bims-glecem Biomed News
on Glycogen metabolism in exercise, cancer and energy metabolism
Issue of 2023–07–16
ten papers selected by
Dipsikha Biswas, Københavns Universitet
  1. Glycogen-binding protein STBD1: Molecule and role in pathophysiology.
  2. Gene Therapy for Glycogen Storage Diseases.
  3. What the Lactate Shuttle Means for Sports Nutrition.
  4. Glycogen availability and pH variation in a medium simulating vaginal fluid influence the growth of vaginal Lactobacillus species and Gardnerella vaginalis.
  5. Computational Insights into Novel Inhibitor N-(3-(tert-Butylcarbamoyl)-4-methoxyphenyl)-indole and Ingliforib Specific against GP Isoenzyme Dimers Interaction Mechanism.
  6. Anesthetic Management of a Patient With McArdle Disease: A Case Report and Review of the Literature.
  7. BMP4 upregulates glycogen synthesis through the SMAD/SLC2A1 (GLUT1) signaling axis in hepatocellular carcinoma (HCC) cells.
  8. Alpha-1,4-transglycosylation Activity of GH57 Glycogen Branching Enzymes Is Higher in the Absence of a Flexible Loop with a Conserved Tyrosine Residue.
  9. GSK-3 Inhibitor Elraglusib Enhances Tumor-Infiltrating Immune Cell Activation in Tumor Biopsies and Synergizes with Anti-PD-L1 in a Murine Model of Colorectal Cancer.
  10. Inhibition of GSK3β activity alleviates acute liver failure via suppressing multiple programmed cell death.
  1. J Cell Physiol. 2023 Jul 12.
    Glycogen-binding protein STBD1: Molecule and role in pathophysiology.
    Qiannan Tang, Meiqing Liu, Hong Zhao, Linxi Chen.
      Starch-binding domain-containing protein 1 (STBD1) is a glycogen-binding protein discovered in skeletal muscle gene differential expression that is pivotal to cellular energy metabolism. Recent studies have indicated that STBD1 is involved in many physiological processes, such as glycophagy, glycogen accumulation, and lipid droplet formation. Moreover, dysregulation of STBD1 causes multiple diseases, including cardiovascular disease, metabolic disease, and even cancer. Deletions and/or mutations in STBD1 promote tumorigenesis. Therefore, STBD1 has garnered considerable interest in the pathology community. In this review, we first summarized the current understanding of STBD1, including its structure, subcellular localization, tissue distribution, and biological functions. Next, we examined the roles and molecular mechanisms of STBD1 in related diseases. Based on available research, we discussed the novel function and future of STBD1, including its potential application as a therapeutic target in glycogen-related diseases. Given the significance of STBD1 in energy metabolism, an in-depth understanding of the protein is crucial for understanding physiological processes and developing therapeutic strategies for related diseases.
    Keywords:  Pompe disease; STBD1; cancer; diabetic cardiomyopathy; glycophagy; ischemic myocardial injury
    DOI:  https://doi.org/10.1002/jcp.31078
  2. J Inherit Metab Dis. 2023 Jul 08.
    Gene Therapy for Glycogen Storage Diseases.
    Dwight D Koeberl, Rebecca L Koch, Jeong-A Lim, Elizabeth D Brooks, Benjamin D Arnson, Baodong Sun, Priya S Kishnani.
      Glycogen storage disorders (GSDs) are inherited disorders of metabolism resulting from the deficiency of individual enzymes involved in the synthesis, transport, and degradation of glycogen. This literature review summarizes the development of gene therapy for the GSDs. The abnormal accumulation of glycogen and deficiency of glucose production in GSDs lead to unique symptoms based upon the enzyme step and tissues involved, such as liver and kidney involvement associated with severe hypoglycemia during fasting and the risk of long-term complications including hepatic adenoma/carcinoma and end stage kidney disease in GSD Ia from glucose-6-phosphatase deficiency, and cardiac/skeletal/smooth muscle involvement associated with myopathy +/- cardiomyopathy and the risk for cardiorespiratory failure in Pompe disease. These symptoms are present to a variable degree in animal models for the GSDs, which have been utilized to evaluate new therapies including gene therapy and genome editing. Gene therapy for Pompe disease and GSD Ia has progressed to Phase I and Phase III clinical trials, respectively, and are evaluating the safety and bioactivity of adeno-associated virus vectors. Clinical research to understand the natural history and progression of the GSDs provides invaluable outcome measures that serve as endpoints to evaluate benefits in clinical trials. While promising, gene therapy and genome editing face challenges with regard to clinical implementation, including immune responses and toxicities that have been revealed during clinical trials of gene therapy that are underway. This article is protected by copyright. All rights reserved.
    Keywords:  Gene therapy; animal models; clinical trials; genome editing; glycogen storage disease
    DOI:  https://doi.org/10.1002/jimd.12654
  3. Nutrients. 2023 May 03. pii: 2178. [Epub ahead of print]15(9):
    What the Lactate Shuttle Means for Sports Nutrition.
