bims-glecem Biomed News
on Glycogen metabolism in exercise, cancer and energy metabolism
Issue of 2023–02–19
twelve papers selected by
Dipsikha Biswas, Københavns Universitet
  1. On the interdependence of ketone body oxidation,glycogen content, glycolysis and energy metabolism in the heart.
  2. Interactomes of Glycogen Synthase Kinase-3 Isoforms.
  3. Pompe's Disease Successfully Treated In Utero.
  4. Diagnosis and management of glycogen storage disease type IV, including adult polyglucosan body disease: A clinical practice resource.
  5. Simulations reveal the role of glucose-6-phosphatase mutations in glycogen storage disease.
  6. Synergic effect of exogenous lactate and caffeine on fat oxidation and hepatic glycogen concentration in resting rats.
  7. Transcriptomic characterization of clinical skeletal muscle biopsy from late-onset Pompe patients.
  8. Hepatopathy of Mauriac syndrome. The importance of therapeutic adherence.
  9. Glycogen synthesis kinase-3β involves in the analgesic effect of liraglutide on diabetic neuropathic pain.
  10. Liver glycogen stores via 13C magnetic resonance spectroscopy in healthy children: randomized, controlled study.
  11. GSK-3β/β-catenin pathway plays crucial roles in the regulation of NK cell cytotoxicity against myeloma cells.
  12. Exercise-brain interaction of neuroplasticity: empirical evidence in the rodent adaptation.
  1. J Physiol. 2023 Feb 17.
    On the interdependence of ketone body oxidation,glycogen content, glycolysis and energy metabolism in the heart.
    Azrul Abdul Kadir, Brianna J Stubbs, Cher-Rin Chong, Henry Lee, Mark Cole, Carolyn Carr, David Hauton, James McCullagh, Rhys D Evans, Kieran Clarke.
      In heart, glucose and glycolysis are important for anaplerosis and potentially therefore for d-beta-hydroxybutyrate (βHB) oxidation. As a glucose store, glycogen may also furnish anaplerosis. We determined the effects of glycogen content on βHB oxidation and glycolytic rates, and their downstream effects on energetics, in the isolated rat heart. High glycogen (HG) and low glycogen (LG) containing hearts were perfused with 11 mM [5-3 H]-glucose and/or 4mM [14 C]-βHB to measure glycolytic rates or βHB oxidation, respectively, then freeze-clamped for glycogen and metabolomic analyses. Free cytosolic [NAD+ ]/[NADH] and mitochondrial [Q+ ]/[QH2 ] ratios were estimated using the lactate dehydrogenase and succinate dehydrogenase reactions, respectively. Phosphocreatine (PCr) and inorganic phosphate (Pi) concentrations were measured using 31 P-NMR spectroscopy. Rates of βHB oxidation in LG hearts were half that in HG hearts, with βHB oxidation directly proportional to glycogen content. βHB oxidation decreased glycolysis in all hearts. Glycogenolysis in glycogen-replete hearts perfused with βHB alone was twice that of hearts perfused with βHB and glucose, which had significantly higher levels of the glycolytic intermediates, fructose 1,6-bisphosphate and 3-phosphoglycerate, and higher free cytosolic [NAD+ ]/[NADH]. βHB oxidation increased the Krebs cycle intermediates citrate, 2-oxoglutarate and succinate, the total nicotinamide adenine dinucleotide phosphate (NADP/H) pool, reduced mitochondrial [Q+ ]/[QH2 ], and increased the calculated free energy of ATP hydrolysis (∆GATP ). Although βHB oxidation inhibited glycolysis, glycolytic intermediates were not depleted, and cytosolic free NAD remained oxidised. βHB oxidation alone increased Krebs cycle intermediates, reduced mitochondrial Q and increased ∆GATP . We conclude that glycogen facilitates cardiac βHB oxidation by anaplerosis. KEY POINTS: Ketone bodies (D-β-hydroxybutyrate; acetoacetate) are increasingly recognised as important cardiac energetic substrates, in both healthy