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PubMed1998

Loss of the hepatic glycogen-binding subunit (GL) of protein phosphatase 1 underlies deficient glycogen synthesis in insulin-dependent diabetic rats and in adrenalectomized starved rats.

Hepatic glycogen synthesis is impaired in insulin-dependent diabetic rats and in adrenalectomized starved rats, and although this is known to be due to defective activation of glycogen synthase by glycogen synthase phosphatase, the underlying molecular mechanism has not been delineated. Glycogen synthase phosphatase comprises the catalytic subunit of protein phosphatase 1 (PP1) complexed with the hepatic glycogen-binding subunit, termed GL. In liver extracts of insulin-dependent diabetic and adrenalectomized starved rats, the level of GL was shown by immunoblotting to be substantially reduced compared with that in control extracts, whereas the level of PP1 catalytic subunit was not affected by these treatments. Insulin administration to diabetic rats restored the level of GL and prolonged administration raised it above the control levels, whereas re-feeding partially restored the GL level in adrenalectomized starved rats. The regulation of GL protein levels by insulin and starvation/feeding was shown to correlate with changes in the level of the GL mRNA, indicating that the long-term regulation of the hepatic glycogen-associated form of PP1 by insulin, and hence the activity of hepatic glycogen synthase, is predominantly mediated through changes in the level of the GL mRNA.

Adrenalectomy↗
PubMed1994

Disruption of glycogen phosphorylase gene expression in Dictyostelium: evidence for altered glycogen metabolism and developmental coregulation of the gene products.

Glycogen phosphorylase 1 and 2, the isozymes responsible for glycogen degradation, are encoded by separate genes in Dictyostelium. The two gene products display different transcriptional and translational expression and distinct post-translational regulation. Using DNA-mediated transformation, Dictyostelium clones which lacked either glycogen phosphorylase 1 or 2 (gp1 or gp2) expression were obtained. The loss of either enzyme did not change axenic growth patterns, developmental progression, or gross organismic morphology. In gp1- strains, glycogen accumulated to a 17- to 28-fold higher level during late stationary phase without any obvious detrimental effects. This implies that no alternative pathway for glycogen degradation is present in amoebae, and that glycogen metabolism is not critical for vegetative cell growth. Developmental glycogen concentrations were not altered significantly in any of the transformants, but in gp2- cells the posttranslational regulation of the intact gp1 enzyme was apparently modulated to compensate for the loss of gp2. Western blots of microdissected, lyophilized Dictyostelium slugs and early culminates showed that gp2 was found in both prestalk and prespore cells, with a slight enrichment in prespore cells. The gp1 protein was highly enriched in prestalk cells in the parental strain. In gp2- transformants, however, gp1 was detected in equal amounts in both cell types. The loss of gp2 led to a shift in the cell-type-specific expression pattern of gp1, presumably due to developmental coordinate regulation of gp1 and gp2 at the translational and/or transcriptional level.

Animals↗
PubMed1999

13C nuclear magnetic resonance study of glycogen resynthesis in muscle after glycogen-depleting exercise in healthy men receiving an infusion of lipid emulsion.

