Review Article | Published:

Exercise-stimulated glucose uptake — regulation and implications for glycaemic control

Nature Reviews Endocrinology volume 13, pages 133148 (2017) | Download Citation

Abstract

Skeletal muscle extracts glucose from the blood to maintain demand for carbohydrates as an energy source during exercise. Such uptake involves complex molecular signalling processes that are distinct from those activated by insulin. Exercise-stimulated glucose uptake is preserved in insulin-resistant muscle, emphasizing exercise as a therapeutic cornerstone among patients with metabolic diseases such as diabetes mellitus. Exercise increases uptake of glucose by up to 50-fold through the simultaneous stimulation of three key steps: delivery, transport across the muscle membrane and intracellular flux through metabolic processes (glycolysis and glucose oxidation). The available data suggest that no single signal transduction pathway can fully account for the regulation of any of these key steps, owing to redundancy in the signalling pathways that mediate glucose uptake to ensure maintenance of muscle energy supply during physical activity. Here, we review the molecular mechanisms that regulate the movement of glucose from the capillary bed into the muscle cell and discuss what is known about their integrated regulation during exercise. Novel developments within the field of mass spectrometry-based proteomics indicate that the known regulators of glucose uptake are only the tip of the iceberg. Consequently, many exciting discoveries clearly lie ahead.

Key points

  • Exercise-stimulated signal transduction can restore glucose metabolism in insulin-resistant muscle through both acute activation of glucose transport and by improving insulin sensitivity for up to 48 hours after exercise

  • Glucose is a major fuel source during exercise and glucose uptake by skeletal muscle can increase by up to 50-fold during bouts of exercise

  • In excess of 1,000 phosphorylation sites in human skeletal muscle are regulated by exercise, which suggests that many regulators of muscle glucose uptake have yet to be discovered

  • Regulation of exercise-stimulated glucose uptake by skeletal muscle requires three major steps (delivery, transport and intramyocellular metabolism), any of which could be rate-limiting during various exercise conditions

  • Intensity and duration of exercise are key determinants of glucose uptake by skeletal muscle

  • Exercise-stimulated glucose transport is regulated by two major pathways that sense either alterations in the intracellular metabolic milieu (probably mediated by AMPK) or mechanical stress (partly mediated by RAC1)

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References

  1. 1.

    Four grams of glucose. Am. J. Physiol. Endocrinol. Metab. 296, E11–E21 (2009).

  2. 2.

    et al. Global phosphoproteomic analysis of human skeletal muscle reveals a network of exercise-regulated kinases and AMPK substrates. Cell Metab. 22, 922–935 (2015).

  3. 3.

    , , & Is contraction-stimulated glucose transport feedforward regulated by Ca2+? Exp. Physiol. 99, 1562–1568 (2014).

  4. 4.

    & Regulation of exercise-induced lipid metabolism in skeletal muscle. Exp. Physiol. 99, 1586–1592 (2014).

  5. 5.

    & Regulation of glucose and glycogen metabolism during and after exercise. J. Physiol. 590, 1069–1076 (2012).

  6. 6.

    & Exercise, GLUT4, and skeletal muscle glucose uptake. Physiol. Rev. 93, 993–1017 (2013).

  7. 7.

    , , , & The effects of increasing exercise intensity on muscle fuel utilisation in humans. J. Physiol. 536 (Pt. 1), 295–304 (2001).

  8. 8.

    et al. Regulation of endogenous fat and carbohydrate metabolism in relation to exercise intensity and duration. Am. J. Physiol. 265, E380–E391 (1993).

  9. 9.

    , , , & Substrate turnover during prolonged exercise in man. Splanchinc and leg metabolism of glucose, free fatty acids and amino acids. J. Clin. Invest. 53, 1080–1090 (1974).

  10. 10.

    et al. Carbohydrate feeding during prolonged strenuous exercise can delay fatigue. J. Appl. Physiol. 55, 230–235 (1983).

  11. 11.

    , , & Glucose metabolism during leg exercise in man. J. Clin. Invest. 50, 2715–2725 (1971).

  12. 12.

    , , & Leg glucose uptake during maximal dynamic exercise in humans. Am. J. Physiol. 251, E65–E70 (1986).

  13. 13.

    , & Increased muscle glucose uptake during contractions: no need for insulin. Am. J. Physiol. 247, E726–E731 (1984).

  14. 14.

    et al. Exercise modulates postreceptor insulin signaling and glucose transport in muscle-specific insulin receptor knockout mice. J. Clin. Invest. 104, 1257–1264 (1999).

  15. 15.

    et al. Role of Akt2 in contraction-stimulated cell signaling and glucose uptake in skeletal muscle. Am. J. Physiol. Endocrinol. Metab. 291, E1031–E1037 (2006).

  16. 16.

    et al. Glucoregulatory and metabolic response to exercise in obese noninsulin-dependent diabetes. Am. J. Physiol. 240, E458–E464 (1981).

  17. 17.

    , , & Effect of exercise on insulin action in human skeletal muscle. J. Appl. Physiol. 66, 876–885 (1989).

  18. 18.

    , , & Muscle glucose metabolism following exercise in the rat. J. Clin. Invest. 69, 785–793 (1982).

  19. 19.

    et al. Effect of muscle glycogen depletion on in vivo insulin action in man. J. Clin. Invest. 72, 1605–1610 (1983).

  20. 20.

    , , , & Effect of physical exercise on sensitivity and responsiveness to insulin in humans. Am. J. Physiol. 254, E248–E259 (1988).

  21. 21.

    & Effects of prior high-intensity exercise on glucose metabolism in normal and insulin-resistant men. Diabetes 34, 973–979 (1985).

  22. 22.

    , , , & Effects of exercise on glycemic control and body mass in type 2 diabetes mellitus: a meta-analysis of controlled clinical trials. JAMA 286, 1218–1227 (2001).