and diseased hearts. As 2-carbon equivalents they are cataplerotic, causing depletion of Kreb's cycle intermediates; therefore their utilisation requires anaplerotic supplementation. Intra-myocardial glycogen has been suggested as a potential anaplerotic source during ketone oxidation. We demonstrate here that cardiac glycogen does indeed provide anaplerotic substrate to facilitate β-hydroxybutyrate oxidation in isolated perfused rat heart, and utilising a novel pulse-chase metabolic approach, quantify this contribution. Further, using metabolomics and 31 P-MR, we show that glycolytic flux from myocardial glycogen increased the heart's ability to oxidise βHB, and βHB oxidation increased the mitochondrial redox potential, ultimately increasing the free energy of ATP hydrolysis. Abstract figure legend Overview of relationship of glycogen to ketone body oxidation and cardiac energetics in isolated perfused rat hearts. Myocardial glycogen was pre-labelled with tritium and its metabolic fate tracked using a pulse-chase technique. Increased glycolytic flux from glycogen facilitated increased exogenous β-hydroxybutyrate (βHB) oxidation through anaplerosis, and the increased βHB oxidation increased mitochondrial redox potential, and hence increased free energy of ATP hydrolysis. This article is protected by copyright. All rights reserved.
    Keywords:  d-β-hydroxybutyrate oxidation; glycogen; glycolysis; metabolomics; redox states
    DOI:  https://doi.org/10.1113/JP284270
  2. J Proteome Res. 2023 Feb 13.
    Interactomes of Glycogen Synthase Kinase-3 Isoforms.
    Kevin W Cormier, Brett Larsen, Anne-Claude Gingras, James R Woodgett.
      Functional differentiation of the two isoforms of the protein-serine/threonine kinase, glycogen synthase kinase-3 (GSK-3), is an unsettled area of research. The isoforms are highly similar in structure and are largely redundant, though there is also evidence for specific roles. Identification of isoform-specific protein interactors may elucidate the differences in function and provide insight into isoform-selective regulation. We therefore sought to identify novel GSK-3 interaction partners and to examine differences in the interactomes of the two isoforms using both affinity purification and proximity-dependent biotinylation (BioID) mass spectrometry methods. While the interactomes of the two isomers are highly similar in HEK293 cells, BioID in HeLa cells yielded a variety of preys that are preferentially associated with one of the two isoforms. DCP1B, which favored GSK-3α, and MISP, which favored GSK-3β, were evaluated for reciprocal interactions. The differences in interactions between isoforms may help in understanding the distinct functions and regulation of the two isoforms as well as offer avenues for the development of isoform-specific strategies.
    Keywords:  BioID; GSK-3; glycogen synthase kinase-3; interactomes; protein isoforms; protein−protein interactions
    DOI:  https://doi.org/10.1021/acs.jproteome.2c00825
  3. Am J Med Genet A. 2023 Mar;191(3): 654-655
    Pompe's Disease Successfully Treated In Utero.
      
    DOI:  https://doi.org/10.1002/ajmg.a.62795
  4. Mol Genet Metab. 2023 Jan 25. pii: S1096-7192(23)00155-5. [Epub ahead of print]138(3): 107525
    Diagnosis and management of glycogen storage disease type IV, including adult polyglucosan body disease: A clinical practice resource.
    Rebecca L Koch, Claudia Soler-Alfonso, Bridget T Kiely, Akihiro Asai, Ariana L Smith, Deeksha S Bali, Peter B Kang, Andrew P Landstrom, H Orhan Akman, T Andrew Burrow, Jennifer L Orthmann-Murphy, Deberah S Goldman, Surekha Pendyal, Areeg H El-Gharbawy, Stephanie L Austin, Laura E Case, Raphael Schiffmann, Michio Hirano, Priya S Kishnani.
