Berthelson, L. Lundholm, H. Fischer, and E. Jansson Activation of estrogen response elements is mediated both via estrogen and muscle contractions in rat skeletal muscle myotubes Am J Physiol Cell Physiol, January 1, 2009; 296(1): C215 - C220. [Abstract] [Full Text] [PDF]

				B. Benziane, T. J. Burton, B. Scanlan, D. Galuska, B. J. Canny, A. V. Chibalin, J. R. Zierath, and N. K. Stepto Divergent cell signaling after short-term intensified endurance training in human skeletal muscle Am J Physiol Endocrinol Metab, December 1, 2008; 295(6): E1427 - E1438. [Abstract] [Full Text] [PDF]

				T. Akimoto, P. Li, and Z. Yan Functional interaction of regulatory factors with the Pgc-1{alpha} promoter in response to exercise by in vivo imaging Am J Physiol Cell Physiol, July 1, 2008; 295(1): C288 - C292. [Abstract] [Full Text] [PDF]

				D. M. Thomson, S. T. Herway, N. Fillmore, H. Kim, J. D. Brown, J. R. Barrow, and W. W. Winder AMP-activated protein kinase phosphorylates transcription factors of the CREB family J Appl Physiol, February 1, 2008; 104(2): 429 - 438. [Abstract] [Full Text] [PDF]

				K. F. Howlett, A. Mathews, A. Garnham, and K. Sakamoto The effect of exercise and insulin on AS160 phosphorylation and 14-3-3 binding capacity in human skeletal muscle Am J Physiol Endocrinol Metab, February 1, 2008; 294(2): E401 - E407. [Abstract] [Full Text] [PDF]

				A. J. Rose, C. Frosig, B. Kiens, J. F. P. Wojtaszewski, and E. A. Richter Effect of endurance exercise training on Ca2+ calmodulin-dependent protein kinase II expression and signalling in skeletal muscle of humans J. Physiol., September 1, 2007; 583(2): 785 - 795. [Abstract] [Full Text] [PDF]

				H. F. Kramer and L. J. Goodyear Exercise, MAPK, and NF-{kappa}B signaling in skeletal muscle J Appl Physiol, July 1, 2007; 103(1): 388 - 395. [Abstract] [Full Text] [PDF]

				D. C. Wright, P. C. Geiger, D.-H. Han, T. E. Jones, and J. O. Holloszy Calcium Induces Increases in Peroxisome Proliferator-activated Receptor {gamma} Coactivator-1{alpha} and Mitochondrial Biogenesis by a Pathway Leading to p38 Mitogen-activated Protein Kinase Activation J. Biol. Chem., June 29, 2007; 282(26): 18793 - 18799. [Abstract] [Full Text] [PDF]

				G. D. Wadley, N. Konstantopoulos, L. Macaulay, K. F. Howlett, A. Garnham, M. Hargreaves, and D. Cameron-Smith Increased insulin-stimulated Akt pSer473 and cytosolic SHP2 protein abundance in human skeletal muscle following acute exercise and short-term training J Appl Physiol, April 1, 2007; 102(4): 1624 - 1631. [Abstract] [Full Text] [PDF]

				J. T. Treebak, J. B. Birk, A. J. Rose, B. Kiens, E. A. Richter, and J. F. P. Wojtaszewski AS160 phosphorylation is associated with activation of {alpha}2beta2{gamma}1- but not {alpha}2beta2{gamma}3-AMPK trimeric complex in skeletal muscle during exercise in humans Am J Physiol Endocrinol Metab, March 1, 2007; 292(3): E715 - E722. [Abstract] [Full Text] [PDF]

				J. A. H. Smith, M. Collins, L. A. Grobler, C. J. Magee, and E. O. Ojuka Exercise and CaMK activation both increase the binding of MEF2A to the Glut4 promoter in skeletal muscle in vivo Am J Physiol Endocrinol Metab, February 1, 2007; 292(2): E413 - E420. [Abstract] [Full Text] [PDF]