  23. 23.

    et al. Two weekly sessions of combined aerobic and resistance exercise are sufficient to provide beneficial effects in subjects with type 2 diabetes mellitus and metabolic syndrome. J. Endocrinol. Invest. 33, 489–495 (2010).

  24. 24.

    , , , & Effect of training on insulin-mediated glucose uptake in human muscle. Am. J. Physiol. 263, E1134–E1143 (1992).

  25. 25.

    et al. Insulin-stimulated muscle glucose clearance in patients with NIDDM. Effects of one-legged physical training. Diabetes 44, 1010–1020 (1995).

  26. 26.

    et al. Reduction in the incidence of type 2 diabetes with lifestyle intervention or metformin. N. Engl. J. Med. 346, 393–403 (2002).

  27. 27.

    , , & Influence of active muscle mass on glucose homeostasis during exercise in humans. J. Appl. Physiol. 71, 552–557 (1991).

  28. 28.

    et al. Central and peripheral hemodynamics in exercising humans: leg versus arm exercise. Scand. J. Med. Sci. Sports 25 (Suppl. 4), 144–157 (2015).

  29. 29.

    & Regulation of increased blood flow (hyperemia) to muscles during exercise: a hierarchy of competing physiological needs. Physiol. Rev. 95, 549–601 (2015).

  30. 30.

    & Influence of training on blood flow to different skeletal muscle fiber types. J. Appl. Physiol. Respir. Environ. Exerc. Physiol. 55, 1072–1078 (1983).

  31. 31.

    & Muscular blood flow distribution patterns as a function of running speed in rats. Am. J. Physiol. 243, H296–H306 (1982).

  32. 32.

    , , & Vasodilator interactions in skeletal muscle blood flow regulation. J. Physiol. 590, 6297–6305 (2012).

  33. 33.

    et al. Electrical stimuli release ATP to increase GLUT4 translocation and glucose uptake via PI3Kγ-Akt-AS160 in skeletal muscle cells. Diabetes 62, 1519–1526 (2013).

  34. 34.

    et al. Mixed meal and light exercise each recruit muscle capillaries in healthy humans. Am. J. Physiol. Endocrinol. Metab. 290, E1191–E1197 (2006).

  35. 35.

    , , , & A new method to study changes in microvascular blood volume in muscle and adipose tissue: real-time imaging in humans and rat. Am. J. Physiol. Heart Circ. Physiol. 301, H450–H458 (2011).

  36. 36.

    , & Muscle interstitial glucose and lactate levels during dynamic exercise in humans determined by microdialysis. J. Appl. Physiol. 87, 1483–1490 (1999).

  37. 37.

    , , & Important role of insulin and flow in stimulating glucose uptake in contracting skeletal muscle. Diabetes 44, 210–215 (1995).

  38. 38.

    et al. Glucose delivery — a clarification of its role in regulating glucose uptake in rat skeletal muscle. Life Sci. 20, 733–736 (1977).

  39. 39.

    , , , & Glucose delivery: a modulator of glucose uptake in contracting skeletal muscle. Am. J. Physiol. 233, E514–E518 (1977).

  40. 40.

    et al. Endothelial nitric oxide synthase is central to skeletal muscle metabolic regulation and enzymatic signaling during exercise in vivo. Am. J. Physiol. Regul. Integr. Comp. Physiol. 298, R1399–R1408 (2010).

  41. 41.

    in Handbook of Physiology. Section 12: Exercise: Regulation and Integration of Multiple Systems (eds Rowell, L. B. & Shepherd, J. T.) (Oxford Univ. Press, 1996).

  42. 42.

    , , & Effect of carbohydrate ingestion on glucose kinetics during exercise. J. Appl. Physiol. 77, 1537–1541 (1994).

  43. 43.

    & Glucose transporters in the 21st Century. Am. J. Physiol. Endocrinol. Metab. 298, E141–E145 (2010).

  44. 44.

    , , & Kinetics of contraction-induced GLUT4 translocation in skeletal muscle fibers from living mice. Diabetes 59, 2134–2144 (2010).

  45. 45.

    , , , & Analysis of GLUT4 distribution in whole skeletal mu scle fibers: identification of distinct storage compartments that are recruited by insulin and muscle contractions. J. Cell Biol. 142, 1429–1446 (1998).

  46. 46.

    , , , & The transferrin receptor defines two distinct contraction-responsive GLUT4 vesicle populations in skeletal muscle. Diabetes 49, 183–189 (2000).

  47. 47.

    & Exercise induces the translocation of GLUT4 to transverse tubules from an intracellular pool in rat skeletal muscle. Biochem. Biophys. Res. Commun. 223, 147–152 (1996).

  48. 48.

    et al. Exercise induces recruitment of the “insulin-responsive glucose transporter”. J. Biol. Chem. 265, 13427–13430 (1990).

  49. 49.

    , & Exercise-induced increase in glucose transport, GLUT4, and VAMP-2 in plasma membrane from human muscle. Am. J. Physiol. 270, E197–E201 (1996).

  50. 50.

    , & Progressive increase in glucose transport and GLUT-4 in human sarcolemmal vesicles during moderate exercise. Am. J. Physiol. 272, E385–E389 (1997).

  51. 51.

    et al. Acute exercise induces GLUT4 translocation in skeletal muscle of normal human subjects and subjects with type 2 diabetes. Diabetes 48, 1192–1197 (1999).

  52. 52.

    et al. Targeted disruption of the glucose transporter 4 selectively in muscle causes insulin resistance and glucose intolerance. Nat. Med. 6, 924–928 (2000).

  53. 53.

    et al. Postexercise glucose uptake and glycogen synthesis in skeletal muscle from GLUT4-deficient mice. FASEB J. 13, 2246–2256 (1999).

