bims-glecem 2023-03-19 papers

bims-glecem

Biomed News

on Glycogen metabolism in exercise, cancer and energy metabolism

Issue of 2023‒03‒19
ten papers selected by
Dipsikha Biswas, Københavns Universitet

Lowered muscle glycogen reduces body mass with no effect on short-term exercise performance in men.
Glycogen Synthase Kinase-3 Inhibitors Block Morphine-Induced Locomotor Activation, Straub Tail, and Depression of Rearing in Mice Via a Possible Central Action.
Production of highly branched α-limit dextrins with enhanced slow digestibility by various glycogen-branching enzymes.
Memory formation in old age requires GSK-3β.
Phosphoglucomutase comes into the spotlight.
Editorial: The protein kinase GSK3 in neurobiological functions and neuronal disorders.
Oxazolo[5,4-f]quinoxaline-type selective inhibitors of glycogen synthase kinase-3α (GSK-3α): Development and impact on temozolomide treatment of glioblastoma cells.
Transport and Utilization of Glycogen Breakdown Products by Gardnerella spp. from the Human Vaginal Microbiome.
Production of branched glucan polymer by a novel thermostable branching enzyme of Bifidobacterium thermophilum via one-pot biosynthesis containing a dual enzyme system.
A tribute to Leif Hertz: The historical context of his pioneering studies of the roles of astrocytes in brain energy metabolism, neurotransmission, cognitive functions, and pharmacology identifies important, unresolved topics for future studies.

Scand J Med Sci Sports. 2023 Mar 17.

Lowered muscle glycogen reduces body mass with no effect on short-term exercise performance in men.

Camilla Tvede Schytz, Niels Ørtenblad, Thor Andersen Birkholm, Peter Plomgaard, Lars Nybo, Kristoffer Jensen Kolnes, Ole Emil Andersen, Carsten Lundby, Joachim Nielsen, Kasper Degn Gejl.

  Performance in short-duration sports is highly dependent on muscle glycogen, but the total degradation is only moderate and considering the water-binding property of glycogen, unnecessary storing of glycogen may cause an unfavorable increase in body mass. To investigate this, we determined the effect of manipulating dietary carbohydrates (CHO) on muscle glycogen content, body mass and short-term exercise performance. In a cross-over design twenty-two men completed two maximal cycle tests of either 1-min (n = 10) or 15-min (n = 12) duration with different pre-exercise muscle glycogen levels. Glycogen manipulation was initiated three days prior to the tests by exercise-induced glycogen-depletion followed by ingestion of a moderate (M-CHO) or high (H-CHO) CHO-diet. Subjects were weighed before each test, and muscle glycogen content was determined in biopsies from m. vastus lateralis before and after each test. Pre-exercise muscle glycogen content was lower following M-CHO than H-CHO (367 mmol · kg-1 DW vs. 525 mmol · kg-1 DW, P < 0.00001), accompanied by a 0.7 kg lower body mass (P < 0.00001). No differences were observed in performance between diets in neither the 1-min (P = 0.33) nor the 15-min (P = 0.99) test. In conclusion, pre-exercise muscle glycogen content and body mass was lower after ingesting moderate compared with high amounts of CHO, while short-term exercise performance was unaffected. This demonstrates that adjusting pre-exercise glycogen levels to the requirements of competition may provide an attractive weight management strategy in weight-bearing sports, particularly in athletes with high resting glycogen levels.

Keywords:  Diet Manipulation; Fatigue; Skeletal Muscle; Taper; Weight Management

DOI:  https://doi.org/10.1111/sms.14354
Neurochem Res. 2023 Mar 13.

Glycogen Synthase Kinase-3 Inhibitors Block Morphine-Induced Locomotor Activation, Straub Tail, and Depression of Rearing in Mice Via a Possible Central Action.

Junichi Kitanaka, Nobue Kitanaka, Kazuo Tomita, F Scott Hall, Kento Igarashi, George R Uhl, Tomoaki Sato.

  We investigated morphine-induced Straub's tail reaction (STR) in mice pretreated with or without glycogen synthase kinase-3 (GSK-3) inhibitors (SB216763 and AR-A014418) by using a newly modified, infrared beam sensor-based automated apparatus. Mice treated with a single injection of morphine (30 mg/kg, i.p.) showed a significant STR with a plateau level at a time point of 20 min after morphine challenge. Pretreatment of mice with SB216763 (5 mg/kg, s.c.) or AR-A014418 (3 mg/kg, i.p.) significantly inhibited morphine-induced STR and attenuated the duration of STR in a dose-dependent fashion. In the striatum and the nucleus accumbens, expression of pGSK-3βTyr216 but not GSK3β or pGSK-3βSer9 was largely but not significantly reduced after treatment with SB216763 (5 mg/kg, s.c.) in combination with/without morphine, indicating that the inhibitory effect of GSK-3 inhibitors on morphine-induced STR and hyperlocomotion might not depend on the direct blockade of GSK-3β function. In constipated mice after morphine challenge (30 mg/kg), the effect of GSK-3 inhibitors on gastrointestinal transit was examined to reveal whether the action of GSK-3 inhibitors on morphine effects was central and/or peripheral. Pretreatment with SB216763 (5 mg/kg) did not block constipation in morphine-injected mice. The mechanism of action seems to be central but not peripheral, although the underlying subcellular mechanism of GSK-3 inhibitors is not clear. Our measurement system is a useful tool for investigating the excitatory effects of morphine in experimental animals.

