scholarly journals Glycogen and its metabolism: some new developments and old themes

2012 ◽  
Vol 441 (3) ◽  
pp. 763-787 ◽  
Author(s):  
Peter J. Roach ◽  
Anna A. Depaoli-Roach ◽  
Thomas D. Hurley ◽  
Vincent S. Tagliabracci
Keyword(s):  
Glycogen Synthase ◽  
Three Dimensional ◽  
Glycogen Metabolism ◽  
Glycogen Storage ◽  
Genetically Engineered ◽  
Relative Importance ◽  
Lafora Disease ◽  
New Developments ◽  
Glycogen Accumulation ◽  
Genetically Engineered Mice

Glycogen is a branched polymer of glucose that acts as a store of energy in times of nutritional sufficiency for utilization in times of need. Its metabolism has been the subject of extensive investigation and much is known about its regulation by hormones such as insulin, glucagon and adrenaline (epinephrine). There has been debate over the relative importance of allosteric compared with covalent control of the key biosynthetic enzyme, glycogen synthase, as well as the relative importance of glucose entry into cells compared with glycogen synthase regulation in determining glycogen accumulation. Significant new developments in eukaryotic glycogen metabolism over the last decade or so include: (i) three-dimensional structures of the biosynthetic enzymes glycogenin and glycogen synthase, with associated implications for mechanism and control; (ii) analyses of several genetically engineered mice with altered glycogen metabolism that shed light on the mechanism of control; (iii) greater appreciation of the spatial aspects of glycogen metabolism, including more focus on the lysosomal degradation of glycogen; and (iv) glycogen phosphorylation and advances in the study of Lafora disease, which is emerging as a glycogen storage disease.

Astrocytic glycogen accumulation drives the pathophysiology of neurodegeneration in Lafora disease

Brain ◽  
2021 ◽  
Author(s):  
Jordi Duran ◽  
Arnau Hervera ◽  
Kia H Markussen ◽  
Olga Varea ◽  
Iliana López-Soldado ◽  
...  
Keyword(s):  
Mouse Model ◽  
Neurodegenerative Disorder ◽  
Glycogen Synthase ◽  
Glycogen Synthesis ◽  
Glycogen Metabolism ◽  
Cell Type ◽  
Lafora Disease ◽  
Glycogen Accumulation ◽  
Lafora Bodies

Abstract The hallmark of Lafora disease, a fatal neurodegenerative disorder, is the accumulation of intracellular glycogen aggregates, called Lafora bodies. Until recently, it was widely believed that brain Lafora bodies were present exclusively in neurons and thus that Lafora disease pathology derived from their accumulation in this cell population. However, recent evidence indicates that Lafora bodies are also present in astrocytes. To define the role of astrocytic Lafora bodies in Lafora disease pathology, we deleted glycogen synthase specifically from astrocytes in a mouse model of the disease (malinKO). Strikingly, blocking glycogen synthesis in astrocytes—thus impeding Lafora bodies accumulation in this cell type—prevented the increase in neurodegeneration markers, autophagy impairment, and metabolic changes characteristic of the malinKO model. Conversely, mice that overaccumulate glycogen in astrocytes showed an increase in these markers. These results unveil the deleterious consequences of the deregulation of glycogen metabolism in astrocytes and change the perspective that Lafora disease is caused solely by alterations in neurons.

scholarly journals Elucidating the role of Agl in bladder carcinogenesis by generation and characterization of genetically engineered mice

2018 ◽  
Vol 40 (1) ◽  
pp. 194-201
Author(s):  
Joseph L Sottnik ◽  
Vandana Mallaredy ◽  
Ana Chauca-Diaz ◽  
Carolyn Ritterson Lew ◽  
Charles Owens ◽  
...  
Keyword(s):  
Glycogen Storage Disease Type ◽  
Gene Signature ◽  
Glycogen Storage ◽  
Genetically Engineered ◽  
Normal Bladder ◽  
Populations At Risk ◽  
Genetically Engineered Mice ◽  
Patient Prognosis ◽  
The Impact