      Glycogen storage disease type IV (GSD IV) is an ultra-rare autosomal recessive disorder caused by pathogenic variants in GBE1 which results in reduced or deficient glycogen branching enzyme activity. Consequently, glycogen synthesis is impaired and leads to accumulation of poorly branched glycogen known as polyglucosan. GSD IV is characterized by a remarkable degree of phenotypic heterogeneity with presentations in utero, during infancy, early childhood, adolescence, or middle to late adulthood. The clinical continuum encompasses hepatic, cardiac, muscular, and neurologic manifestations that range in severity. The adult-onset form of GSD IV, referred to as adult polyglucosan body disease (APBD), is a neurodegenerative disease characterized by neurogenic bladder, spastic paraparesis, and peripheral neuropathy. There are currently no consensus guidelines for the diagnosis and management of these patients, resulting in high rates of misdiagnosis, delayed diagnosis, and lack of standardized clinical care. To address this, a group of experts from the United States developed a set of recommendations for the diagnosis and management of all clinical phenotypes of GSD IV, including APBD, to support clinicians and caregivers who provide long-term care for individuals with GSD IV. The educational resource includes practical steps to confirm a GSD IV diagnosis and best practices for medical management, including (a) imaging of the liver, heart, skeletal muscle, brain, and spine, (b) functional and neuromusculoskeletal assessments, (c) laboratory investigations, (d) liver and heart transplantation, and (e) long-term follow-up care. Remaining knowledge gaps are detailed to emphasize areas for improvement and future research.
    Keywords:  Adult polyglucosan body disease; Andersen disease; Clinical practice guideline; Diagnosis guideline; Glycogen branching enzyme; Glycogen storage disease type IV; Management guideline
    DOI:  https://doi.org/10.1016/j.ymgme.2023.107525
  5. Biophys J. 2023 Feb 10. pii: S0006-3495(22)02057-4. [Epub ahead of print]122(3S1): 185a
    Simulations reveal the role of glucose-6-phosphatase mutations in glycogen storage disease.
    Matt Sinclair, Jonathan Sheehan, Richard A Stein, Derek P Claxton, Emad Tajkhorshid.
      
    DOI:  https://doi.org/10.1016/j.bpj.2022.11.1141
  6. Phys Act Nutr. 2022 12;26(4): 5-13
    Synergic effect of exogenous lactate and caffeine on fat oxidation and hepatic glycogen concentration in resting rats.
    Choongsung Yoo, Jisu Kim, Sunghwan Kyun, Takeshi Hashimoto, Hironori Tomi, Kiwon Lim.
       PURPOSE: Although several physiological roles of lactate have been revealed in the last decades, its effects on energy metabolism and substrate oxidation remain unknown. Therefore, we investigated the effects of lactate on the energy metabolism of resting rats.
    METHODS: Male rats were divided into control (Con; distilled water), caffeine (Caf; 10 mg/kg), L-lactate (Lac; 2 g/kg), and lactate-plus-caffeine (Lac+Caf; 2 g/ kg + 10 mg) groups. Following oral administration of supplements, resting energy expenditure (study 1), biochemical blood parameters, and mRNA expression involved in energy metabolism in the soleus muscle were measured at different time points within 120 minutes of administration (study 2). Moreover, glycogen level and Pyruvate dehydrogenase (PDH) activity were measured.
    RESULTS: Groups did not differ in total energy expenditure throughout the 6 hour post-treatment evaluation. Within the first 4 hours, the Lac and Lac+Caf groups showed higher fat oxidation rates than the Con group (p<0.05). Lactate treatment decreased blood free fatty acid levels (p<0.05) and increased the mRNA expression of fatty acid translocase (FAT/CD36) (p<0.05) and peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC-1α) (p<0.05) in the skeletal muscle. Hepatic glycogen level in the Lac+Caf group was significantly increased (p<0.05). Moreover, after 30 and 120 minutes, PDH activity was significantly higher in lactate-supplemented groups compared to Con group (p<0.05).
    CONCLUSION: Our findings showed that Lac+Caf enhanced fat metabolism in the whole body and skeletal muscle while increasing hepatic glycogen concentration and PDH activity. This indicates Lac+Caf can be used as a potential post-workout supplement.