  54. 54.

    , , & Signal transduction meets vesicle traffic: the software and hardware of GLUT4 translocation. Am. J. Physiol. Cell. Physiol. 306, C879–C886 (2014).

  55. 55.

    et al. Insulin resistance and a diabetes mellitus-like syndrome in mice lacking the protein kinase Akt2 (PKB β). Science 292, 1728–1731 (2001).

  56. 56.

    , & Splanchnic and muscle metabolism during exercise in NIDDM patients. Am. J. Physiol. 269 (3 Pt. 1), E583–E590 (1995).

  57. 57.

    , & Ca2+–calmodulin-dependent protein kinase expression and signalling in skeletal muscle during exercise. J. Physiol. 574 (Pt. 3), 889–903 (2006).

  58. 58.

    , & Calcium stimulates glucose transport in skeletal muscle by a pathway independent of contraction. Am. J. Physiol. 260, C555–C561 (1991).

  59. 59.

    , , & Ca2+ and AMPK both mediate stimulation of glucose transport by muscle contractions. Diabetes 53, 330–335 (2004).

  60. 60.

    , , , & Caffeine-induced Ca2+ release increases AMPK-dependent glucose uptake in rodent soleus muscle. Am. J. Physiol. Endocrinol. Metab. 293, E286–E292 (2007).

  61. 61.

    et al. Contraction-stimulated glucose transport in muscle is controlled by AMPK and mechanical stress but not sarcoplasmatic reticulum Ca2+ release. Mol. Metab. 3, 742–753 (2014).

  62. 62.

    et al. CaMKII regulates contraction- but not insulin-induced glucose uptake in mouse skeletal muscle. Am. J. Physiol. Endocrinol. Metab. 298, E1150–E1160 (2010).

  63. 63.

    , , & Rutin potentiates calcium uptake via voltage-dependent calcium channel associated with stimulation of glucose uptake in skeletal muscle. Arch. Biochem. Biophys. 532, 55–60 (2013).

  64. 64.

    , , , & Exercise ameliorates insulin resistance via Ca2+ signals distinct from those of insulin for GLUT4 translocation in skeletal muscles. Diabetes 64, 1224–1234 (2015).

  65. 65.

    Cyclic ADP-ribose and NAADP: fraternal twin messengers for calcium signaling. Sci. China Life Sci. 54, 699–711 (2011).

  66. 66.

    & Ca2+ microdomains, NAADP and type 1 ryanodine receptor in cell activation. Biochim. Biophys. Acta 1863 (6 Pt B), 1379–1384 (2016).

  67. 67.

    , & The versatility and universality of calcium signalling. Nat. Rev. Mol. Cell Biol. 1, 11–21 (2000).

  68. 68.

    et al. AICAR prevents heat-induced sudden death in RyR1 mutant mice independent of AMPK activation. Nat. Med. 18, 244–251 (2012).

  69. 69.

    , & Changes in [Ca2+]i induced by several glucose transport-enhancing stimuli in rat epitrochlearis muscle. J. Appl. Physiol. 94, 1813–1820 (2003).

  70. 70.

    et al. 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 (2005).

  71. 71.

    , , , & Stretch-stimulated glucose uptake in skeletal muscle is mediated by reactive oxygen species and p38 MAP-kinase. J. Physiol. 587, 3363–3373 (2009).

  72. 72.

    Effects of stretch and starvation on glucose uptake of rat soleus and extensor digitorum longus muscles. Muscle Nerve 9, 144–147 (1986).

  73. 73.

    , , & Akt signaling in skeletal muscle: regulation by exercise and passive stretch. Am. J. Physiol. Endocrinol. Metab. 285, E1081–E1088 (2003).

  74. 74.

    , , , & Stretch-stimulated glucose transport in skeletal muscle is regulated by Rac1. J. Physiol. 593, 645–656 (2015).

  75. 75.

    , , & Effect of tension on contraction-induced glucose transport in rat skeletal muscle. Am. J. Physiol. 277, E208–E214 (1999).

  76. 76.

    , , & A myosin II ATPase inhibitor reduces force production, glucose transport, and phosphorylation of AMPK and TBC1D1 in electrically stimulated rat skeletal muscle. Am. J. Physiol. Endocrinol. Metab. 296, E993–E1002 (2009).

  77. 77.

    , , & Mechanical load plays little role in contraction-mediated glucose transport in mouse skeletal muscle. J. Physiol. 579, 527–534 (2007).

  78. 78.

    et al. Rac1 signaling is required for insulin-stimulated glucose uptake and is dysregulated in insulin-resistant murine and human skeletal muscle. Diabetes 62, 1865–1875 (2013).

  79. 79.

    et al. Rac1 is a novel regulator of contraction-stimulated glucose uptake in skeletal muscle. Diabetes 62, 1139–1151 (2013).

  80. 80.

    et al. Rac1 governs exercise-stimulated glucose uptake in skeletal muscle through regulation of GLUT4 translocation in mice. J. Physiol. 594, 4997–5008 (2016).

  81. 81.

    , , & Laminin-induced activation of Rac1 and JNKp46 is initiated by Src family kinases and mimics the effects of skeletal muscle contraction. Biochemistry 46, 14907–14916 (2007).

  82. 82.

    , & Skeletal muscle signaling pathway through the dystrophin glycoprotein complex and Rac1. J. Biol. Chem. 278, 39287–39295 (2003).

  83. 83.

    et al. TRPC3-mediated Ca2+ influx contributes to Rac1-mediated production of reactive oxygen species in MLP-deficient mouse hearts. Biochem. Biophys. Res. Commun. 409, 108–113 (2011).

  84. 84.

    & Adhesion signaling — crosstalk between integrins, Src and Rho. J. Cell Sci. 122, 1059–1069 (2009).

  85. 85.