AbstractAmylo-α-1,6-glucosidase,4-α-glucanotransferase (AGL) is an enzyme primarily responsible for glycogen debranching. Germline mutations lead to glycogen storage disease type III (GSDIII). We recently found AGL to be a tumor suppressor in xenograft models of human bladder cancer (BC) and low levels of AGL expression in BC are associated with poor patient prognosis. However, the impact of low AGL expression on the susceptibility of normal bladder to carcinogenesis is unknown. We address this gap by developing a germline Agl knockout (Agl−/−) mouse that recapitulates biochemical and histological features of GSDIII. Agl−/− mice exposed to N-butyl-N-(4-hydroxybutyl) nitrosamine (BBN) had a higher BC incidence compared with wild-type mice (Agl+/+). To determine if the increased BC incidence observed was due to decreased Agl expression in the urothelium specifically, we developed a urothelium-specific conditional Agl knockout (Aglcko) mouse using a Uroplakin II-Cre allele. BBN-induced carcinogenesis experiments repeated in Aglcko mice revealed that Aglcko mice had a higher BC incidence than control (Aglfl/fl) mice. RNA sequencing revealed that tumors from Agl−/− mice had 19 differentially expressed genes compared with control mice. An ‘Agl Loss’ gene signature was developed and found to successfully stratify normal and tumor samples in two BC patient datasets. These results support the role of AGL loss in promoting carcinogenesis and provide a rationale for evaluating Agl expression levels, or Agl Loss gene signature scores, in normal urothelium of populations at risk of BC development such as older male smokers.

Regulation of glycogen accumulation in L6 myotubes cultured under optimized differentiation conditions

1998 ◽  
Vol 275 (6) ◽  
pp. E925-E933 ◽  
Author(s):  
Peter Elsner ◽  
Bjørn Quistorff ◽  
Thomas S. Hermann ◽  
John Dich ◽  
Niels Grunnet
Keyword(s):  
Retinoic Acid ◽  
Glycogen Synthase ◽  
Accumulation Rate ◽  
Decisive Role ◽  
Glycogen Metabolism ◽  
Total Activity ◽  
Glycogen Accumulation ◽  
L6 Myotubes ◽  
Igf I ◽  
Spontaneous Contractions

The differentiation of the L6 myogenic cell line was enhanced by the addition of dexamethasone, retinoic acid, insulin-like growth factor I (IGF-I), and creatine. Spontaneous contractions appeared from day 10 or 11 and persisted to day 14 or 15. Glucose transport was increased by insulin (100 nM) and IGF-I (5 nM) by ∼60%. The highest level of glycogen was measured in myotubes differentiated under the influence of a combination of 5 nM dexamethasone, 100 nM retinoic acid, 5 nM IGF-I, and 10 mM creatine with glucose as substrate. The glycogen accumulation rate was constant from 0 to 2 h of incubation and decreased gradually to zero at 4 h. From 0 to 0.5 h of the glycogen accumulation, the glycogen synthase a(GS a) activity was 30–35% of the total activity, with a subsequent gradual decline to 2.5% after 6 h. The glycogen phosphorylase a(GPh a) activity was constant at ∼80% from 0 to 0.5 h, increasing to ∼100% after 6 h. The activity ratio of GS a to GPh a decreased about sixfold without significant change in the rate of glycogen accumulation. This indicates that factors other than phosphorylation/dephosphorylation play a decisive role in the regulation of glycogen metabolism in L6 myotubes. Intracellular glucose (glucosei) and glucose 6-phosphate (G-6- P) may be such factors. The observed values of these parameters may in fact explain an activation of GS a(G-6- P) and an inhibition of GPh a(glucosei).

scholarly journals Circadian clock regulation of the glycogen synthase (gsn) gene by WCC is critical for rhythmic glycogen metabolism inNeurospora crassa