    Keywords:  CPT1b; FAT/CD36; PGC-1α; carbohydrate oxidation; fatty acid translocase; glycogen; respiratory exchange ratio
    DOI:  https://doi.org/10.20463/pan.2022.0019
  7. Mol Genet Metab. 2023 Jan 25. pii: S1096-7192(23)00156-7. [Epub ahead of print]138(3): 107526
    Transcriptomic characterization of clinical skeletal muscle biopsy from late-onset Pompe patients.
    Sofia Kinton, Michael R Dufault, Mindy Zhang, Kelly George.
      Pompe disease is a rare lysosomal storage disorder arising from recessive mutations in the acid α-glucosidase gene and resulting in the accumulation of glycogen, particularly in the cardiac and skeletal muscle. The current standard of care is administration of enzyme replacement therapy in the form of alglucosidase alfa or the recently approved avalglucosidase alfa. In order to better understand the underlying cellular processes that are disrupted in Pompe disease, we conducted gene expression analysis on skeletal muscle biopsies obtained from late-onset Pompe disease patients (LOPD) prior to treatment and following six months of enzyme replacement with avalglucosidase alfa. The LOPD patients had a distinct transcriptomic signature as compared to control patient samples, largely characterized by perturbations in pathways involved in lysosomal function and energy metabolism. Although patients were highly heterogeneous, they collectively exhibited a strong trend towards attenuation of the dysregulated genes following just six months of treatment. Notably, the enzyme replacement therapy had a strong stabilizing effect on gene expression, with minimal worsening in genes that were initially dysregulated. Many of the cellular process that were altered in LOPD patients were also affected in the more clinically severe infantile-onset (IOPD) patients. Additionally, both LOPD and IOPD patients demonstrated enrichment across several inflammatory pathways, despite a lack of overt immune cell infiltration. This study provides further insight into Pompe disease biology and demonstrates the positive effects of avalglucosidase alfa treatment.
    Keywords:  Alglucosidase alfa; Avalglucosidase alfa; Pompe disease; Skeletal muscle; Transcriptomics
    DOI:  https://doi.org/10.1016/j.ymgme.2023.107526
  8. Rev Esp Enferm Dig. 2023 Feb 13.
    Hepatopathy of Mauriac syndrome. The importance of therapeutic adherence.
    Antonio Moreno Tirado, Paloma González Lázaro, María Zhao Montero Benítez, Pedro Jiménez Torrecilla.
      The Pierre Mauriac syndrome described in the year 1930, is characterized by growth failure, cushingoid appearance, hepatomegaly and hypertransaminasemia, in a patient with chronic uncontrolled DM1. The most common age of presentation is usually in adolescence, although cases have been described in both children and adults. The hallmark of this syndrome is extreme liver enlargement from massive acucumulation of glycogen. The diagnosis of hepatopathy requires high clinical suspicion and the presence of glycogen accumulation must be corroborated with a liver biopsy. The accumulation of glycogen in hepatocytes is partly caused by long periods of hyperglycemia, in which glucose enters the hepatocyte independently of insulin and is converted to glycogen. Mauriac syndrome is currently a rare cause of liver disease, due to improvements in control and treatment of patients with DM1. However, some cases are described in people with complicated social situations or without therapeutic compliance. This is a reversible condition after improvement in glycemic control with adequate insulinization. For this reason, we believe it convenient to suspect this clinical picture in patients with poor glycemic control and symptoms of pain and abdominal distension.
    DOI:  https://doi.org/10.17235/reed.2023.9513/2023
  9. J Diabetes Complications. 2023 Feb 04. pii: S1056-8727(23)00014-4. [Epub ahead of print]37(3): 108416
    Glycogen synthesis kinase-3β involves in the analgesic effect of liraglutide on diabetic neuropathic pain.
    Yuanpin Zhang, Qi Zhang, Yuetian Bai, Hangping Zheng, Lijin Ji, Xiaoming Zhu, Wanwan Sun, Xiaoxia Liu, Shuo Zhang, Yiming Li, Bin Lu.
       AIMS: Explore whether Glycogen synthesis kinase-3β (GSK3β) involved in the analgesic effect of liraglutide on diabetic neuropathic pain (DNP).