In healthy individuals, glycogen recovery after a strong depletion is known to be rapid and insulin independent during the initial phase, and subsequently, slow and insulin dependent. Free fatty acids (FFAs) as a putative source of insulin resistance (IR) could thus impair glycogen recovery during the second period. Using in vivo 13C nuclear magnetic resonance (NMR), we studied the effect of long-chain triglyceride emulsion on gastrocnemius glycogen resynthesis during a 3-h recovery period after 90 min of moderate exercise consisting of plantar flexion on overnight-fasted healthy men (n = 8). In separate experiments, each subject was infused with 10% Ivelip (0.015 ml x kg(-1) x min(-1)) or 10% glycerol (0.13 mg x kg(-1) x min(-1)). NMR spectra were acquired before and at the end of the exercise and during the recovery period. Whole-body glucose and lipid oxidation rates (indirect calorimetry), plasma insulin, C-peptide, glucose, lactate, beta-hydroxybutyrate, triglycerides, and FFAs were determined. Glycogen consumption was 47.6 +/- 4.5% (glycerol) and 49.7 +/- 4.8% (Ivelip) of the initial glycogen. An acquired IR in the Ivelip group was significant at the onset of the recovery period by homeostasis model assessment (P = 0.002). Glycogen resynthesis in the glycerol group appeared faster during the 1st h than during the subsequent 2nd h of the postexercise period. The glycogen resynthesis level was significantly lower in the Ivelip group than in the glycerol group during the recovery period (P = 0.04 during the 1st h and P = 0.001 during the next 2 h). During the recovery, plasma lactate and whole-body oxidation rates were similar in the two groups, whereas glycemia was significantly higher in the Ivelip group. A decreased cellular uptake of glucose as a substrate for glycogenosynthesis, rather than a competition between oxidation of carbohydrate and FFA, is discussed.

Adult↗
PubMed1983

Regulation of bacterial glycogen synthesis. Stimulation of glycogen synthesis by endogenous and exogenous cyclic adenosine 3':5'-monophosphate in Escherichia coli and the requirement for a functional CRP gene.

In Escherichia coli cya mutants, deficient in adenylate cyclase (EC 4.6.1.1), basal cellular rates of glycogen synthesis were lower and the relative increases produced by exogenous cyclic adenosine 3',5'-monophosphate during growth on glucose were greater than in their respective parent strains. These observations provide strong evidence that endogenous cyclic AMP is one of the key regulators of glycogen synthesis in growing E. coli. In crp mutants, deficient in cyclic AMP receptor protein (CRP), the basal cellular rates of glycogen synthesis were much lower than in their respective parent strains. Stimulation of glycogen synthesis by exogenous cyclic AMP was markedly attenuated in the three crp mutants. Thus, stimulation of glycogen synthesis by either endogenous or exogenous cyclic AMP appears to require CRP. Functional CRP appeared to be required for all three responses observed after cyclic AMP addition: an abrupt step-up in the cellular rate of glycogen synthesis, a continuing exponential increase in rate, and a stimulation of the rate during a subsequent nitrogen starvation. To account for these responses, we derived a mathematical model in which the cyclic AMP-CRP complex regulates the differential rate of synthesis of an enzyme metabolizing an effector of the rate-limiting enzyme of glycogen synthesis.

Cyclic AMP↗
PubMed1983

Studies of the residual glycogen branching enzyme activity present in human skin fibroblasts from patients with type IV glycogen storage disease.

Human skin fibroblasts from patients with Type IV glycogen storage disease, in which there is a demonstrable deficiency of glycogen branching enzyme, were shown to be able to synthesize [14C]glycogen containing [14C]glucose at branch points when sonicates containing endogenous glycogen synthase a were incubated with UDP[14C]glucose. The branch point content of the glycogen synthesized by the Type IV cells was essentially the same as that formed by normal cells, but the total synthetic capacity of the Type IV cells was lower. A new assay for the branching enzyme using glycogen synthase as the indicator enzyme has been developed. Using this assay it has been shown that the residual branching enzyme of affected children and of their heterozygote parents is less easily inhibited by an IgG antibody raised in rabbits against the normal human liver enzyme than is the branching enzyme of normal fibroblasts.

1,4-alpha-Glucan Branching Enzyme↗
PubMed1985

Glycogen storage disease confined to the heart with deficient activity of cardiac phosphorylase kinase: a new type of glycogen storage disease.