    , , & Disruption of cortical actin in skeletal muscle demonstrates an essential role of the cytoskeleton in glucose transporter 4 translocation in insulin-sensitive tissues. J. Biol. Chem. 279, 40699–40706 (2004).

  86. 86.

    , , , & Actin isoform expression patterns during mammalian development and in pathology: insights from mouse models. Cell. Motil. Cytoskeleton 66, 798–815 (2009).

  87. 87.

    , , , & Role of RalA downstream of Rac1 in insulin-dependent glucose uptake in muscle cells. Cell. Signal. 24, 2111–2117 (2012).

  88. 88.

    et al. Role for RalA downstream of Rac1 in skeletal muscle insulin signalling. Biochem. J. 469, 445–454 (2015).

  89. 89.

    , , & NADPH oxidases: an overview from structure to innate immunity-associated pathologies. Cell. Mol. Immunol. 12, 5–23 (2015).

  90. 90.

    , & Reactive oxygen species and calcium signals in skeletal muscle: a crosstalk involved in both normal signaling and disease. Cell Calcium 60, 172–179 (2016).

  91. 91.

    & AMPK and the biochemistry of exercise: implications for human health and disease. Biochem. J. 418, 261–275 (2009).

  92. 92.

    et al. Muscle-specific AMPK β1β2-null mice display a myopathy due to loss of capillary density in nonpostural muscles. FASEB J. 28, 2098–2107 (2014).

  93. 93.

    et al. AMPK controls exercise endurance, mitochondrial oxidative capacity, and skeletal muscle integrity. FASEB J. 28, 3211–3224 (2014).

  94. 94.

    et al. AMP-activated protein kinase (AMPK) β1β2 muscle null mice reveal an essential role for AMPK in maintaining mitochondrial content and glucose uptake during exercise. Proc. Natl Acad. Sci. USA 108, 16092–16097 (2011).

  95. 95.

    et al. 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 (2003).

  96. 96.

    , & AMPKα2 deficiency uncovers time-dependency in the regulation of contraction-induced palmitate and glucose uptake in mouse muscle. J. Appl. Physiol. 111, 125–134 (2011).

  97. 97.

    & Insulin and contraction stimulate exocytosis, but increased AMP-activated protein kinase activity resulting from oxidative metabolism stress slows endocytosis of GLUT4 in cardiomyocytes. J. Biol. Chem. 280, 4070–4078 (2005).

  98. 98.

    & Predominant α2/β2/γ3 AMPK activation during exercise in human skeletal muscle. J. Physiol. 577, 1021–1032 (2006).

  99. 99.

    et al. 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 (2007).

  100. 100.

    et al. Knockout of the α2 but not α1 5′-AMP-activated protein kinase isoform abolishes 5-aminoimidazole-4-carboxamide-1-β-4-ribifuranoside but not contraction-induced glucose uptake in skeletal muscle. J. Biol. Chem. 279, 1070–1079 (2004).

  101. 101.

    et al. The 5′-AMP-activated protein kinase γ3 isoform has a key role in carbohydrate and lipid metabolism in glycolytic skeletal muscle. J. Biol. Chem. 279, 38441–38447 (2004).

  102. 102.

    et al. Gain-of-function R225W mutation in human AMPKγ3 causing increased glycogen and decreased triglyceride in skeletal muscle. PLoS ONE 2, e903 (2007).

  103. 103.

    et al. Naturally occurring R225W mutation of the gene encoding AMP-activated protein kinase (AMPKγ3) results in increased oxidative capacity and glucose uptake in human primary myotubes. Diabetologia 53, 1986–1997 (2010).

  104. 104.

    , , , & 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 (2004).

  105. 105.

    et al. Effect of birth weight and 12 weeks of exercise training on exercise-induced AMPK signaling in human skeletal muscle. Am. J. Physiol. Endocrinol. Metab. 304, E1379–E1390 (2013).

  106. 106.

    et al. Short-term exercise training in humans reduces AMPK signalling during prolonged exercise independent of muscle glycogen. J. Physiol. 568, 665–676 (2005).

  107. 107.

    et al. Discovery of TBC1D1 as an insulin-, AICAR-, and contraction-stimulated signaling nexus in mouse skeletal muscle. J. Biol. Chem. 283, 9787–9796 (2008).

  108. 108.

    et al. AS160 regulates insulin- and contraction-stimulated glucose uptake in mouse skeletal muscle. J. Biol. Chem. 281, 31478–31485 (2006).

  109. 109.

    et al. Genetic disruption of AMPK signaling abolishes both contraction- and insulin-stimulated TBC1D1 phosphorylation and 14-3-3 binding in mouse skeletal muscle. Am. J. Physiol. Endocrinol. Metab. 297, E665–E675 (2009).

  110. 110.

    et al. Deletion of both Rab-GTPase-activating proteins TBC14KO and TBC1D4 in mice eliminates insulin- and AICAR-stimulated glucose transport. Diabetes 64, 746–775 (2015).

  111. 111.

    et al. The RabGAP TBC1D1 plays a central role in exercise-regulated glucose metabolism in skeletal muscle. Diabetes 64, 1914–1922 (2015).

  112. 112.

    , , , & Clustering of GLUT4, TUG, and RUVBL2 protein levels correlate with myosin heavy chain isoform pattern in skeletal muscles, but AS160 and TBC1D1 levels do not. J. Appl. Physiol. 111, 1106–1117 (2011).

  113. 113.

    et al. Human muscle fibre type-specific regulation of AMPK and downstream targets by exercise. J. Physiol. 593, 2053–2069 (2015).

  114. 114.

    et al. The Rab-GTPase-activating protein TBC1D1 regulates skeletal muscle glucose metabolism. Am. J. Physiol. Endocrinol. Metab. 303, E524–E533 (2012).