    METHODS: DNP was induced by streptozocin (STZ) in WT and GSK3β(S9A) mice, which carried a constitutively active form of GSK3β. DNP mice were intracerebroventricularly injected with liraglutide 5 weeks after STZ injection. The behavior of neuropathic pain was evaluated 2 h after drugs administration. The microglial activation and the expression of NOD-like receptor protein 3 (NLRP3) in microglia in cortex were evaluated. The role of GSK3β in the inhibitory effect of liraglutide on the NLRP3 inflammasome was explored in BV2 microglia.
    RESULTS: Intracerebroventricular administration of liraglutide significantly relieved neuropathic pain and inhibited the activation of cortical microglia in WT mice with DNP. But the effect of liraglutide disappeared in GSK3β(S9A) mice. In BV2 microglia, GSK3β inhibitor significantly suppressed NLRP3 inflammasome activation. And activating GSK3β through GSK3β(S9A) lentivirus significantly blocked the inhibitory effect of liraglutide on NLRP3 inflammasome in BV2 microglia. Intracerebroventricular administration of liraglutide significantly inhibited the expression of NLRP3 in cortex microglia of DNP group in WT mice but failed in GSK3β(S9A) mice.
    CONCLUSION: GSK3β involves in the analgesic effect of liraglutide on DNP through NLRP3 inflammasome in microglia.
    Keywords:  Diabetic neuropathic pain; Glycogen synthesis kinase-3β; Liraglutide; NOD-like receptor protein 3 inflammasome
    DOI:  https://doi.org/10.1016/j.jdiacomp.2023.108416
  10. Am J Clin Nutr. 2023 Jan 20. pii: S0002-9165(23)00542-7. [Epub ahead of print]
    Liver glycogen stores via 13C magnetic resonance spectroscopy in healthy children: randomized, controlled study.
    Astrid Mh Horstman, Stephen J Bawden, Abi Spicer, Noura Darwish, Amélie Goyer, Léonie Egli, Natacha Rupp, Kaori Minehira, Penny Gowland, Denis Breuillé, Ian A Macdonald, Elizabeth J Simpson.
       BACKGROUND: Owing to its role in glucose homeostasis, liver glycogen concentration ([LGly]) can be a marker of altered metabolism seen in disorders that impact the health of children. However, there is a paucity of normative data for this measure in children to allow comparison with patients, and time-course assessment of [LGly] in response to feeding has not been reported. In addition, carbon-13 magnetic resonance spectroscopy (13C-MRS) is used extensively in research to assess liver metabolites in adult health and disease noninvasively, but similar measurements in children are lacking.
    OBJECTIVES: The main objectives were to quantify the depletion of [LGly] after overnight fasting and the subsequent response to feeding.
    METHODS: In a randomly assigned, open-label, incomplete block design study, healthy, normal-weight children (8-12 y) attended 2 evening visits, each separated by ≥5 d and directly followed by a morning visit. An individually tailored, standardized meal was consumed 3-h prior to evening assessments. Participants then remained fasted until the morning visit. [LGly] was assessed once in the fed (20:00) and fasted state (08:00) using 13C-MRS. After the 8:00 assessment, 200 ml of a mixed-macronutrient drink containing 15.5 g (402 kJ) or 31 g carbohydrates (804 kJ), or water only, was consumed, with 13C-MRS measurements then performed hourly for 4 h. Each child was randomly assigned to 2 of 3 drink options across the 2 mornings. Data are expressed as mean (SD).
    RESULTS: Twenty-four children including females and males (13F:11M) completed the study [9.9 (1.1) y, BMI percentile 45.7 (25.9)]. [LGly] decreased from 377.9 (141.3) to 277.3 (107.4) mmol/L overnight; depletion rate 0.14 (0.15) mmol/L min. Incremental responses of [LGly] to test drinks differed (P < 0.001), with incremental net area under the curve of [LGly] over 4 h being higher for 15.5 g [-67.1 (205.8) mmol/L·240 min; P < 0.01] and 31 g carbohydrates [101.6 (180.9) mmol/L·240 min; P < 0.005] compared with water [-253.1 (231.2) mmol/L·240 min].