The case of a male infant with marked deposition of glycogen, confined to the heart, is presented. Clinically, prominent cardiomegaly had been evident from immediately after birth until the infant's death due to heart failure. There were no significant clinical manifestations in other organs, including liver and skeletal muscle, during the clinical course. Autopsy revealed abnormal deposition of normally structured glycogen in the heart, but no deposition in the liver, skeletal muscle, or other systemic organs. This unusual pattern of glycogen deposition was also confirmed by measurement of the glycogen content of each organ. This is the first report of glycogen storage disease confined to the heart. Enzymatic analysis revealed no decrease in the activities of acid maltase, amylo-1,6-glucosidase, and phosphorylase in the heart or in the liver or skeletal muscle. However, phosphorylase kinase activity was not detectable in the heart, although high activity levels were observed in the liver and skeletal muscle. In this case the inborn error of metabolism responsible for the isolated deposition of glycogen in heart muscle may have been due to a deficiency of cardiac phosphorylase kinase.

Cardiomyopathies↗
PubMed1985

Calcium ions and glycogen act synergistically as inhibitors of hepatic glycogen-synthase phosphatase.

We investigated the inhibitory effect of Ca2+ in the micromolar range on the activation of glycogen synthase in crude gel-filtered liver extracts [van de Werve (1981) Biochem. Biophys. Res. Commun. 102, 1323-1329]. The magnitude of the inhibition was highly dependent on the glycogen concentration in the final liver extract. Ca2+ inhibited the activation of purified hepatic synthase b by the G-component of synthase phosphatase, as present in the isolated glycogen-protein complex. The cytosolic S-component was not inhibited. Maximal inhibition of the crude G-component occurred at 0.3 microM-Ca2+. The inhibition was not influenced by the addition of either calmodulin or calmodulin antagonists, or by various proteinase inhibitors. The use of purified G-component revealed that the inhibition by 0.3 microM-Ca2+ increased from 45% to 85% when the concentration of glycogen was raised from 1.5 to 20 mg/ml. Muscle glycogen synthase, extensively phosphorylated in vitro, was also used as substrate for purified G-component. Activation and dephosphorylation were similarly inhibited by 0.3 microM-Ca2+, but the magnitude of the inhibition was much greater with the hepatic substrate. No effect of 0.3 microM-Ca2+ was found on the activity of phosphorylase phosphatase in various liver preparations. We conclude that the inhibition of synthase activation by Ca2+ is one of the mechanisms by which cyclic AMP-independent glycogenolytic hormones promote the inactivation of glycogen synthase in the liver, especially in the fed state.

Animals↗
PubMed2005

Exercise capacity of mice genetically lacking muscle glycogen synthase: in mice, muscle glycogen is not essential for exercise.

The glucose storage polymer glycogen is generally considered to be an important source of energy for skeletal muscle contraction and a factor in exercise endurance. A genetically modified mouse model lacking muscle glycogen was used to examine whether the absence of the polysaccharide affects the ability of mice to run on a treadmill. The MGSKO mouse has the GYS1 gene, encoding the muscle isoform of glycogen synthase, disrupted so that skeletal muscle totally lacks glycogen. The morphology of the soleus and quadriceps muscles from MGSKO mice appeared normal. MGSKO-null mice, along with wild type littermates, were exercised to exhaustion. There were no significant differences in the work performed by MGSKO mice as compared with their wild type littermates. The amount of liver glycogen consumed during exercise was similar for MGSKO and wild type animals. Fasting reduced exercise endurance, and after overnight fasting, there was a trend to reduced exercise endurance for the MGSKO mice. These studies provide genetic evidence that in mice muscle glycogen is not essential for strenuous exercise and has relatively little effect on endurance.

Animals↗
PubMed1985

Incorporation of [14C]glucose into alpha-1,4 bonds of glycogen by leukocytes and fibroblasts of patients with type III glycogen storage disease.