  115. 115.

    et al. A common Greenlandic TBC1D4 variant confers muscle insulin resistance and type 2 diabetes. Nature 512, 190–193 (2014).

  116. 116.

    , , & Rab8A and Rab13 are activated by insulin and regulate GLUT4 translocation in muscle cells. Proc. Natl Acad. Sci. USA 107, 19909–19914 (2010).

  117. 117.

    et al. Phosphatidylinositol 3-phosphate 5-kinase (PIKfyve) is an AMPK target participating in contraction-stimulated glucose uptake in skeletal muscle. Biochem. J. 455, 195–206 (2013).

  118. 118.

    et al. Muscle-specific Pikfyve gene disruption causes glucose intolerance, insulin resistance, adiposity, and hyperinsulinemia but not muscle fiber-type switching. Am. J. Physiol. Endocrinol. Metab. 305, E119–E131 (2013).

  119. 119.

    et al. Exercise-induced BCL2-regulated autophagy is required for muscle glucose homeostasis. Nature 481, 511–515 (2012).

  120. 120.

    et al. The lysosomal v-ATPase-Ragulator complex is a common activator for AMPK and mTORC1, acting as a switch between catabolism and anabolism. Cell Metab. 20, 526–540 (2014).

  121. 121.

    , , & Autophagy is not required to sustain exercise and PRKAA1/AMPK activity but is important to prevent mitochondrial damage during physical activity. Autophagy 10, 1883–1894 (2014).

  122. 122.

    et al. The noncanonical role of ULK/ATG1 in ER-to-Golgi trafficking is essential for cellular homeostasis. Mol. Cell 62, 491–506 (2016).

  123. 123.

    , , , & SEC16A is a RAB10 effector required for insulin-stimulated GLUT4 trafficking in adipocytes. J. Cell Biol. 214, 61–76 (2016).

  124. 124.

    et al. ULK1/2 constitute a bifurcate node controlling glucose metabolic fluxes in addition to autophagy. Mol. Cell 62, 359–370 (2016).

  125. 125.

    et al. 5′-AMP activated protein kinase α2 controls substrate metabolism during post-exercise recovery via regulation of pyruvate dehydrogenase kinase 4. J. Physiol. 593, 4765–4780 (2015).

  126. 126.

    , , & Acute exercise increases nitric oxide synthase activity in skeletal muscle. Am. J. Physiol. 277 (2 Pt. 1), E390–E394 (1999).

  127. 127.

    , , & Skeletal muscle glucose uptake during contraction is regulated by nitric oxide and ROS independently of AMPK. Am. J. Physiol. Endocrinol. Metab. 298, E577–E585 (2010).

  128. 128.

    , , & Real-time measurement of nitric oxide in single mature mouse skeletal muscle fibres during contractions. J. Physiol. 581 (Pt. 1), 309–318 (2007).

  129. 129.

    & The dynamics of the nitric oxide release-transient from stretched muscle cells. Int. J. Biochem. Cell Biol. 41, 625–631 (2009).

  130. 130.

    et al. nNOS and eNOS modulate cGMP formation and vascular response in contracting fast-twitch skeletal muscle. Physiol. Genom. 2, 21–27 (2000).

  131. 131.

    & Evidence that nitric oxide increases glucose transport in skeletal muscle. J. Appl. Physiol. 82, 359–363 (1997).

  132. 132.

    , , , & Local nitric oxide synthase inhibition reduces skeletal muscle glucose uptake but not capillary blood flow during in situ muscle contraction in rats. Diabetes 56, 2885–2892 (2007).

  133. 133.

    , , , & Nitric oxide synthase inhibition reduces glucose uptake during exercise in individuals with type 2 diabetes more than in control subjects. Diabetes 51, 2572–2580 (2002).

  134. 134.

    , & Nitric oxide synthase inhibition reduces leg glucose uptake but not blood flow during dynamic exercise in humans. Diabetes 48, 1815–1821 (1999).

  135. 135.

    et al. No effect of NOS inhibition on skeletal muscle glucose uptake during in situ hindlimb contraction in healthy and diabetic Sprague-Dawley rats. Am. J. Physiol. Regul. Integr. Comp. Physiol. 308, R862–R871 (2015).

  136. 136.

    , & Nitric oxide stimulates skeletal muscle glucose transport through a calcium/contraction- and phosphatidylinositol-3-kinase-independent pathway. Diabetes 46, 1915–1919 (1997).

  137. 137.

    , , & Nitric oxide increases glucose uptake through a mechanism that is distinct from the insulin and contraction pathways in rat skeletal muscle. Diabetes 50, 241–247 (2001).

  138. 138.

    et al. Effect of nitric oxide synthase inhibition on the exchange of glucose and fatty acids in human skeletal muscle. Nutr. Metab. (Lond.) 10, 43 (2013).

  139. 139.

    et al. Glucose uptake during contraction in isolated skeletal muscles from neuronal nitric oxide synthase μ knockout mice. J. Appl. Physiol. 118, 1113–1121 (2015).

  140. 140.

    , , , & Release of reactive oxygen and nitrogen species from contracting skeletal muscle cells. Free Radic. Biol. Med. 37, 1064–1072 (2004).

  141. 141.

    et al. Reactive oxygen in skeletal muscle. I. Intracellular oxidant kinetics and fatigue in vitro. J. Appl. Physiol. 73, 1797–1804 (1992).

  142. 142.

    et al. Role of reactive oxygen species in contraction-mediated glucose transport in mouse skeletal muscle. J. Physiol. 575, 251–262 (2006).

  143. 143.

    , , & Oxidative stress after human exercise: effect of N-acetylcysteine supplementation. J. Appl. Physiol. 76, 2570–2577 (1994).

  144. 144.

    et al. Decreasing xanthine oxidase-mediated oxidative stress prevents useful cellular adaptations to exercise in rats. J. Physiol. 567, 113–120 (2005).