				D. C. Wright, D.-H. Han, P. M. Garcia-Roves, P. C. Geiger, T. E. Jones, and J. O. Holloszy Exercise-induced Mitochondrial Biogenesis Begins before the Increase in Muscle PGC-1{alpha} Expression J. Biol. Chem., January 5, 2007; 282(1): 194 - 199. [Abstract] [Full Text] [PDF]

				N. Fujii, N. Jessen, and L. J. Goodyear AMP-activated protein kinase and the regulation of glucose transport Am J Physiol Endocrinol Metab, November 1, 2006; 291(5): E867 - E877. [Abstract] [Full Text] [PDF]

				K. Sakamoto, D. E. Arnolds, N. Fujii, H. F. Kramer, M. F. Hirshman, and L. J. Goodyear Role of Akt2 in contraction-stimulated cell signaling and glucose uptake in skeletal muscle Am J Physiol Endocrinol Metab, November 1, 2006; 291(5): E1031 - E1037. [Abstract] [Full Text] [PDF]

				D. W. Russ and R. M. Lovering Influence of activation frequency on cellular signalling pathways during fatiguing contractions in rat skeletal muscle Exp Physiol, November 1, 2006; 91(6): 957 - 966. [Abstract] [Full Text] [PDF]

				K. J. Nadeau, L. B. Ehlers, L. E. Aguirre, R. L. Moore, K. N. Jew, H. K. Ortmeyer, B. C. Hansen, J. E. B. Reusch, and B. Draznin Exercise training and calorie restriction increase SREBP-1 expression and intramuscular triglyceride in skeletal muscle Am J Physiol Endocrinol Metab, July 1, 2006; 291(1): E90 - E98. [Abstract] [Full Text] [PDF]

				A. Deshmukh, V. G. Coffey, Z. Zhong, A. V. Chibalin, J. A. Hawley, and J. R. Zierath Exercise-Induced Phosphorylation of the Novel Akt Substrates AS160 and Filamin A in Human Skeletal Muscle Diabetes, June 1, 2006; 55(6): 1776 - 1782. [Abstract] [Full Text] [PDF]

				D. C. Wright, P. C. Geiger, D.-H. Han, and J. O. Holloszy Are tyrosine kinases involved in mediating contraction-stimulated muscle glucose transport? Am J Physiol Endocrinol Metab, January 1, 2006; 290(1): E123 - E128. [Abstract] [Full Text] [PDF]

				M. J Jackson Reactive oxygen species and redox-regulation of skeletal muscle adaptations to exercise Phil Trans R Soc B, December 29, 2005; 360(1464): 2285 - 2291. [Abstract] [Full Text] [PDF]

				B. R. Barnes, Y. C. Long, T. L. Steiler, Y. Leng, D. Galuska, J. F.P. Wojtaszewski, L. Andersson, and J. R. Zierath Changes in Exercise-Induced Gene Expression in 5'-AMP-Activated Protein Kinase {gamma}3-Null and {gamma}3 R225Q Transgenic Mice Diabetes, December 1, 2005; 54(12): 3484 - 3489. [Abstract] [Full Text] [PDF]

				A. Creer, P. Gallagher, D. Slivka, B. Jemiolo, W. Fink, and S. Trappe Influence of muscle glycogen availability on ERK1/2 and Akt signaling after resistance exercise in human skeletal muscle J Appl Physiol, September 1, 2005; 99(3): 950 - 956. [Abstract] [Full Text] [PDF]

				A. J. Rose and E. A. Richter Skeletal Muscle Glucose Uptake During Exercise: How is it Regulated? Physiology, August 1, 2005; 20(4): 260 - 270. [Abstract] [Full Text] [PDF]

				T. Akimoto, S. C. Pohnert, P. Li, M. Zhang, C. Gumbs, P. B. Rosenberg, R. S. Williams, and Z. Yan Exercise Stimulates Pgc-1{alpha} Transcription in Skeletal Muscle through Activation of the p38 MAPK Pathway J. Biol. Chem., May 20, 2005; 280(20): 19587 - 19593. [Abstract] [Full Text] [PDF]