Keywords:  Glycogen synthase kinase-3; Hyperlocomotion; Infrared beam sensor-based automated apparatus; Morphine; Straub’s tail reaction

DOI:  https://doi.org/10.1007/s11064-023-03902-2
Carbohydr Polym. 2023 Jun 15. pii: S0144-8617(23)00194-7. [Epub ahead of print]310 120730

Production of highly branched α-limit dextrins with enhanced slow digestibility by various glycogen-branching enzymes.

Ye-Eun Shim, Young-Bo Song, Sang-Ho Yoo, Byung-Hoo Lee.

  α-Limit dextrins (α-LDx) are slowly digestible carbohydrates that attenuate postprandial glycemic response and trigger the secretion of satiety-related hormones. In this study, more highly branched α-LDx were enzymatically synthesized to enhance the slowly digestible property by various origins of glycogen branching enzyme (GBE), which catalyzes the transglycosylation to form α-1,6 branching points after cleaving α-1,4 linkages. Results showed that the proportion of branched α-LDx in starch molecules increased around 2.2-8.1 % compared to α-LDx from starch without GBE treatment as the ratio of α-1,6 linkages increased after different types of GBE treatments. Furthermore, the enzymatic increment of branching points enhanced the slowly digestible properties of α-LDx at the mammalian α-glucosidase level by 17.3-28.5 %, although the rates of glucose generation were different depending on the source of GBE treatment. Thus, the highly branched α-LDx with a higher amount of α-1,6 linkages and a higher molecular weight can be applied as a functional ingredient to deliver glucose throughout the entire small intestine without a glycemic spike which has the potential to control metabolic diseases such as obesity and type 2 diabetes.

Keywords:  Glucose generation; Glycogen branching enzymes; Highly branched α-limit dextrins; Slowly digestible carbohydrates

DOI:  https://doi.org/10.1016/j.carbpol.2023.120730
Aging Brain. 2021 ;1 100022

Memory formation in old age requires GSK-3β.

Riki Koike, Yuta Takaichi, Yoshiyuki Soeda, Akihiko Takashima.

  Glycogen synthase kinase 3β (GSK-3β) is a therapeutic target for various age-related neurodegenerative diseases. It is linked to the two main pathological features of Alzheimer's disease (AD), tau and amyloid β (Aβ); GSK-3β is a major candidate to pathologically hyperphosphorylate tau and modulate Aβ production. However, inhibition of GSK-3β in clinical studies in humans has been found to not significantly improve cognitive function of AD patients, prompting us to study the physiological role of GSK-3β in old mice. Using a contextual fear-conditioning paradigm, we now report that old gsk-3β+/- mice are deficient in both short-term and long-term memory formation, suggesting that GSK-3β is required for memory formation at old age. Biochemical and immunohistochemical analyses showed that the number of synapses does not differ between gsk-3β+/- and age-matched wild-type (wt) littermate mice. Based on these observations, we propose that, GSK-3β may contribute to help maintain brain function during aging. Our results may explain the poor efficacy of GSK-3β inhibitors in preserving memory capacity in AD patients.

Keywords:  Aging; Alzheimer's disease; Consolidation; GSK-3β; Memory

DOI:  https://doi.org/10.1016/j.nbas.2021.100022
J Exp Bot. 2023 Mar 13. 74(5): 1293-1296

Phosphoglucomutase comes into the spotlight.

Sofía Doello, Karl Forchhammer.



Keywords:   Synechocystis ; Cyanobacteria; glycogen; phosphoglucomutase; starch

DOI:  https://doi.org/10.1093/jxb/erac513
Front Mol Neurosci. 2023 ;16 1155905

Editorial: The protein kinase GSK3 in neurobiological functions and neuronal disorders.

Florian Plattner, Shin-Ichi Hisanaga, Raymond Chuen-Chung Chang, Anna Matynia.



Keywords:  bipolar disorder; glycogen synthase kinase 3; lithium; neurodegenerative diseases; pharmacological inhibitor; protein kinase

DOI:  https://doi.org/10.3389/fnmol.2023.1155905
Bioorg Chem. 2023 Mar 04. pii: S0045-2068(23)00116-5. [Epub ahead of print]134 106456

Oxazolo[5,4-f]quinoxaline-type selective inhibitors of glycogen synthase kinase-3α (GSK-3α): Development and impact on temozolomide treatment of glioblastoma cells.