  145. 145.

    et al. Adaptive stress response of glutathione and uric acid metabolism in man following controlled exercise and diet. Acta Physiol. Scand. 176, 43–56 (2002).

  146. 146.

    Redox regulation of muscle adaptations to contractile activity and aging. J. Appl. Physiol. 119, 163–171 (2015).

  147. 147.

    , & Mechanical stretch-induced activation of ROS/RNS signaling in striated muscle. Antioxid. Redox Signal. 20, 929–936 (2014).

  148. 148.

    , , , & Real-time imaging of NADPH oxidase activity in living cells using a novel fluorescent protein reporter. PLoS ONE 8, e63989 (2013).

  149. 149.

    et al. ROS production via P2Y1-PKC-NOX2 is triggered by extracellular ATP after electrical stimulation of skeletal muscle cells. PLoS ONE 10, e0129882 (2015).

  150. 150.

    , , , & Local hindlimb antioxidant infusion does not affect muscle glucose uptake during in situ contractions in rat. J. Appl. Physiol. 108, 1275–1283 (2010).

  151. 151.

    et al. N-Acetylcysteine infusion does not affect glucose disposal during prolonged moderate-intensity exercise in humans. J. Physiol. 588, 1623–1634 (2010).

  152. 152.

    & Regulation of NAD(P)H oxidases by AMPK in cardiovascular systems. Free Radic. Biol. Med. 52, 1607–1619 (2012).

  153. 153.

    Regulation of NADPH oxidases: the role of Rac proteins. Circ. Res. 98, 453–462 (2006).

  154. 154.

    et al. Nox2 mediates skeletal muscle insulin resistance induced by a high fat diet. J. Biol. Chem. 290, 13427–13439 (2015).

  155. 155.

    , , , & 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 (2002).

  156. 156.

    , , & Regulation of plasma long-chain fatty acid oxidation in relation to uptake in human skeletal muscle during exercise. Am. J. Physiol. Endocrinol. Metab. 287, E696–E705 (2004).

  157. 157.

    , & Regulation of glucose utilization in human skeletal muscle during moderate dynamic exercise. Am. J. Physiol. 260, E411–E415 (1991).

  158. 158.

    et al. Contraction-stimulated muscle glucose transport and GLUT-4 surface content are dependent on glycogen content. Am. J. Physiol. 277, E1103–E1110 (1999).

  159. 159.

    & Glucose uptake and transport in contracting, perfused rat muscle with different pre-contraction glycogen concentrations. J. Physiol. 427, 347–359 (1990).

  160. 160.

    et al. Effect of glycogen synthase overexpression on insulin-stimulated muscle glucose uptake and storage. Am. J. Physiol. Endocrinol. Metab. 286, E363–E369 (2004).

  161. 161.

    et al. Impaired glucose metabolism and exercise capacity with muscle-specific glycogen synthase 1 (gys1) deletion in adult mice. Mol. Metab. 5, 221–232 (2016).

  162. 162.

    et al. Role of 5′AMP-activated protein kinase in glycogen synthase activity and glucose utilization: insights from patients with McArdle's disease. J. Physiol. 541, 979–989 (2002).

  163. 163.

    , , , & Isoform-specific and exercise intensity-dependent activation of 5′-AMP-activated protein kinase in human skeletal muscle. J. Physiol. 528, 221–226 (2000).

  164. 164.

    et al. Exercise induces isoform-specific increase in 5′AMP-activated protein kinase activity in human skeletal muscle. Biochem. Biophys. Res. Commun. 273, 1150–1155 (2000).

  165. 165.

    et al. Effect of exercise intensity on skeletal muscle AMPK signaling in humans. Diabetes 52, 2205–2212 (2003).

  166. 166.

    et al. AMPK β subunit targets metabolic stress sensing to glycogen. Curr. Biol. 13, 867–871 (2003).

  167. 167.

    et al. The recruitment of AMP-activated protein kinase to glycogen is regulated by autophosphorylation. J. Biol. Chem. 290, 11715–11728 (2015).

  168. 168.

    et al. When phosphorylated at Thr148, the β2 subunit of AMP activated kinase does not associate with glycogen in skeletal muscle. Am. J. Physiol. Cell Physiol. 311, C35–C42 (2016).

  169. 169.

    & No spontaneous second wind in muscle phosphofructokinase deficiency. Neurology 62, 82–86 (2004).

  170. 170.

    , , , & GAPDH binds GLUT4 reciprocally to hexokinase-II and regulates glucose transport activity. Biochem. J. 419, 475–484 (2009).

  171. 171.

    , , , & Distributed control of glucose uptake by working muscles of conscious mice: roles of transport and phosphorylation. Am. J. Physiol. Endocrinol. Metab. 286, E77–E84 (2004).

  172. 172.

    et al. Control of exercise-stimulated muscle glucose uptake by GLUT4 is dependent on glucose phosphorylation capacity in the conscious mouse. J. Biol. Chem. 279, 50956–50961 (2004).

  173. 173.

    et al. Hexokinase II protein content is a determinant of exercise endurance capacity in the mouse. J. Physiol. 566, 533–541 (2005).

  174. 174.

    et al. Control of muscle glucose uptake: test of the rate-limiting step paradigm in conscious, unrestrained mice. J. Physiol. 562, 925–935 (2005).

  175. 175.

    & Multiple forms of hexokinase in the rat: tissue distribution, age dependency, and properties. Proc. Natl Acad. Sci. USA 54, 1218–1225 (1965).

  176. 176.

    & Multiple hexokinases of rat tissues: purification and comparison of soluble forms. J. Biol. Chem. 241, 3546–3560 (1966).

  177. 177.

    & Hexokinase isozyme distribution in human skeletal muscle. Diabetes 50, 1253–1262 (2001).