    George A Brooks.
      The discovery of the lactate shuttle (LS) mechanism may have two opposite perceptions, It may mean very little, because the body normally and inexorably uses the LS mechanism. On the contrary, one may support the viewpoint that understanding the LS mechanism offers immense opportunities for understanding nutrition and metabolism in general, as well as in a sports nutrition supplementation setting. In fact, regardless of the specific form of the carbohydrate (CHO) nutrient taken, the bodily CHO energy flux is from a hexose sugar glucose or glucose polymer (glycogen and starches) to lactate with subsequent somatic tissue oxidation or storage as liver glycogen. In fact, because oxygen and lactate flow together through the circulation to sites of utilization, the bodily carbon energy flow is essentially the lactate disposal rate. Consequently, one can consume glucose or glucose polymers in various forms (glycogen, maltodextrin, potato, corn starch, and fructose or high-fructose corn syrup), and the intestinal wall, liver, integument, and active and inactive muscles make lactate which is the chief energy fuel for red skeletal muscle, heart, brain, erythrocytes, and kidneys. Therefore, if one wants to hasten the delivery of CHO energy delivery, instead of providing CHO foods, supplementation with lactate nutrient compounds can augment body energy flow.
    Keywords:  DKA; acid-base balance; blood buffer; energy; gluconeogenic precursor; glycolysis; lactate shuttle; lipolysis; mitochondrial reticulum; nutrient; oxidative phosphorylation
    DOI:  https://doi.org/10.3390/nu15092178
  4. BMC Microbiol. 2023 Jul 13. 23(1): 186
    Glycogen availability and pH variation in a medium simulating vaginal fluid influence the growth of vaginal Lactobacillus species and Gardnerella vaginalis.
    Stephany Navarro, Habib Abla, Betsaida Delgado, Jane A Colmer-Hamood, Gary Ventolini, Abdul N Hamood.
       BACKGROUND: Glycogen metabolism by Lactobacillus spp. that dominate the healthy vaginal microbiome contributes to a low vaginal pH (3.5-4.5). During bacterial vaginosis (BV), strict and facultative anaerobes including Gardnerella vaginalis become predominant, leading to an increase in the vaginal pH (> 4.5). BV enhances the risk of obstetrical complications, acquisition of sexually transmitted infections, and cervical cancer. Factors critical for the maintenance of the healthy vaginal microbiome or the transition to the BV microbiome are not well defined. Vaginal pH may affect glycogen metabolism by the vaginal microflora, thus influencing the shift in the vaginal microbiome.
    RESULTS: The medium simulating vaginal fluid (MSVF) supported growth of L. jensenii 62G, L. gasseri 63 AM, and L. crispatus JV-V01, and G. vaginalis JCP8151A at specific initial pH conditions for 30 d. L. jensenii at all three starting pH levels (pH 4.0, 4.5, and 5.0), G. vaginalis at pH 4.5 and 5.0, and L. gasseri at pH 5.0 exhibited the long-term stationary phase when grown in MSVF. L. gasseri at pH 4.5 and L. crispatus at pH 5.0 displayed an extended lag phase over 30 d suggesting inefficient glycogen metabolism. Glycogen was essential for the growth of L. jensenii, L. crispatus, and G. vaginalis; only L. gasseri was able to survive in MSVF without glycogen, and only at pH 5.0, where it used glucose. All four species were able to survive for 15 d in MSVF with half the glycogen content but only at specific starting pH levels - pH 4.5 and 5.0 for L. jensenii, L. gasseri, and G. vaginalis and pH 5.0 for L. crispatus.
    CONCLUSIONS: These results suggest that variations in the vaginal pH critically influence the colonization of the vaginal tract by lactobacilli and G. vaginalis JCP8151A by affecting their ability to metabolize glycogen. Further, we found that L. jensenii 62G is capable of glycogen metabolism over a broader pH range (4.0-5.0) while L. crispatus JV-V01 glycogen utilization is pH sensitive (only functional at pH 5.0). Finally, our results showed that G. vaginalis JCP8151A can colonize the vaginal tract for an extended period as long as the pH remains at 4.5 or above.
    Keywords:  Gardnerella vaginalis; Glucose; Glycogen; Lactobacillus crispatus; Lactobacillus gasseri; Lactobacillus jensenii; Medium simulating vaginal fluid; pH
    DOI:  https://doi.org/10.1186/s12866-023-02916-8
  5. Molecules. 2023 Jun 22. pii: 4909. [Epub ahead of print]28(13):
    Computational Insights into Novel Inhibitor N-(3-(tert-Butylcarbamoyl)-4-methoxyphenyl)-indole and Ingliforib Specific against GP Isoenzyme Dimers Interaction Mechanism.
    Youde Wang, Shuai Li, Zhiwei Yan, Liying Zhang.