2019 ◽  
Vol 116 (21) ◽  
pp. 10435-10440 ◽  
Author(s):  
Mokryun Baek ◽  
Stela Virgilio ◽  
Teresa M. Lamb ◽  
Oneida Ibarra ◽  
Juvana Moreira Andrade ◽  
...  
Keyword(s):  
Circadian Clock ◽  
Glucose Homeostasis ◽  
Molecular Mechanisms ◽  
Glycogen Synthase ◽  
Glycogen Metabolism ◽  
Cellular Functions ◽  
Glycogen Accumulation ◽  
Homeostatic Process ◽  
Allosteric Control ◽  
Clock Component

Circadian clocks generate rhythms in cellular functions, including metabolism, to align biological processes with the 24-hour environment. Disruption of this alignment by shift work alters glucose homeostasis. Glucose homeostasis depends on signaling and allosteric control; however, the molecular mechanisms linking the clock to glucose homeostasis remain largely unknown. We investigated the molecular links between the clock and glycogen metabolism, a conserved glucose homeostatic process, inNeurospora crassa. We find that glycogen synthase (gsn) mRNA, glycogen phosphorylase (gpn) mRNA, and glycogen levels, accumulate with a daily rhythm controlled by the circadian clock. Because the synthase and phosphorylase are critical to homeostasis, their roles in generating glycogen rhythms were investigated. We demonstrate that whilegsnwas necessary for glycogen production, constitutivegsnexpression resulted in high and arrhythmic glycogen levels, and deletion ofgpnabolishedgsnmRNA rhythms and rhythmic glycogen accumulation. Furthermore, we show thatgsnpromoter activity is rhythmic and is directly controlled by core clock component white collar complex (WCC). We also discovered that WCC-regulated transcription factors, VOS-1 and CSP-1, modulate the phase and amplitude of rhythmicgsnmRNA, and these changes are similarly reflected in glycogen oscillations. Together, these data indicate the importance of clock-regulatedgsntranscription over signaling or allosteric control of glycogen rhythms, a mechanism that is potentially conserved in mammals and critical to metabolic homeostasis.

scholarly journals Antagonistic Controls of Autophagy and Glycogen Accumulation by Snf1p, the Yeast Homolog of AMP-Activated Protein Kinase, and the Cyclin-Dependent Kinase Pho85p

2001 ◽  
Vol 21 (17) ◽  
pp. 5742-5752 ◽  
Author(s):  
Zhong Wang ◽  
Wayne A. Wilson ◽  
Marie A. Fujino ◽  
Peter J. Roach
Keyword(s):  
Protein Kinase ◽  
Stationary Phase ◽  
Glycogen Synthase ◽  
Glycogen Synthesis ◽  
Glycogen Storage ◽  
Wild Type ◽  
Gene Encoding ◽  
Glycogen Accumulation ◽  
Yeast Homolog ◽  
Glycogen Stores

ABSTRACT In the yeast Saccharomyces cerevisiae, glycogen is accumulated as a carbohydrate reserve when cells are deprived of nutrients. Yeast mutated in SNF1, a gene encoding a protein kinase required for glucose derepression, has diminished glycogen accumulation and concomitant inactivation of glycogen synthase. Restoration of synthesis in an snf1 strain results only in transient glycogen accumulation, implying the existence of otherSNF1-dependent controls of glycogen storage. A genetic screen revealed that two genes involved in autophagy, APG1and APG13, may be regulated by SNF1. Increased autophagic activity was observed in wild-type cells entering the stationary phase, but this induction was impaired in ansnf1 strain. Mutants defective for autophagy were able to synthesize glycogen upon approaching the stationary phase, but were unable to maintain their glycogen stores, because subsequent synthesis was impaired and degradation by phosphorylase, Gph1p, was enhanced. Thus, deletion of GPH1 partially reversed the loss of glycogen accumulation in autophagy mutants. Loss of the vacuolar glucosidase, SGA1, also protected glycogen stores, but only very late in the stationary phase. Gph1p and Sga1p may therefore degrade physically distinct pools of glycogen. Pho85p is a cyclin-dependent protein kinase that antagonizes SNF1control of glycogen synthesis. Induction of autophagy inpho85 mutants entering the stationary phase was exaggerated compared to the level in wild-type cells, but was blocked in apg1 pho85 mutants. We propose that Snf1p and Pho85p are, respectively, positive and negative regulators of autophagy, probably via Apg1 and/or Apg13. Defective glycogen storage in snf1cells can be attributed to both defective synthesis upon entry into stationary phase and impaired maintenance of glycogen levels caused by the lack of autophagy.