  178. 178.

    et al. Human muscle fiber type-specific insulin signaling: impact of obesity and type 2 diabetes. Diabetes 64, 485–497 (2015).

  179. 179.

    , & Subcellular localization of hexokinases I and II directs the metabolic fate of glucose. PLoS ONE 6, e17674 (2011).

  180. 180.

    , , & Akt phosphorylates HK-II at Thr-473 and increases mitochondrial HK-II association to protect cardiomyocytes. J. Biol. Chem. 288, 23798–23806 (2013).

  181. 181.

    et al. Low glucose-1, 6-bisphosphate and high fructose-2, 6-bisphosphate concentrations in muscles of patients with glycogenosis types VII and V. Biochem. Biophys. Res. Commun. 176, 7–10 (1991).

  182. 182.

    et al. Phosphoinositide 3-kinase regulates glycolysis through mobilization of aldolase from the actin cytoskeleton. Cell 164, 433–446 (2016).

  183. 183.

    , & The dual effects of Ca2+ on binding of the glycolytic enzymes, phosphofructokinase and aldolase, to muscle cytoskeleton. Biochem. Med. Metab. Biol. 49, 173–181 (1993).

  184. 184.

    , , , & Aldolase mediates the association of F-actin with the insulin-responsive glucose transporter GLUT4. J. Biol. Chem. 274, 17742–17747 (1999).

  185. 185.

    & Muscles, exercise and obesity: skeletal muscle as a secretory organ. Nat. Rev. Endocrinol. 8, 45–465 (2012).

  186. 186.

    et al. Autocrine role of interleukin-13 on skeletal muscle glucose metabolism in type 2 diabetic patients involves microRNA let-7. Am. J. Physiol. Endocrinol. Metab. 305, E1359–E1366 (2013).

  187. 187.

    et al. Irisin, a novel myokine, regulates glucose uptake in skeletal muscle cells via AMPK. Mol. Endocrinol. 29, 873–881 (2015).

  188. 188.

    et al. Neuregulins mediate calcium-induced glucose transport during muscle contraction. J. Biol. Chem. 281, 21690–21697 (2006).

  189. 189.

    , , & Urocortin 3 activates AMPK and AKT pathways and enhances glucose disposal in rat skeletal muscle. J. Endocrinol. 223, 143–154 (2014).

  190. 190.

    , , , & Interleukin-6 release from human skeletal muscle during exercise: relation to AMPK activity. J. Appl. Physiol. 295, 2273–2277 (2003).

  191. 191.

    et al. The effect of graded exercise on IL-6 release and glucose uptake in human skeletal muscle. J. Physiol. 546, 299–305 (2003).

  192. 192.

    et al. Interleukin-6 increases insulin-stimulated glucose disposal in humans and glucose uptake and fatty acid oxidation in vitro via AMP-activated protein kinase. Diabetes 55, 2688–2697 (2006).

  193. 193.

    et al. IL-6 is not essential for exercise-induced increases in glucose uptake. J. Appl. Physiol. 114, 1151–1157 (2013).

  194. 194.

    , & Interleukin-6 mediates exercise-induced increase in insulin sensitivity in mice. Exp. Physiol. 97, 1224–1235 (2012).

  195. 195.

    et al. ATP released by electrical stimuli elicits calcium transients and gene expression in skeletal muscle. J. Biol. Chem. 284, 34490–34505 (2009).

  196. 196.

    , , & Compression-induced ATP release from rat skeletal muscle with and without lengthening contraction. Neurosci. Lett. 434, 277–281 (2008).

  197. 197.

    , , , & Muscle interstitial ATP and norepinephrine concentrations in the human leg during exercise and ATP infusion. J. Appl. Physiol. 107, 1757–1762 (2009).

  198. 198.

    , & ATP signaling in skeletal muscle: from fiber plasticity to regulation of metabolism. Exerc. Sport Sci. Rev. 42, 110–116 (2014).

  199. 199.

    et al. Akt and Rac1 signaling are jointly required for insulin-stimulated glucose uptake in skeletal muscle and downregulated in insulin resistance. Cell. Signal. 26, 323–331 (2014).

  200. 200.

    , & Wortmannin inhibits insulin-stimulated but not contraction-stimulated glucose transport activity in skeletal muscle. FEBS Lett. 361, 51–54 (1995).

  201. 201.

    , , , & Kinetics of glucose transport in rat muscle: effects of insulin and contractions. Am. J. Physiol. 253, E12–E20 (1987).

  202. 202.

    , , & Contraction stimulates translocation of glucose transporter GLUT4 in skeletal muscle through a mechanism distinct from that of insulin. Proc. Natl Acad. Sci. USA 92, 5817–5821 (1995).

  203. 203.

    et al. Acute exercise and physiological insulin induce distinct phosphorylation signatures on TBC1D1 and TBC1D4 proteins in human skeletal muscle. J. Physiol. 592, 351–375 (2014).

  204. 204.

    et al. Rac1 in muscle is dispensable for improved insulin action after exercise in mice. Endocrinology 157, 3009–3015 (2016).

  205. 205.

    et al. Prior AICAR stimulation increases insulin sensitivity in mouse skeletal muscle in an AMPK-dependent manner. Diabetes 64, 2042–2055 (2014).

  206. 206.

    , & Enhanced leg glucose uptake and normal hepatic glucose output during exercise in patients with NIDDM [abstract]. Diabetes 42 (Suppl. 1), 107A (1993).

  207. 207.

    & Activation of glucose transport in diabetic muscle: responses to contraction and insulin. Am. J. Physiol. 249, C233–C237 (1985).

  208. 208.

    & Skeletal muscle insulin resistance is the primary defect in type 2 diabetes. Diabetes Care 32 (Suppl. 2), 157–163 (2009).

  209. 209.

