title: Role of 5'AMP-activated protein kinase in glycogen synthase activity and glucose utilization: insights from patients with McArdle's disease.
abstract: It has been suggested that 5'AMP-activated protein kinase (AMPK) is involved in the regulation of glucose and glycogen metabolism in skeletal muscle. We used patients with chronic high muscle glycogen stores and deficient glycogenolysis (McArdle's disease) as a model to address this issue. Six McArdle patients were compared with control subjects during exercise. Muscle alpha2AMPK activity increased in McArdle patients (from 1.3 +/- 0.2 to 1.9 +/- 0.2 pmol min(-1) mg(-1), P = 0.05) but not in control subjects (from 1.0 +/- 0.1 to 1.3 +/- 0.3 pmol min(-1) mg(-1)). Exercise-induced phosphorylation of the in vivo AMPK substrate acetyl CoA carboxylase (ACCbeta; Ser(221)) was higher (P < 0.01) in McArdle patients than in control subjects (18 +/- 3 vs. 10 +/- 1 arbitrary units). Exercise-induced whole-body glucose utilization was also higher in McArdle patients than in control subjects (P < 0.05). No correlation between individual AMPK or ACCbeta values and glucose utilization was observed. Glycogen synthase (GS) activity was decreased in McArdle patients from 11 +/- 1.3 to 5 +/- 1.2 % (P < 0.05) and increased in control subjects from 19 +/- 1.6 to 23 +/- 2.3 % (P < 0.05) in response to exercise. This was not associated with activity changes of GS kinase 3 or protein phosphatase 1, but the changes in GS activity could be due to changes in activity of AMPK or protein kinase A (PKA) as a negative correlation between either ACCbeta phosphorylation (Ser(221)) or plasma adrenaline and GS activity was observed. These findings suggest that GS activity is increased by glycogen breakdown and decreased by AMPK and possibly PKA activation and that the resultant GS activity depends on the relative strengths of the various stimuli. Furthermore, AMPK may be involved in the regulation of glucose utilization during exercise in humans, although the lack of correlation between individual AMPK activity or ACCbeta phosphorylation (Ser(221)) values and individual glucose utilization during exercise implies that AMPK may not be an essential regulator.
authors.affiliation: Copenhagen Muscle Research Centre, Department of Human Physiology, Institute of Exercise and Sport Sciences, University of Copenhagen, Denmark. jnnielsen@aki.ku.dk
authors.forename: Jakob N
authors.initials: JN
authors.lastname: Nielsen
authors.forename: Jørgen F P
authors.initials: JF
authors.lastname: Wojtaszewski
authors.forename: Ronald G
authors.initials: RG
authors.lastname: Haller
authors.forename: D Grahame
authors.initials: DG
authors.lastname: Hardie
authors.forename: Bruce E
authors.initials: BE
authors.lastname: Kemp
authors.forename: Erik A
authors.initials: EA
authors.lastname: Richter
authors.forename: John
authors.initials: J
authors.lastname: Vissing
mesh_terms: D055372:AMP-Activated Protein Kinases; D000103:Acetyl-CoA Carboxylase / Q000378:metabolism; D000328:Adult; D001786:Blood Glucose / Q000378:metabolism; D015444:Exercise / Q000502:physiology; D005260:Female; D005947:Glucose / Q000378:metabolism*; D051275:Glucose Transporter Type 4; D006003:Glycogen / Q000378:metabolism; D006012:Glycogen Storage Disease Type V / Q000201:enzymology / Q000378:metabolism*; D006006:Glycogen Synthase / Q000378:metabolism*; D006439:Hemodynamics / Q000502:physiology; D006728:Hormones / Q000097:blood; D006801:Humans; D019344:Lactic Acid / Q000097:blood; D008297:Male; D009004:Monosaccharide Transport Proteins / Q000378:metabolism; D009097:Multienzyme Complexes / Q000378:metabolism*; D009124:Muscle Proteins; D018482:Muscle, Skeletal / Q000201:enzymology / Q000378:metabolism; D010725:Phosphocreatine / Q000378:metabolism; D010749:Phosphoprotein Phosphatases / Q000378:metabolism; D010766:Phosphorylation; D054645:Protein Phosphatase 1; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism*; D015656:Respiratory Mechanics / Q000502:physiology; D015398:Signal Transduction / Q000502:physiology
chemical_list: D001786:Blood Glucose; D051275:Glucose Transporter Type 4; D006728:Hormones; D009004:Monosaccharide Transport Proteins; D009097:Multienzyme Complexes; D009124:Muscle Proteins; C495692:SLC2A4 protein, human; D010725:Phosphocreatine; D019344:Lactic Acid; D006003:Glycogen; D006006:Glycogen Synthase; D017346:Protein Serine-Threonine Kinases; D055372:AMP-Activated Protein Kinases; D010749:Phosphoprotein Phosphatases; D054645:Protein Phosphatase 1; D000103:Acetyl-CoA Carboxylase; D005947:Glucose