scholarly journals Transgenic overexpression of protein targeting to glycogen markedly increases adipocytic glycogen storage in mice

2007 ◽  
Vol 292 (3) ◽  
pp. E952-E963 ◽  
Author(s):  
Michael J. Jurczak ◽  
Arpad M. Danos ◽  
Victoria R. Rehrmann ◽  
Margaret B. Allison ◽  
Cynthia C. Greenberg ◽  
...  
Keyword(s):  
Adipose Tissue ◽  
Fatty Acid ◽  
Glycogen Synthase ◽  
Glycogen Synthesis ◽  
Transgenic Animals ◽  
Glycogen Metabolism ◽  
Glycogen Storage ◽  
Fatty Acid Binding ◽  
Fat Depots

Adipocytes express the rate-limiting enzymes required for glycogen metabolism and increase glycogen synthesis in response to insulin. However, the physiological function of adipocytic glycogen in vivo is unclear, due in part to the low absolute levels and the apparent biophysical constraints of adipocyte morphology on glycogen accumulation. To further study the regulation of glycogen metabolism in adipose tissue, transgenic mice were generated that overexpressed the protein phosphatase-1 (PP1) glycogen-targeting subunit (PTG) driven by the adipocyte fatty acid binding protein (aP2) promoter. Exogenous PTG was detected in gonadal, perirenal, and brown fat depots, but it was not detected in any other tissue examined. PTG overexpression resulted in a modest redistribution of PP1 to glycogen particles, corresponding to a threefold increase in the glycogen synthase activity ratio. Glycogen synthase protein levels were also increased twofold, resulting in a combined greater than sixfold enhancement of basal glycogen synthase specific activity. Adipocytic glycogen levels were increased 200- to 400-fold in transgenic animals, and this increase was maintained to 1 yr of age. In contrast, lipid metabolism in transgenic adipose tissue was not significantly altered, as assessed by lipogenic rates, weight gain on normal or high-fat diets, or circulating free fatty acid levels after a fast. However, circulating and adipocytic leptin levels were doubled in transgenic animals, whereas adiponectin expression was unchanged. Cumulatively, these data indicate that murine adipocytes are capable of storing far higher levels of glycogen than previously reported. Furthermore, these results were obtained by overexpression of an endogenous adipocytic protein, suggesting that mechanisms may exist in vivo to maintain adipocytic glycogen storage at a physiological set point.

scholarly journals Gys1 antisense therapy rescues neuropathological bases of murine Lafora disease

2021 ◽  
Author(s):  
Saija Ahonen ◽  
Silvia Nitschke ◽  
Tamar R. Grossman ◽  
Holly Kordasiewicz ◽  
Peixiang Wang ◽  
...  
Keyword(s):  
Antisense Oligonucleotide ◽  
Glycogen Synthase ◽  
Lafora Disease ◽  
Neuroinflammatory Response ◽  
Glycogen Accumulation ◽  
Body Formation ◽  
Lafora Bodies ◽  
Progressive Myoclonus Epilepsy ◽  
Myoclonus Epilepsy ◽  
Lafora Body

AbstractLafora disease is a fatal progressive myoclonus epilepsy. At root, it is due to constant acquisition of branches that are too long in a subgroup of glycogen molecules, leading them to precipitate and accumulate into Lafora bodies, which drive a neuroinflammatory response and neurodegeneration. As a potential therapy, we aimed to downregulate glycogen synthase, the enzyme responsible for glycogen branch elongation, in the disease’s mouse models. We synthesized an antisense oligonucleotide (Gys1-ASO) that targets the mRNA of the brain-expressed glycogen synthase 1 gene (Gys1). We administered Gys1-ASO by intracerebroventricular injection and analyzed the pathological hallmarks of Lafora disease, namely glycogen accumulation, Lafora body formation, and neuroinflammation. Gys1-ASO prevented Lafora body formation in young mice that had not yet formed them. In older mice that already exhibited Lafora bodies, Gys1-ASO inhibited further accumulation, markedly preventing large Lafora bodies characteristic of advanced disease. Inhibition of Lafora body formation was associated with prevention of astrogliosis and strong trends towards correction of dysregulated expression of disease immune and neuroinflammatory markers. Lafora disease manifests gradually in previously healthy teenagers. Our work provides proof of principle that an antisense oligonucleotide targeting the GYS1 mRNA could prevent, and halt progression of, this catastrophic epilepsy.