Mohamed Hasyeoui, Frédéric Lassagne, William Erb, Manal Nael, Khaled M Elokely, Apirat Chaikuad, Stefan Knapp, Adrian Jorda, Soraya L Vallés, Emie Quissac, Maïté Verreault, Thomas Robert, Stéphane Bach, Ali Samarat, Florence Mongin.

  The 2-(3-pyridyl)oxazolo[5,4-f]quinoxalines CD-07 and FL-291 are ATP-competitive GSK-3 kinase inhibitors. Here, we investigated the impact of FL-291 on neuroblastoma cell viability and showed that treatment at 10 μM (i.e. ∼500 times the IC50 against the GSK-3 isoforms) has no significant effect on the viability of NSC-34 motoneuron-like cells. A study performed on primary neurons (non-cancer cells) led to similar results. The structures co-crystallized with GSK-3β revealed similar binding modes for FL-291 and CD-07, with their hinge-oriented planar tricyclic system. Both GSK isoforms show the same orientations for the amino acids at the binding pocket except for Phe130 (α) and Phe67 (β), leading to a larger pocket on the opposite side of the hinge region for the α isoform. Calculations of the thermodynamic properties of the binding pockets highlighted the required features of potential ligands; these should have a hydrophobic core (which could be larger in the case of GSK-3β) surrounded by polar areas (a little more polar in the case of GSK-3α). A library of 27 analogs of FL-291 and CD-07 was thus designed and synthesized by taking advantage of this hypothesis. While the introduction of substituents at different positions of the pyridine ring, the replacement of the pyridine by other heterocyclic moieties, or the replacement of the quinoxaline ring by a quinoline moiety did not lead to any improvement, the replacement of the N-(thio)morpholino of FL-291/CD-07 by a slightly more polar N-thiazolidino led to a significant result. Indeed, the new inhibitor MH-124 showed clear selectivity for the α isoform, with IC50 values of 17 nM and 239 nM on GSK-3α and GSK-3β, respectively. Finally, the efficacy of MH-124 was evaluated on two glioblastoma cell lines. Although MH-124 alone did not have a significant impact on cell survival, its addition to temozolomide (TMZ) significantly reduced the TMZ IC50 values on the cells tested. The use of the Bliss model allowed a synergy to be evidenced at certain concentrations.

Keywords:  Co-crystallization; GSK-3α; Glioblastoma; Kinase inhibition; Molecular modelling; Oxazolo[5,4-f]quinoxaline

DOI:  https://doi.org/10.1016/j.bioorg.2023.106456
Microbiol Spectr. 2023 Mar 15. e0443522

Transport and Utilization of Glycogen Breakdown Products by Gardnerella spp. from the Human Vaginal Microbiome.

Pashupati Bhandari, Janet E Hill.

  Multiple Gardnerella species frequently cooccur in vaginal microbiomes, and several factors, including competition for nutrients such as glycogen could determine their population structure. Although Gardnerella spp. can hydrolyze glycogen to produce glucose, maltose, maltotriose, and maltotetraose, how these sugars are transported and utilized for growth is unknown. We determined the distribution of genes encoding transporter proteins associated with the uptake of glucose, maltose, and malto-oligosaccharides and maltodextrins among Gardnerella species. A total of five different ABC transporters were identified in Gardnerella spp. of which MusEFGK2I and MalXFGK were conserved across all 15 Gardnerella isolates. RafEFGK and TMSP (trehalose, maltose, sucrose, and palatinose) operons were specific to G. vaginalis while the MalEFG transporter was identified in G. leopoldii only. Although no glucose specific sugar-symporters were identified, putative "glucose/galactose porters" and components of a phosphotransferase system were identified. In laboratory experiments, all Gardnerella isolates grew more in the presence of glucose, maltose, maltotriose, and maltotetraose compared to unsupplemented media. In addition, most isolates (10/15) showed significantly more growth on maltotetraose compared to glucose (Kruskal Wallis, P < 0.05) suggesting their preference for longer chain malto-oligosaccharides. Our findings show that although putative MusEFGK2I and MalXFGK transporters are found in all Gardnerella spp., some species-specific transporters are also present. Observed distribution of genes encoding transporter systems was consistent with laboratory observations that Gardnerella spp. grow better on longer chain malto-oligosaccharides. IMPORTANCE Increased abundance of Gardnerella spp. is a diagnostic characteristic of bacterial vaginosis, an imbalance in the human vaginal microbiome associated with troubling symptoms and negative reproductive health outcomes, including increased transmission of sexually transmitted infections and preterm birth. Competition for nutrients is likely an important factor in causing dramatic shifts in the vaginal microbial community. Gardnerella produces enzymes to digest glycogen, an important nutrient source for vaginal bacteria, but little is known about the mechanisms in Gardnerella for uptake of the products of this digestion, or whether Gardnerella use some or all of the products. Our results indicate that Gardnerella may have evolved to preferentially use a subset of the glycogen breakdown products, which would help them reduce direct competition with some other bacteria in the vagina.