				J. G. Tidball Mechanical signal transduction in skeletal muscle growth and adaptation J Appl Physiol, May 1, 2005; 98(5): 1900 - 1908. [Abstract] [Full Text] [PDF]

				P. C. Geiger, D. C. Wright, D.-H. Han, and J. O. Holloszy Activation of p38 MAP kinase enhances sensitivity of muscle glucose transport to insulin Am J Physiol Endocrinol Metab, April 1, 2005; 288(4): E782 - E788. [Abstract] [Full Text] [PDF]

				M. Sheffield-Moore, C. W. Yeckel, E. Volpi, S. E. Wolf, B. Morio, D. L. Chinkes, D. Paddon-Jones, and R. R. Wolfe Postexercise protein metabolism in older and younger men following moderate-intensity aerobic exercise Am J Physiol Endocrinol Metab, September 1, 2004; 287(3): E513 - E522. [Abstract] [Full Text] [PDF]

				T. Vassilakopoulos, M. Divangahi, G. Rallis, O. Kishta, B. Petrof, A. Comtois, and S. N. A. Hussain Differential Cytokine Gene Expression in the Diaphragm in Response to Strenuous Resistive Breathing Am. J. Respir. Crit. Care Med., July 15, 2004; 170(2): 154 - 161. [Abstract] [Full Text] [PDF]

				J. D. Parkington, N. K. LeBrasseur, A. P. Siebert, and R. A. Fielding Contraction-mediated mTOR, p70S6k, and ERK1/2 phosphorylation in aged skeletal muscle J Appl Physiol, July 1, 2004; 97(1): 243 - 248. [Abstract] [Full Text] [PDF]

				H. K. R. Karlsson, P.-A. Nilsson, J. Nilsson, A. V. Chibalin, J. R. Zierath, and E. Blomstrand Branched-chain amino acids increase p70S6k phosphorylation in human skeletal muscle after resistance exercise Am J Physiol Endocrinol Metab, July 1, 2004; 287(1): E1 - E7. [Abstract] [Full Text] [PDF]

				N. Fujii, M. D. Boppart, S. D. Dufresne, P. F. Crowley, A. C. Jozsi, K. Sakamoto, H. Yu, W. G. Aschenbach, S. Kim, H. Miyazaki, et al. Overexpression or ablation of JNK in skeletal muscle has no effect on glycogen synthase activity Am J Physiol Cell Physiol, July 1, 2004; 287(1): C200 - C208. [Abstract] [Full Text] [PDF]

				Y. Leng, T. L. Steiler, and J. R. Zierath Effects of Insulin, Contraction, and Phorbol Esters on Mitogen-Activated Protein Kinase Signaling in Skeletal Muscle From Lean and ob/ob Mice Diabetes, June 1, 2004; 53(6): 1436 - 1444. [Abstract] [Full Text] [PDF]

				M. KJAeR Role of Extracellular Matrix in Adaptation of Tendon and Skeletal Muscle to Mechanical Loading Physiol Rev, April 1, 2004; 84(2): 649 - 698. [Abstract] [Full Text] [PDF]

				S. Perrini, J. Henriksson, J. R. Zierath, and U. Widegren Exercise-Induced Protein Kinase C Isoform-Specific Activation in Human Skeletal Muscle Diabetes, January 1, 2004; 53(1): 21 - 24. [Abstract] [Full Text] [PDF]

				C. Y. Christ-Roberts, T. Pratipanawatr, W. Pratipanawatr, R. Berria, R. Belfort, and L. J. Mandarino Increased insulin receptor signaling and glycogen synthase activity contribute to the synergistic effect of exercise on insulin action J Appl Physiol, December 1, 2003; 95(6): 2519 - 2529. [Abstract] [Full Text]

				K. LEMIEUX, D. KONRAD, A. KLIP, and A. MARETTE The AMP-activated protein kinase activator AICAR does not induce GLUT4 translocation to transverse tubules but stimulates glucose uptake and p38 mitogen-activated protein kinases {alpha} and {beta} in skeletal muscle FASEB J, September 1, 2003; 17(12): 1658 - 1665. [Abstract] [Full Text] [PDF]

