Effect of Acute Exercise on AMPK Signaling in Skeletal Muscle of Subjects With Type 2 Diabetes

Activation of AMP-activated protein kinase (AMPK) by exercise induces several cellular processes in muscle. Exercise activation of AMPK is unaffected in lean (BMI ∼25 kg/m2) subjects with type 2 diabetes. However, most type 2 diabetic subjects are obese (BMI >30 kg/m2), and exercise stimulation of AMPK is blunted in obese rodents. We examined whether obese type 2 diabetic subjects have impaired exercise stimulation of AMPK, at different signaling levels, spanning from the upstream kinase, LKB1, to the putative AMPK targets, AS160 and peroxisome proliferator–activated receptor coactivator (PGC)-1α, involved in glucose transport regulation and mitochondrial biogenesis, respectively. Twelve type 2 diabetic, eight obese, and eight lean subjects exercised on a cycle ergometer for 40 min. Muscle biopsies were done before, during, and after exercise. Subjects underwent this protocol on two occasions, at low (50% Vo2max) and moderate (70% Vo2max) intensities, with a 4–6 week interval. Exercise had no effect on LKB1 activity. Exercise had a time- and intensity-dependent effect to increase AMPK activity and AS160 phosphorylation. Obese and type 2 diabetic subjects had attenuated exercise-stimulated AMPK activity and AS160 phosphorylation. Type 2 diabetic subjects had reduced basal PGC-1 gene expression but normal exercise-induced increases in PGC-1 expression. Our findings suggest that obese type 2 diabetic subjects may need to exercise at higher intensity to stimulate the AMPK-AS160 axis to the same level as lean subjects.

[1]  K. Sahlin,et al.  Lactate content and pH in muscle obtained after dynamic exercise. , 1976, Pflugers Archiv : European journal of physiology.

[2]  P. Jynge,et al.  High performance liquid chromatography: a rapid isocratic method for determination of creatine compounds and adenine nucleotides in myocardial tissue. , 1986, Journal of molecular and cellular cardiology.

[3]  A. Benabid,et al.  Impairment of muscular metabolism in chronic respiratory failure. A human 31P MRS study , 1991, NMR in biomedicine.

[4]  B. Kemp,et al.  Insulin activation of acetyl-CoA carboxylase accompanied by inhibition of the 5'-AMP-activated protein kinase. , 1992, The Journal of biological chemistry.

[5]  D. Hardie,et al.  Inactivation of acetyl-CoA carboxylase and activation of AMP-activated protein kinase in muscle during exercise. , 1996, The American journal of physiology.

[6]  B. Kemp,et al.  Contraction-induced Changes in Acetyl-CoA Carboxylase and 5′-AMP-activated Kinase in Skeletal Muscle* , 1997, The Journal of Biological Chemistry.

[7]  L. Goodyear,et al.  Exercise, glucose transport, and insulin sensitivity. , 1998, Annual review of medicine.

[8]  Tatsuya Hayashi,et al.  Evidence for 5′AMP-Activated Protein Kinase Mediation of the Effect of Muscle Contraction on Glucose Transport , 1998, Diabetes.

[9]  M. Matsuda,et al.  Insulin sensitivity indices obtained from oral glucose tolerance testing: comparison with the euglycemic insulin clamp. , 1999, Diabetes care.

[10]  D. Hardie,et al.  AMP-activated protein kinase, a metabolic master switch: possible roles in Type 2 diabetes. , 1999, American journal of physiology. Endocrinology and metabolism.

[11]  E. Horton,et al.  Acute exercise induces GLUT4 translocation in skeletal muscle of normal human subjects and subjects with type 2 diabetes. , 1999, Diabetes.

[12]  W. Derave,et al.  Dissociation of AMP-activated protein kinase activation and glucose transport in contracting slow-twitch muscle. , 2000, Diabetes.

[13]  B. Hansen,et al.  Isoform‐specific and exercise intensity‐dependent activation of 5′‐AMP‐activated protein kinase in human skeletal muscle , 2000, The Journal of physiology.

[14]  O. Ljungqvist,et al.  Exercise induces isoform-specific increase in 5'AMP-activated protein kinase activity in human skeletal muscle. , 2000, Biochemical and biophysical research communications.

[15]  O. Ljungqvist,et al.  AMP-activated protein kinase (AMPK) is activated in muscle of subjects with type 2 diabetes during exercise. , 2001, Diabetes.

[16]  G. Shulman,et al.  Effect of 5-aminoimidazole-4-carboxamide-1-beta-D-ribofuranoside infusion on in vivo glucose and lipid metabolism in lean and obese Zucker rats. , 2001, Diabetes.

[17]  G. Shulman,et al.  Chronic activation of AMP kinase results in NRF-1 activation and mitochondrial biogenesis. , 2001, American journal of physiology. Endocrinology and metabolism.