    CONCLUSIONS: After overnight fasting, [LGly] decreased by 22.9 (25.1)%, and [LGly] incremental net area under the curve over 4 h was higher after subsequent consumption of 15.5 g and 31 g carbohydrates, compared to water. Am J Clin Nutr 20XX;xx:xx-xx.
    Keywords:  carbohydrate metabolism; fasting; feeding; gastric emptying; muscle glycogen concentration
    DOI:  https://doi.org/10.1016/j.ajcnut.2023.01.014
  11. FASEB J. 2023 Mar;37(3): e22821
    GSK-3β/β-catenin pathway plays crucial roles in the regulation of NK cell cytotoxicity against myeloma cells.
    Jing Ren, Xiumei Feng, Yanan Guo, Dexiao Kong, Yongjing Wang, Juan Xiao, Wen Jiang, Xiaoli Feng, Xiaoli Liu, Ai Li, Congcong Sun, Mingming He, Bingen Li, Juandong Wang, Yang Jiang, Chengyun Zheng.
      The plasma cell malignancy, multiple myeloma (MM), has significantly improved by the application of new drugs and autologous hematopoietic stem cell transplantation. However, MM remains incurable. A number of studies have revealed an anti-MM effect of natural killer (NK) cells; however, their clinical efficacy is limited. Furthermore, glycogen synthase kinase (GSK)-3β inhibitors show an antitumor function. In this study, we aimed to evaluate the potential roles of a GSK-3β inhibitor (TWS119) in the regulation of NK cell cytotoxicity against MM. Our results showed that, in the presence of TWS119, the NK cell line, NK-92, and in vitro-expanded primary NK cells exhibited a significantly higher degranulation activity, expression of activating receptors, cellular cytotoxicity, and cytokine secretion when they were exposed to MM cells. Mechanistic studies indicated that TWS119 treatment markedly upregulated RAB27A expression, a key molecule for NK cell degranulation, and induced the colocalization of β-catenin with NF-κB in the nucleus of NK cells. More importantly, GSK-3β inhibition combined with the adoptive transfer of TWS119-treated NK-92 cells significantly reduced tumor volume and prolonged the survival time of myeloma-bearing mice. In summary, our novel findings suggest that targeting GSK-3β through the activation of β-catenin/NF-κB pathway may be an important approach to improve therapeutic efficacy of NK cell transfusion for MM.
    Keywords:  GSK-3β; NF-κB; NK cells; immunotherapy; β-catenin
    DOI:  https://doi.org/10.1096/fj.202201658RR
  12. Phys Act Nutr. 2022 Dec;26(4): 1-4
    Exercise-brain interaction of neuroplasticity: empirical evidence in the rodent adaptation.
    Minchul Lee.
       PURPOSE: Exercise is gradually being recognized as an essential component of brain plasticity at the molecular, functional, and structural changes levels. What are the causes of the observed exercise reimbursements in neuroscience? Several types of exercises have been studied in various doses in neurological, physiological, psychological, and biochemical experiments. More clarity is required to reveal exercise-brain interactions such as optimal exercise condition variables and neuroplasticity.
    METHODS: This review briefly highlights the empirical evidence of the positive effects neuroprotective activity on neuroscientific advancement.
    RESULTS: The key areas are as follows: (a) stress exercise model using rodents, (b) hippocampal activation and plasticity with exercise, (c) glycogen metabolism in the brain, and (d) adaptation as a high-intensity interval training model in animals involved in exercise-induced brain plasticity.
    CONCLUSION: Overall, exercise-induced molecular, functional, and structural changes in the neuronal system may affect rodents' performance. This study emphasizes the significance of understanding exercise neuroscience and makes recommendations for future research.
    Keywords:  brain glycogen; exercise; hippocampus; neuronal plasticity; resistance wheel; stress
    DOI:  https://doi.org/10.20463/pan.2022.0018
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