				D Williamson, P Gallagher, M Harber, C Hollon, and S Trappe Mitogen-activated protein kinase (MAPK) pathway activation: effects of age and acute exercise on human skeletal muscle J. Physiol., March 15, 2003; 547(3): 977 - 987. [Abstract] [Full Text] [PDF]

				M. Yu, N. K Stepto, A. V Chibalin, L. G D Fryer, D. Carling, A. Krook, J. A Hawley, and J. R Zierath Metabolic and mitogenic signal transduction in human skeletal muscle after intense cycling exercise J. Physiol., January 15, 2003; 546(2): 327 - 335. [Abstract] [Full Text] [PDF]

				A. R. Gosmanov, N. C. Nordtvedt, R. Brown, and D. B. Thomason Exercise effects on muscle beta -adrenergic signaling for MAPK-dependent NKCC activity are rapid and persistent J Appl Physiol, October 1, 2002; 93(4): 1457 - 1465. [Abstract] [Full Text] [PDF]

				J. R. Zierath Exercise Effects of Muscle Insulin Signaling and Action: Invited Review: Exercise training-induced changes in insulin signaling in skeletal muscle J Appl Physiol, August 1, 2002; 93(2): 773 - 781. [Abstract] [Full Text] [PDF]

				K. Sakamoto and L. J. Goodyear Exercise Effects on Muscle Insulin Signaling and Action: Invited Review: Intracellular signaling in contracting skeletal muscle J Appl Physiol, July 1, 2002; 93(1): 369 - 383. [Abstract] [Full Text] [PDF]

				K. Sakamoto, M. F. Hirshman, W. G. Aschenbach, and L. J. Goodyear Contraction Regulation of Akt in Rat Skeletal Muscle J. Biol. Chem., March 29, 2002; 277(14): 11910 - 11917. [Abstract] [Full Text] [PDF]

				M. Yu, E. Blomstrand, A. V Chibalin, A. Krook, and J. R Zierath Marathon running increases ERK1/2 and p38 MAP kinase signalling to downstream targets in human skeletal muscle J. Physiol., October 1, 2001; 536(1): 273 - 282. [Abstract] [Full Text] [PDF]

				C. Wretman, A. Lionikas, U. Widegren, J. Lannergren, H. Westerblad, and J. Henriksson Effects of concentric and eccentric contractions on phosphorylation of MAPKerk1/2 and MAPKp38 in isolated rat skeletal muscle J. Physiol., August 15, 2001; 535(1): 155 - 164. [Abstract] [Full Text] [PDF]

				L. C. Martineau and P. F. Gardiner Insight into skeletal muscle mechanotransduction: MAPK activation is quantitatively related to tension J Appl Physiol, August 1, 2001; 91(2): 693 - 702. [Abstract] [Full Text] [PDF]

				G. A. Nader and K. A. Esser Intracellular signaling specificity in skeletal muscle in response to different modes of exercise J Appl Physiol, May 1, 2001; 90(5): 1936 - 1942. [Abstract] [Full Text] [PDF]

				M. D. Boppart, M. F. Hirshman, K. Sakamoto, R. A. Fielding, and L. J. Goodyear Static stretch increases c-Jun NH2-terminal kinase activity and p38 phosphorylation in rat skeletal muscle Am J Physiol Cell Physiol, February 1, 2001; 280(2): C352 - C358. [Abstract] [Full Text] [PDF]

				M. Yu, E. Blomstrand, A. V. Chibalin, H. Wallberg-Henriksson, J. R. Zierath, and A. Krook Exercise-associated differences in an array of proteins involved in signal transduction and glucose transport J Appl Physiol, January 1, 2001; 90(1): 29 - 34. [Abstract] [Full Text] [PDF]

				A. Krook, U. Widegren, X. J. Jiang, J. Henriksson, H. Wallberg-Henriksson, D. Alessi, and J. R. Zierath Effects of exercise on mitogen- and stress-activated kinase signal transduction in human skeletal muscle Am J Physiol Regulatory Integrative Comp Physiol, November 1, 2000; 279(5): R1716 - R1721. [Abstract] [Full Text] [PDF]