[18]  N. Fujii,et al.  AMP-activated protein kinase activity and glucose uptake in rat skeletal muscle. , 2001, American journal of physiology. Endocrinology and metabolism.

[19]  M. Bucan,et al.  A role for AMP-activated protein kinase in contraction- and hypoxia-regulated glucose transport in skeletal muscle. , 2001, Molecular cell.

[20]  Thomas D. Schmittgen,et al.  Analysis of relative gene expression data using real-time quantitative PCR and the 2(-Delta Delta C(T)) Method. , 2001, Methods.

[21]  J. Zierath,et al.  Isoform-specific regulation of 5' AMP-activated protein kinase in skeletal muscle from obese Zucker (fa/fa) rats in response to contraction. , 2002, Diabetes.

[22]  J. Balschi,et al.  The Relationship between AMP-activated Protein Kinase Activity and AMP Concentration in the Isolated Perfused Rat Heart* , 2002, The Journal of Biological Chemistry.

[23]  H. Lodish,et al.  Enhanced muscle fat oxidation and glucose transport by ACRP30 globular domain: Acetyl–CoA carboxylase inhibition and AMP-activated protein kinase activation , 2002, Proceedings of the National Academy of Sciences of the United States of America.

[24]  S. Uchida,et al.  Adiponectin stimulates glucose utilization and fatty-acid oxidation by activating AMP-activated protein kinase , 2002, Nature Medicine.

[25]  I. Tabata,et al.  Effects of low-intensity prolonged exercise on PGC-1 mRNA expression in rat epitrochlearis muscle. , 2002, Biochemical and biophysical research communications.

[26]  L. Goodyear,et al.  Contraction Regulation of Akt in Rat Skeletal Muscle* , 2002, The Journal of Biological Chemistry.

[27]  S. Kane,et al.  A Method to Identify Serine Kinase Substrates , 2002, The Journal of Biological Chemistry.

[28]  B. Canny,et al.  Progressive increase in human skeletal muscle AMPKalpha2 activity and ACC phosphorylation during exercise. , 2002, American journal of physiology. Endocrinology and metabolism.

[29]  Y. Hellsten,et al.  Glycogen-dependent effects of 5-aminoimidazole-4-carboxamide (AICA)-riboside on AMP-activated protein kinase and glycogen synthase activities in rat skeletal muscle. , 2002, Diabetes.

[30]  Young-Bum Kim,et al.  Leptin stimulates fatty-acid oxidation by activating AMP-activated protein kinase , 2002, Nature.

[31]  B. Kemp,et al.  Skeletal muscle basal AMP-activated protein kinase activity is chronically elevated in alloxan-diabetic dogs: impact of exercise. , 2003, Journal of applied physiology.

[32]  Y. Hellsten,et al.  Regulation of 5'AMP-activated protein kinase activity and substrate utilization in exercising human skeletal muscle. , 2003, American journal of physiology. Endocrinology and metabolism.

[33]  B. Pedersen,et al.  Interleukin-6 release from human skeletal muscle during exercise: relation to AMPK activity. , 2003, Journal of applied physiology.

[34]  N. Fujii,et al.  Glucose Metabolism and Energy Homeostasis in Mouse Hearts Overexpressing Dominant Negative α2 Subunit of AMP-activated Protein Kinase* , 2003, Journal of Biological Chemistry.

[35]  N. Fujii,et al.  Glucose metabolism and energy homeostasis in mouse hearts overexpressing dominant negative alpha2 subunit of AMP-activated protein kinase. , 2003, The Journal of biological chemistry.

[36]  H. Koistinen,et al.  5-amino-imidazole carboxamide riboside increases glucose transport and cell-surface GLUT4 content in skeletal muscle from subjects with type 2 diabetes. , 2003, Diabetes.

[37]  B. Kemp,et al.  Effect of exercise intensity on skeletal muscle AMPK signaling in humans. , 2003, Diabetes.

[38]  John M Asara,et al.  Insulin-stimulated Phosphorylation of a Rab GTPase-activating Protein Regulates GLUT4 Translocation* , 2003, The Journal of Biological Chemistry.

[39]  J. James,et al.  A Novel Domain in AMP-Activated Protein Kinase Causes Glycogen Storage Bodies Similar to Those Seen in Hereditary Cardiac Arrhythmias , 2003, Current Biology.

[40]  P. Puigserver,et al.  Peroxisome proliferator-activated receptor-gamma coactivator 1 alpha (PGC-1 alpha): transcriptional coactivator and metabolic regulator. , 2003, Endocrine reviews.

[41]  T. McGraw,et al.  Insulin stimulation of GLUT4 exocytosis, but not its inhibition of endocytosis, is dependent on RabGAP AS160. , 2004, Molecular biology of the cell.

[42]  K. Sahlin,et al.  Lactate content and pH in muscle samples obtained after dynamic exercise , 1976, Pflügers Archiv.