scholarly journals Heating after intense repeated contractions inhibits glycogen accumulation in mouse EDL muscle: role of phosphorylase in postexercise glycogen metabolism

2018 ◽  
Vol 315 (5) ◽  
pp. C706-C713 ◽  
Author(s):  
Sarah J. Blackwood ◽  
Ester Hanya ◽  
Abram Katz
Keyword(s):  
Glycogen Synthase ◽  
Glycogen Synthesis ◽  
Glycogen Metabolism ◽  
Type Ii ◽  
Muscle Type ◽  
Phosphorylase Activity ◽  
Glycogen Accumulation ◽  
Longus Muscle ◽  
Edl Muscle

The effects of heating on glycogen synthesis (incorporation of [14C]glucose into glycogen) and accumulation after intense repeated contractions were investigated. Isolated mouse extensor digitorum longus muscle (type II) was stimulated electrically to perform intense tetanic contractions at 25°C. After 120 min recovery at 25°C, glycogen accumulated to almost 80% of basal, whereas after recovery at 35°C, glycogen remained low (~25% of basal). Glycogen synthesis averaged 0.97 ± 0.07 µmol·30 min−1·g wet wt−1 during recovery at 25°C and 1.48 ± 0.08 during recovery at 35°C ( P < 0.001). There were no differences in phosphorylase and glycogen synthase total activities nor in phosphorylase fractional activity, whereas glycogen synthase fractional activity was increased by ~50% after recovery at 35°C vs. 25°C. Inorganic phosphate (Pi, substrate for phosphorylase) was markedly increased (~300% of basal) following contraction but returned to control levels after 120 min recovery at 25°C. In contrast, Pi remained elevated after recovery at 35°C (>2-fold higher than recovery at 25°C). Estimates of glycogen breakdown indicated that phosphorylase activity (either via inhibition at 25°C or activation at 35°C) was responsible for ~60% of glycogen accumulation during recovery at 25°C and ~45% during recovery at 35°C. These data demonstrate that despite the enhancing effect of heating on glycogen synthesis during recovery from intense contractions, glycogen accumulation is inhibited owing to Pi-mediated activation of phosphorylase. Thus phosphorylase can play a quantitatively important role in glycogen biogenesis during recovery from repeated contractions in isolated type II muscle.

scholarly journals Gluconeogenesis and glycogen metabolism during development of Pacific abalone, Haliotis discus hannai

2020 ◽  
Vol 318 (3) ◽  
pp. R619-R633 ◽  
Author(s):  
Mugen Koyama ◽  
Fumiya Furukawa ◽  
Yuka Koga ◽  
Shohei Funayama ◽  
Suehiro Furukawa ◽  
...  
Keyword(s):  
Glycogen Synthase ◽  
Egg Yolk ◽  
Glycogen Metabolism ◽  
Glycogen Storage ◽  
Glucose Content ◽  
Pacific Abalone ◽  
Nutrient Sources ◽  
Haliotis Discus ◽  
Inhibition Of Glycolysis ◽  
Veliger Larvae