Keywords:  ABC transporter; Gardnerella; carbohydrate; glycogen; vaginal microbiome

DOI:  https://doi.org/10.1128/spectrum.04435-22
Carbohydr Polym. 2023 Jun 01. pii: S0144-8617(23)00110-8. [Epub ahead of print]309 120646

Production of branched glucan polymer by a novel thermostable branching enzyme of Bifidobacterium thermophilum via one-pot biosynthesis containing a dual enzyme system.

Seong-Ho Jin, Tae-Eun Kwon, Jeon-Uk Kang, Sun-Hwa Yoo, Pahn-Shick Chang, Sang-Ho Yoo.

  Glycogen-like particles (GLPs) are applied in food, pharmaceutical, and cosmetics. The large-scale production of GLPs is limited by their complicated multi-step enzymic processes. In this study, GLPs were produced in a one-pot dual-enzyme system using Bifidobacterium thermophilum branching enzyme (BtBE) and Neisseria polysaccharea amylosucrase (NpAS). BtBE showed excellent thermal stability (half-life of 1732.9 h at 50 °C). Substrate concentration was the most influential factor during GLPs production in this system: GLPs yield and [sucrose]ini decreased from 42.4 % to 17.4 % and 0.3 to 1.0 M, respectively. Molecular weight and apparent density of GLPs decreased significantly with increasing [sucrose]ini. Regardless of the [sucrose]ini, the DP 6 of branch chain length was predominantly occupied. GLP digestibility increased with increasing [sucrose]ini, indicating that the degree of GLP hydrolysis may be negatively related to its apparent density. This one-pot biosynthesis of GLPs using a dual-enzyme system could be useful for the development of industrial processes.

Keywords:  Amylosucrase; Apparent density; Bifidobacterium thermophilum; Branching enzyme; Digestibility; Glycogen-like particle

DOI:  https://doi.org/10.1016/j.carbpol.2023.120646
J Neurochem. 2023 Mar 16.

A tribute to Leif Hertz: The historical context of his pioneering studies of the roles of astrocytes in brain energy metabolism, neurotransmission, cognitive functions, and pharmacology identifies important, unresolved topics for future studies.

Gerald A Dienel, Arne Schousboe, Mary C McKenna, Douglas L Rothman.

  Leif Hertz, M.D., D.Sc. (honōris causā) (1930-2018) was one of the original and noteworthy participants in the International Conference on Brain Energy Metabolism (ICBEM) series since its inception in 1993. The biennial ICBEM conferences are organized by neuroscientists interested in energetics and metabolism underlying neural functions; they have had a high impact on conceptual and experimental advances in these fields and on promoting collaborative interactions among neuroscientists. Leif made major contributions to ICBEM discussions and understanding of metabolic and signaling characteristics of astrocytes and their roles in brain function. His studies ranged from uptake of K+ from extracellular fluid and its stimulation of astrocytic respiration, identification and regulation of enzymes specifically or preferentially expressed in astrocytes in the glutamate-glutamine cycle of excitatory neurotransmission, a requirement for astrocytic glycogenolysis for fueling K+ uptake, involvement of glycogen in memory consolidation in the chick, and pharmacology of astrocytes. This tribute to Leif Hertz highlights his major discoveries, the high impact of his work on astrocyte-neuron interactions, and his unparalleled influence on understanding the cellular basis of brain energy metabolism. His work over seven decades has helped integrate the roles of astrocytes into neurotransmission where oxidative and glycogenolytic metabolism during neurotransmitter glutamate turnover are key aspects of astrocytic energetics. Leif recognized that brain astrocytic metabolism is greatly underestimated unless the volume fraction of astrocytes is taken into account. Adjustment for pathway rates expressed per gram tissue for volume fraction indicates that astrocytes have much higher oxidative rates than neurons and astrocytic glycogen concentrations and glycogenolytic rates during sensory stimulation in vivo are similar to those in resting and exercising muscle, respectively. These novel insights are typical of Leif's astute contributions to the energy metabolism field, and his publications have identified unresolved topics that provide the neuroscience community with challenges and opportunities for future research.

Keywords:  Glu/GABA-Gln cycle; astrocyte and neuron cell culture; astrocytic metabolism and energetics; astrocytic pharmacology; cellular maturation in vitro; glycogen

DOI:  https://doi.org/10.1111/jnc.15812