[43]  B. Viollet,et al.  Knockout of the alpha2 but not alpha1 5'-AMP-activated protein kinase isoform abolishes 5-aminoimidazole-4-carboxamide-1-beta-4-ribofuranosidebut not contraction-induced glucose uptake in skeletal muscle. , 2004, The Journal of biological chemistry.

[44]  D. Hardie,et al.  AMPK activity and isoform protein expression are similar in muscle of obese subjects with and without type 2 diabetes. , 2004, American journal of physiology. Endocrinology and metabolism.

[45]  B. Pedersen,et al.  AMPK activity is diminished in tissues of IL-6 knockout mice: the effect of exercise. , 2004, Biochemical and biophysical research communications.

[46]  Jérôme Boudeau,et al.  LKB1 is a master kinase that activates 13 kinases of the AMPK subfamily, including MARK/PAR‐1 , 2004, The EMBO journal.

[47]  D. Hardie,et al.  Activity of LKB1 and AMPK-related kinases in skeletal muscle: effects of contraction, phenformin, and AICAR. , 2004, American journal of physiology. Endocrinology and metabolism.

[48]  L. Goodyear,et al.  Exercise regulates Akt and glycogen synthase kinase-3 activities in human skeletal muscle. , 2004, Biochemical and biophysical research communications.

[49]  Peter Schjerling,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* , 2004, Journal of Biological Chemistry.

[50]  R. DeFronzo,et al.  Lipid Infusion Decreases the Expression of Nuclear Encoded Mitochondrial Genes and Increases the Expression of Extracellular Matrix Genes in Human Skeletal Muscle* , 2005, Journal of Biological Chemistry.

[51]  M. Raney,et al.  AMPK activation is not critical in the regulation of muscle FA uptake and oxidation during low-intensity muscle contraction. , 2005, American journal of physiology. Endocrinology and metabolism.

[52]  P. Neufer,et al.  Effects of alpha-AMPK knockout on exercise-induced gene activation in mouse skeletal muscle. , 2005, FASEB journal : official publication of the Federation of American Societies for Experimental Biology.

[53]  G. Lienhard,et al.  Increased phosphorylation of Akt substrate of 160 kDa (AS160) in rat skeletal muscle in response to insulin or contractile activity. , 2005, Diabetes.

[54]  F. Thong,et al.  Turning signals on and off: GLUT4 traffic in the insulin-signaling highway. , 2005, Physiology.

[55]  Kei Sakamoto,et al.  Deficiency of LKB1 in skeletal muscle prevents AMPK activation and glucose uptake during contraction , 2005, The EMBO journal.

[56]  P. Neufer,et al.  Effects of α‐AMPK knockout on exercise‐induced gene activation in mouse skeletal muscle , 2005 .

[57]  N. Fujii,et al.  AMP-activated Protein Kinase α2 Activity Is Not Essential for Contraction- and Hyperosmolarity-induced Glucose Transport in Skeletal Muscle* , 2005, Journal of Biological Chemistry.

[58]  B. Pedersen,et al.  Oral glucose ingestion attenuates exercise-induced activation of 5'-AMP-activated protein kinase in human skeletal muscle. , 2006, Biochemical and biophysical research communications.

[59]  R. DeFronzo,et al.  LKB1-AMPK signaling in muscle from obese insulin-resistant Zucker rats and effects of training. , 2006, American journal of physiology. Endocrinology and metabolism.

[60]  B. Kemp,et al.  Carbohydrate ingestion does not alter skeletal muscle AMPK signaling during exercise in humans. , 2006, American journal of physiology. Endocrinology and metabolism.

[61]  A. Deshmukh,et al.  Exercise-Induced Phosphorylation of the Novel Akt Substrates AS160 and Filamin A in Human Skeletal Muscle , 2006, Diabetes.

[62]  A. Ashworth,et al.  Deficiency of LKB1 in heart prevents ischemia-mediated activation of AMPKalpha2 but not AMPKalpha1. , 2006, American journal of physiology. Endocrinology and metabolism.

[63]  N. Fujii,et al.  Distinct Signals Regulate AS160 Phosphorylation in Response to Insulin, AICAR, and Contraction in Mouse Skeletal Muscle , 2006, Diabetes.

[64]  B. Viollet,et al.  AMPK-Mediated AS160 Phosphorylation in Skeletal Muscle Is Dependent on AMPK Catalytic and Regulatory Subunits , 2006, Diabetes.

[65]  B. Canny,et al.  Effect of exercise intensity and hypoxia on skeletal muscle AMPK signaling and substrate metabolism in humans. , 2006, American journal of physiology. Endocrinology and metabolism.

[66]  H. Pilegaard,et al.  Higher skeletal muscle α2AMPK activation and lower energy charge and fat oxidation in men than in women during submaximal exercise , 2006, The Journal of physiology.