In two patients assay of alpha-1,6-amyloglucosidase activity by incorporation of [14C]glucose into glycogen revealed normal activity in leukocytes, erythrocytes, and fibroblasts, whereas no activity was detected in liver and muscle. No activity in any tissue was found when enzyme activity was assayed by following the release of glucose from a phosphorylase limit dextrin. Labeling of glycogen by incubation with crude tissue homogenates according to the protocol used for the [14C]glucose method and subsequent degradation of the outer portion of the polysaccharide molecule with beta-amylase showed that with tissues from normal controls more than 90% of the label of the glycogen was retained in the limit dextrin. When fibroblasts or leukocytes of the patients served as enzyme source up to 80% of the label was released after incubation with beta-amylase or phosphorylase a. Addition of Tris to the assay inhibited enzyme activity in fibroblast homogenates of the patients and of controls to the same extent and had no effect on the distribution of the label between supernatant and limit dextrin after beta-amylolysis of the labeled glycogen. A pH curve performed with fibroblast preparations from the patients and a normal control did not reveal differences in the effect of changes in pH on [14C]glucose incorporation. We propose that incorporation of [14C]glucose into glycogen by the enzyme present in the patients' cells was into alpha-1,4 linkages in glycogen.

Cells, Cultured↗
PubMed1987

Glycogen debranching enzyme: purification, antibody characterization, and immunoblot analyses of type III glycogen storage disease.

Type III glycogen storage disease is caused by a deficiency of glycogen debranching-enzyme activity. Many patients with this disease have both liver and muscle involvement, whereas others have only liver involvement without clinical or laboratory evidence of myopathy. To improve our understanding of the molecular basis of the disease, debranching enzyme was purified 238-fold from porcine skeletal muscle. In sodium dodecyl sulfate-polyacrylamide gel electrophoresis the purified enzyme gave a single band with a relative molecular weight of 160,000 that migrated to the same position as purified rabbit-muscle debranching enzyme. Antiserum against porcine debranching enzyme was prepared in rabbit. The antiserum reacted against porcine debranching enzyme with a single precipitin line and demonstrated a reaction having complete identity to those of both the enzyme present in crude muscle and the enzyme present in liver extracts. Incubation of antiserum with purified porcine debranching enzyme inhibited almost all enzyme activity, whereas such treatment with preimmune serum had little effect. The antiserum also inhibited debranching-enzyme activity in crude liver extracts from both pigs and humans to the same extent as was observed in muscle. Immunoblot analysis probed with anti-porcine-muscle debranching-enzyme antiserum showed that the antiserum can detect debranching enzyme in both human muscle and human liver. The bands detected in human samples by the antiserum were the same size as the one detected in porcine muscle. Five patients with Type III and six patients with other types of glycogen storage disease were subjected to immunoblot analysis. Although anti-porcine antiserum detected specific bands in all liver and muscle samples from patients with other types of glycogen storage disease (Types I, II, and IX), the antiserum detected no cross-reactive material in any of the liver or muscle samples from patients with Type III glycogen storage disease. These data indicate (1) immunochemical similarity of debranching enzyme in liver and muscle and (2) that deficiency of debranching-enzyme activity in Type III glycogen storage disease is due to absence of debrancher protein in the patients that we studied.

Animals↗
PubMed1983

Coordinated feedback regulation of muscle glycogen metabolism: inhibition of purified phosphorylase phosphatase by glycogen.

An assay method was devised for accurately measuring the activity of phosphorylase phosphatase in the presence of glycogen. Both oyster glycogen and rabbit liver glycogen inhibited the activity of purified phosphorylase phosphatase catalytic subunit in a concentration-dependent manner. In the presence of 120 mM KCl, micromolar AMP increased the sensitivity of the phosphatase to glycogen inhibition. The present studies suggest that glycogen feedback inhibition may be a coordinated mechanism producing a decrease in phosphorylase phosphatase activity as well as glycogen synthase phosphatase activity.

Adenosine Monophosphate↗
PubMed1995

Insulin stimulation of glycogen synthesis and glycogen synthase activity is blocked by wortmannin and rapamycin in 3T3-L1 adipocytes: evidence for the involvement of phosphoinositide 3-kinase and p70 ribosomal protein-S6 kinase.