				M. D Boppart, S. Asp, J. F P Wojtaszewski, R. A Fielding, T. Mohr, and L. J Goodyear Marathon running transiently increases c-Jun NH2-terminal kinase and p38{gamma} activities in human skeletal muscle J. Physiol., August 1, 2000; 526(3): 663 - 669. [Abstract] [Full Text] [PDF]

				A. A. Osman, M. Pendergrass, J. Koval, K. Maezono, K. Cusi, T. Pratipanawatr, and L. J. Mandarino Regulation of MAP kinase pathway activity in vivo in human skeletal muscle Am J Physiol Endocrinol Metab, June 1, 2000; 278(6): E992 - E999. [Abstract] [Full Text] [PDF]

				Y. Kraniou, D. Cameron-Smith, M. Misso, G. Collier, and M. Hargreaves Effects of exercise on GLUT-4 and glycogenin gene expression in human skeletal muscle J Appl Physiol, February 1, 2000; 88(2): 794 - 796. [Abstract] [Full Text] [PDF]

				J. W. Ryder, R. Fahlman, H. Wallberg-Henriksson, D. R. Alessi, A. Krook, and J. R. Zierath Effect of Contraction on Mitogen-activated Protein Kinase Signal Transduction in Skeletal Muscle. INVOLVEMENT OF THE MITOGEN- AND STRESS-ACTIVATED PROTEIN KINASE 1 J. Biol. Chem., January 14, 2000; 275(2): 1457 - 1462. [Abstract] [Full Text] [PDF]

				A. V. Chibalin, M. Yu, J. W. Ryder, X. M. Song, D. Galuska, A. Krook, H. Wallberg-Henriksson, and J. R. Zierath Exercise-induced changes in expression and activity of proteins involved in insulin signal transduction in skeletal muscle: Differential effects on insulin-receptor substrates 1 and 2 PNAS, January 4, 2000; 97(1): 38 - 43. [Abstract] [Full Text] [PDF]

				A. S. Blair, E. Hajduch, G. J. Litherland, and H. S. Hundal Regulation of Glucose Transport and Glycogen Synthesis in L6 Muscle Cells during Oxidative Stress. EVIDENCE FOR CROSS-TALK BETWEEN THE INSULIN AND SAPK2/p38 MITOGEN-ACTIVATED PROTEIN KINASE SIGNALING PATHWAYS J. Biol. Chem., December 17, 1999; 274(51): 36293 - 36299. [Abstract] [Full Text] [PDF]

				M. D. Boppart, D. Aronson, L. Gibson, R. Roubenoff, L. W. Abad, J. Bean, L. J. Goodyear, and R. A. Fielding Eccentric exercise markedly increases c-Jun NH2-terminal kinase activity in human skeletal muscle J Appl Physiol, November 1, 1999; 87(5): 1668 - 1673. [Abstract] [Full Text] [PDF]

				T. Hayashi, M. F. Hirshman, S. D. Dufresne, and L. J. Goodyear Skeletal muscle contractile activity in vitro stimulates mitogen-activated protein kinase signaling Am J Physiol Cell Physiol, October 1, 1999; 277(4): C701 - C707. [Abstract] [Full Text] [PDF]

				J. F. P. Wojtaszewski, J. Lynge, A. B. Jakobsen, L. J. Goodyear, and E. A. Richter Differential regulation of MAP kinase by contraction and insulin in skeletal muscle: metabolic implications Am J Physiol Endocrinol Metab, October 1, 1999; 277(4): E724 - E732. [Abstract] [Full Text] [PDF]

				A. Thorell, M. F. Hirshman, J. Nygren, L. Jorfeldt, J. F. P. Wojtaszewski, S. D. Dufresne, E. S. Horton, O. Ljungqvist, and L. J. Goodyear Exercise and insulin cause GLUT-4 translocation in human skeletal muscle Am J Physiol Endocrinol Metab, October 1, 1999; 277(4): E733 - E741. [Abstract] [Full Text] [PDF]