In lecithotrophic larvae, egg yolk nutrients are essential for development. Although yolk proteins and lipids are the major nutrient sources for most animal embryos and larvae, the contribution of carbohydrates to development has been less understood. In this study, we assessed glucose and glycogen metabolism in developing Pacific abalone, a marine gastropod mollusc caught and cultured in east Asia. We found that glucose and glycogen content gradually elevated in developing abalone larvae, and coincident expression increases of gluconeogenic genes and glycogen synthase suggested abalone larvae had activated gluconeogenesis and glycogenesis during this stage. At settling, however, glycogen sharply decreased, with concomitant increases in glucose content and expression of Pyg and G6pc, suggesting the settling larvae had enhanced glycogen conversion to glucose. A liquid chromatography-mass spectrometry (LC/MS)-based metabolomic approach that detected intermediates of these pathways further supported active metabolism of glycogen. Immunofluorescence staining and in situ hybridization suggested the digestive gland has an important role as glycogen storage tissue during settlement, while many other tissues also showed a capacity to metabolize glycogen. Finally, inhibition of glycolysis affected survival of the settling veliger larvae, revealing that glucose is, indeed, an important nutrient source in settling larvae. Our results suggest glucose and glycogen are required for proper energy balance in developing abalone and especially impact survival during settling.

Abstract P198: Aberrant Activation of γ2-AMPK Causes Cardiac Hypertrophy Independent of Glycogen Storage

2011 ◽  
Vol 109 (suppl_1) ◽  
Author(s):  
Maengjo Kim ◽  
Roger Hunter ◽  
Kei Sakamoto ◽  
Christine E Seidman ◽  
Jonathan G Seidman ◽  
...  
Keyword(s):  
Cardiac Hypertrophy ◽  
Double Mutant ◽  
Glycogen Synthase ◽  
Mammalian Target Of Rapamycin ◽  
Point Mutations ◽  
Glycogen Storage ◽  
Energy Deficit ◽  
Heart Weight ◽  
Glycogen Accumulation ◽  
Mtor Activity

AMP-activated protein kinase (AMPK) is an energy sensor and a key regulator of cell metabolism, hence a promising drug target. The cardiac functions of AMPK have not been understood. Point mutations in the regulatory γ2-subunit (encoded by PRKAG2 gene) have been shown to cause a unique form of cardiomyopathy in humans characterized by cardiac hypertrophy, arrhythmias and glycogen storage. We have previously shown that PRKAG2 mutation caused aberrant activation of AMPK in the absence of energy deficit and subsequently triggered re-routing of excessive glucose into glycogen pool. In this study, we addressed two questions: 1) whether cardiac hypertrophy in PRKAG2 cardiomyopathy was secondary of glycogen storage; 2) which hypertrophic signaling pathways are involved. We sought to reduce glycogen storage in transgenic mice expressing a mutant PRKAG2 (N488I) in the heart (TGγ2 N488I ) by crossing them to knock-in mice harboring a mutation in the muscle form of glycogen synthase (GYS1 KI ) that greatly reduced GYS activity in response to glucose-6-phosphate. Compared to TGγ2 N488I , TGγ2 N488I -GYS1-KI (double mutant) hearts showed lower GYS activity (0.7 ± 0.07 vs. 6.9 ± 0.49 nmol/min/mg, p<0.0001) and reduced glycogen content (35 ± 4.5 vs. 169 ± 40 umol/g, p<0.0001). Nonetheless, cardiac hypertrophy remained in the double mutant. The heart weight to body weight ratios were 6.8 ± 0.7 mg/g for TGγ2 N488I , 6.7 ± 0.5 mg/g for the double mutant compared to 4.0 ± 0.2 mg/g in the wild type. Furthermore, we have observed significant changes in FOXO (forkhead-O transcription factor) and mTOR (mammalian target of rapamycin) pathways in the TGγ2 N488I hearts. Increased phosphorylation of FOXO3a (Ser321, Ser253) and FoxO1a (Ser256) led to nuclear exclusion and degradation of FOXO proteins. Increased mTOR activity was evidenced by enhanced phosphorylation of Ser2448 as well as its downstream targets S6 and 4E-BP. Taken together these data indicate that aberrant γ2-AMPK activation causes cardiac hypertrophy independent of excessive glycogen accumulation. We found that increased mTOR activity and decreased FOXO signaling contributes to cardiac hypertrophy in TGγ2 N488I mice, suggesting novel mechanisms underlying cardiac hypertrophy caused by abnormal γ2-AMPK activity.

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