We have investigated the involvement of phosphoinositide (PI) 3-kinase and p70 ribosomal protein-S6 kinase (p70s6k) in mediating insulin stimulation of glycogen synthesis in 3T3-L1 adipocytes using specific inhibitors. Wortmannin inhibited PI 3-kinase activity (IC50 approximately 10 nM), inhibition being complete at 100 nm. Wortmannin (100 nM) completely blocked the ability of insulin to activate glycogen synthase in 3T3-L1 adipocytes and the ability of insulin to stimulate glucose incorporation into glycogen in 3T3-L1 fibroblasts. Rapamycin, which blocks insulin-stimulated activation of p70s6k, decreased insulin activation of glycogen synthase in a dose-dependent manner (IC50 approximately 0.8 ng/ml), with a maximum approx. 75% inhibition of insulin's stimulatory effect. Rapamycin inhibited insulin-stimulated glucose incorporation into glycogen to a similar extent and with similar dose-dependency, while having no effect on insulin-stimulated glucose transport. We conclude that PI 3-kinase and p70s6k are involved in the signalling pathways by which insulin stimulates glycogen synthase in 3T3-L1 adipocytes.

3T3 Cells↗
PubMed1998

Regulation of GLUT4 protein and glycogen synthase during muscle glycogen synthesis after exercise.

The pattern of muscle glycogen synthesis following its depletion by exercise is biphasic. Initially, there is a rapid, insulin independent increase in the muscle glycogen stores. This is then followed by a slower insulin dependent rate of synthesis. Contributing to the rapid phase of glycogen synthesis is an increase in muscle cell membrane permeability to glucose, which serves to increase the intracellular concentration of glucose-6-phosphate (G6P) and activate glycogen synthase. Stimulation of glucose transport by muscle contraction as well as insulin is largely mediated by translocation of the glucose transporter isoform GLUT4 from intracellular sites to the plasma membrane. Thus, the increase in membrane permeability to glucose following exercise most likely reflects an increase in GLUT4 protein associated with the plasma membrane. This insulin-like effect on muscle glucose transport induced by muscle contraction, however, reverses rapidly after exercise is stopped. As this direct effect on transport is lost, it is replaced by a marked increase in the sensitivity of muscle glucose transport and glycogen synthesis to insulin. Thus, the second phase of glycogen synthesis appears to be related to an increased muscle insulin sensitivity. Although the cellular modifications responsible for the increase in insulin sensitivity are unknown, it apparently helps maintain an increased number of GLUT4 transporters associated with the plasma membrane once the contraction-stimulated effect on translocation has reversed. It is also possible that an increase in GLUT4 protein expression plays a role during the insulin dependent phase.

Animals↗
PubMed1999

Regulation of glycogen breakdown by glycogen level in contracting rat muscle.

The interaction of glycogen concentration, insulin and beta-adrenergic stimulation in the regulation of glycogen breakdown was studied in perfused rat muscles. Rats were pre-conditioned to obtain two groups with either normal (N) or 'supercompensated' (SC) muscle glycogen. The next day their hindlimbs were perfused with a medium containing insulin (0, 40 and 100 microU mL(-1)) and/or isoproterenol (0 and 1.5 nmol L(-1)). Contractions were induced by electrical stimulation of the sciatic nerve. Compared with N, glycogen breakdown in white gastrocnemius during contractions was greater in SC at any hormonal combination (P < 0.05). Conversely, in red gastrocnemius (RG) the higher glycogenolytic rate in SC, compared with N, faded as the insulin concentration was raised from 0 to 100 microU mL(-1). However, isoproterenol restored the higher glycogenolytic rate in SC. In any condition, RG glycogen synthase fractional activity was lower (P < 0.05) during contractions in SC than in N. Furthermore, the percentage of phosphorylase a was higher in SC except when muscles were exposed to insulin alone. In conclusion, high initial glycogen concentration in fast-glycolytic muscle causes high glycogenolytic rate during contractions, irrespective of hormonal stimulation. In contrast, due to down-regulation of phosphorylase activity, such a relationship does not exist in insulin-stimulated fast-oxidative muscle.