    , , , & Effect of training on the dose-response relationship for insulin action in men. J. Appl. Physiol. 66, 695–703 (1989).

  210. 210.

    , & Calphostin C is an inhibitor of contraction, but not insulin-stimulated glucose transport, in skeletal muscle. Acta Physiol. Scand. 167, 69–75 (1999).

  211. 211.

    et al. 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, E1308–1317 (2007).

  212. 212.

    et al. Sucrose nonfermenting AMPK-related kinase (SNARK) mediates contraction-stimulated glucose transport in mouse skeletal muscle. Proc. Natl Acad. Sci. USA 107, 15541–15546 (2010).

  213. 213.

    et al. Deficiency of LKB1 in skeletal muscle prevents AMPK activation and glucose uptake during contraction. EMBO J. 24, 1810–1820 (2005).

  214. 214.

    et al. LKB1 regulates lipid oxidation during exercise independently of AMPK. Diabetes 62, 1490–1499 (2013).

  215. 215.

    , , , & A role for AMP-activated protein kinase in contraction- and hypoxia-regulated glucose transport in skeletal muscle. Mol. Cell 7, 1085–1094 (2001).

  216. 216.

    , , , & 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 (2008).

  217. 217.

    et al. Genetic impairment of α2-AMPK signaling does not reduce muscle glucose uptake during treadmill exercise in mice. Am. J. Physiol. Endocrinol. Metab. 297, E924–E934 (2009).

  218. 218.

    et al. Skeletal muscle AMP-activated protein kinase is essential for the metabolic response to exercise in vivo. J. Biol. Chem. 284, 23925–23934 (2009).

  219. 219.

    et al. Knockout of the α2 but not α1 5′-AMP-activated protein kinase isoform abolishes 5-aminoimidazole-4-carboxamide-1-β-4-ribofuranosidebut not contraction-induced glucose uptake in skeletal muscle. J. Biol. Chem. 279, 1070–1079 (2004).

  220. 220.

    et al. AMPKα is critical for enhancing skeletal muscle fatty acid utilization during in vivo exercise in mice. FASEB J. 29, 1725–1738 (2015).

  221. 221.

    , & Contraction- and hypoxia-stimulated glucose transport in skeletal muscle is affected differently by wortmannin. Evidence for different signalling mechanisms. Biochim. Biophys. Acta 1340, 396–404 (1998).

  222. 222.

    , , , & Knockout of the predominant conventional PKC isoform, PKCα, in mouse skeletal muscle does not affect contraction-stimulated glucose uptake. Am. J. Physiol. Endocrinol. Metab. 297, E340–E348 (2009).

  223. 223.

    et al. Calmodulin-binding domain of AS160 regulates contraction- but not insulin-stimulated glucose uptake in skeletal muscle. Diabetes 56, 2854–2862 (2007).

  224. 224.

    et al. Contraction regulates site-specific phosphorylation of TBC1D1 in skeletal muscle. Biochem. J. 431, 311–320 (2010).

  225. 225.

    et al. TBC1D1 regulates insulin- and contraction-induced glucose transport in mouse skeletal muscle. Diabetes 59, 1358–1365 (2010).

  226. 226.

    et al. Glucose kinetics and exercise tolerance in mice lacking the GLUT4 glucose transporter. J. Physiol. 582, 801–812 (2007).

  227. 227.

    , , , & Skeletal muscle glucose uptake during treadmill exercise in neuronal nitric oxide synthase-μ knockout mice. Am. J. Physiol. Endocrinol. Metab. 310, E838–E845 (2016).

  228. 228.

    et al. Hexokinase II overexpression improves exercise-stimulated but not insulin-stimulated muscle glucose uptake in high-fat-fed C57BL/6J mice. Diabetes 53, 306–314 (2014).

  229. 229.

    , & Overexpression of hexokinase II increases insulinand exercise-stimulated muscle glucose uptake in vivo. Am. J. Physiol. 276, E70–E77 (1999).

  230. 230.

    et al. Hexokinase II partial knockout impairs exercise-stimulated glucose uptake in oxidative muscles of mice. Am. J. Physiol. Endocrinol. Metab. 285, E958–E963 (2003).

  231. 231.

    et al. Decreased insulin action in skeletal muscle from patients with McArdle's disease. Am. J. Physiol. Endocrinol. Metab. 282, E1267–E1275 (2002).

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Acknowledgements

E.A.R is supported by grants from the Danish Council for Independent Research Natural Sciences (grant 4002-00492B), the Danish Council for Independent Research Medical Sciences (grant 0602-02273B), the Novo Nordisk Foundation (grant 1015429) and the University of Copenhagen Excellence Program for Interdisciplinary Research (“Physical activity and nutrition for improvement of health”). L.S. and M.K. are supported by Postdoctoral Fellowships from the Danish Council for Independent Research Medical Sciences (grants 5053–00155 and 4004–00233, respectively). T.E.J. is supported by an excellence grant from the Novo Nordisk Foundation (grant 15182).

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  1. Molecular Physiology Group, Department of Nutrition, Exercise and Sports, Faculty of Science, University of Copenhagen, Copenhagen, Denmark.

    • Lykke Sylow
    • , Maximilian Kleinert
    • , Erik A. Richter
    •  & Thomas E. Jensen
  2. Institute for Diabetes and Obesity, Helmholtz Zentrum München, German Research Center for Environmental Health, Neuherberg, Germany.

    • Maximilian Kleinert

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L.S., M.K., E.A.R. and T.E.J. researched the data for the article. L.S., M.K., E.A.R. and T.E.J. provided a substantial contribution to discussions of the content. L.S., M.K., E.A.R. and T.E.J. contributed equally to writing the article and to review and/or editing of the manuscript before submission.

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The authors declare no competing financial interests.

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https://doi.org/10.1038/nrendo.2016.162

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