Adrenergic beta-Agonists↗
PubMed2001

Glycogen and glycogen phosphorylase associated with sarcoplasmic reticulum: effects of fatiguing activity.

The purpose of the present study was to investigate the effects of fatiguing muscular activity on glycogen, glycogen phosphorylase (GP), and Ca(2+) uptake associated with the sarcoplasmic reticulum (SR). Tetanic contractions (100 ms, 75 Hz) of the gastrocnemius and plantaris muscles, elicited once per second for 15 min, significantly reduced force to 26.5 +/- 4.0% and whole muscle glycogen to 23% of rested levels. SR glycogen levels were 415.4 +/- 76.6 and 20.4 +/- 2.1 microg/mg SR protein in rested and fatigued samples, respectively. The optical density of GP from SDS-PAGE was reduced to 21% of control, whereas pyridoxal 5'-phosphate concentration, a quantitative indicator of GP content, was significantly reduced to 3% of control. GP activity after exercise, in the direction of glycogen breakdown, was reduced to 4% of control. Maximum SR Ca(2+) uptake rate was also significantly reduced to 81% of control. These data demonstrate that glycogen and GP associated with skeletal muscle SR are reduced after fatiguing activity.

Animals↗
PubMed1979

Glycogen synthase of Hymenolepis diminuta. II. Nutritional state, interconversion of forms, and primer glycogen molecular weight as control factors.

Glycogen synthase I (UDP glucose: glycogen alpha-4-glycosyltransferase, EC2.4.1.11) of the tapeworm Hymenolepis diminuta is the form of the enzyme which is active in vivo, while the D-form represents an inactive "storage form." Utilizing the differential effect of inorganic phosphate (Pi) on the I and D-forms, the ratio of the 2 forms in vivo has been determined under conditions of starvation of the host and refeeding of the parasite with glucose. This procedure reveals that conversion of the inactive D-form to the active I-form takes place when glycogen-depleted worms are incubated in glucose. The activity of glycogen synthase I also is affected by the molecular weight of the primer glycogen. With certain molecular weight fractions, enzymatic activity is higher than with others. This specificity of the glycogen primer could explain the relatively low concentrations of those molecular weight fractions which confer the highest synthase activity.

Animals↗
PubMed1985

Stimulation of autophosphorylation of rabbit skeletal muscle phosphorylase kinase by glycogen synthase on glycogen particles.

Glycogen synthase stimulated the autophosphorylation and autoactivation of phosphorylase kinase from rabbit skeletal muscle. This stimulation was additive to that by glycogen and the reaction was dependent on Ca2+. The effect by glycogen synthase was maximum within the activity ratio (the activity of enzyme without glucose-6-P divided by the activity with 10 mM glucose-6-P) of 0.3 and over 0.3 it was rather inhibitory. The results suggest that autophosphorylation of phosphorylase kinase in the presence of glycogen synthase on glycogen particles may be an important regulatory mechanism of glycogen metabolism in skeletal muscle.

Animals↗
PubMedDate not supplied

[Kinetics of the reaction between muscle glycogen phosphorylase B and glycogen].

Kinetics of glycogen binding by glycogen phosphorylase b has been studied by stopped flow and temperature jump methods. This reaction is followed by increase in light scattering whose amplitude depends upon the enzyme binding sites concentration of glycogen particles occupied by the enzyme. It has been shown that the complex formation has the first order with respect to enzyme and glycogen concentrations. Relaxation kinetics is compatible with proposed bimolecular reaction scheme. Microscopic rate constants of the forward and reverse reactions of glycogen binding by glycogen phosphorylase b are determined in temperature range from 12,7 to 30 degrees C. The possibility of diffusional control of the binding rate is discussed.

Animals↗