      The high conservation of the three subtypes of glycogen phosphorylase (GP) presents significant challenges for specific inhibitor studies targeting GP. Our prior screening revealed that compound 1 exhibited unequal inhibitory activity against the three GP subtypes, with a noticeable effect against brain GP (PYGB). The commercially available ingliforib demonstrated potent inhibitory activity specifically against liver GP (PYGL). To guide the further design and screening of high-specificity inhibitors, the possible reasons for the differential inhibitory activity of two compounds against different GP subtypes were analyzed, with ingliforib as a reference, through molecular docking and molecular dynamics simulations. Initially, the study predicted the binding modes of ligands with the three GP receptor subtypes using molecular docking. Subsequently, this was validated by molecular dynamics experiments, and possible amino acid residues that had important interactions were explored. The strong correlation between the calculated interaction free energies and experimental inhibitory activity implied the reasonable binding conformations of the compounds. These findings offer insight into the different inhibitory activity of compound 1 and ingliforib against all three GP subtypes and provide guidance for the design of specific target molecules that regulate subtype selectivity.
    Keywords:  GP subtype molecular docking; N-(3-(tert-butylcarbamoyl)-4-methoxyphenyl)-indole; glycogen phosphorylase; ingliforib; molecular dynamics
    DOI:  https://doi.org/10.3390/molecules28134909
  6. Cureus. 2023 Jun;15(6): e40092
    Anesthetic Management of a Patient With McArdle Disease: A Case Report and Review of the Literature.
    Rohini Kotha, Anastasia Jones, Gregory T Girgenti, Daniel A Nahrwold.
      McArdle disease (glycogen storage disorder type V) is a rare inherited condition resulting in impaired energy metabolism. Challenges in anesthetized patients with McArdle disease include hypoglycemia, rhabdomyolysis, myoglobinuria, acute renal failure, and postoperative fatigue. We review the literature and discuss a successful anesthetic that had no perioperative complications for a patient with McArdle disease undergoing robotic-assisted lung wedge resection. Preoperatively, we obtained a complete blood count, chemistry panel, and creatine kinase level. Intraoperatively, we proceeded with general endotracheal anesthesia and monitored point-of-care electrolytes, hemoglobin, and blood glucose. The patient had an uneventful postoperative recovery and was discharged home on postoperative Day 3. Patients with McArdle disease can undergo safe surgery with appropriate perioperative planning and a well-managed anesthetic. Efforts should focus on mitigating the risks of hypoglycemia, rhabdomyolysis, myoglobinuria, acute renal failure, and postoperative fatigue.
    Keywords:  acute renal failure; general anesthesia; glycogen storage disorder type v; hypoglycemia; malignant hyperthermia; mcardle disease; myoglobinuria; postoperative fatigue; rhabdomyolysis
    DOI:  https://doi.org/10.7759/cureus.40092
  7. Cancer Metab. 2023 Jul 13. 11(1): 9
    BMP4 upregulates glycogen synthesis through the SMAD/SLC2A1 (GLUT1) signaling axis in hepatocellular carcinoma (HCC) cells.
    Jiamin Zhong, Luyao Tian, Yannian Gou, Piao Zhao, Xiangyu Dong, Meichun Guo, Guozhi Zhao, Aohua Li, Ailing Hao, Tong-Chuan He, Jiaming Fan.
       BACKGROUND: Excessive hepatic glycogen accumulation benefits tumorigenesis and cancer cell survival. We previously reported that BMP4 has the strongest ability to promote glycogenesis among the 14 BMPs in hepatocytes and augmented hepatocellular carcinoma (HCC) cell survival under hypoxia and hypoglycemia conditions by promoting the glycolysis pathway. However, the mechanism underlying BMP4's effect on glycogenesis in HCC remains elusive.
    METHODS: The expression of BMP4 and SLC2A1 were acquired by analyzing the TCGA-LIHC dataset, as well as by immunohistochemical analysis of the 40 pairs of human HCC samples and para-tumor tissues. Gene expressions were detected by qPCR, immunoflurorescence staining, and Western blotting. Overexpression and silencing of BMP4 were accomplished through adenoviruses Ad-B4 and Ad-siB4 infection. Hepatic glycogen was detected by PAS staining. SLC2A1 (GLUT1) function was blocked by the inhibitor BAY-876. ChIP assay was used to determine the binding of SMADs to the promoter region of SLC2A1 in HCC cells. Lastly, the in vivo effect of BMP4-regulated SLC2A1 on HCC tumor growth was assessed in a xenograft model of HCC.
    RESULTS: The elevated expression of BMP4 in HCC tumor tissues was highly correlated with hepatic glycogen accumulation in clinical samples. SLC2A1 was highly expressed in HCC tumor tissue and correlated with clinical stage and prognosis. Exogenous BMP4 augmented glycogen accumulation and upregulated the expression of glycogen synthesis-related genes in Huh7 and HepG2 cells, both of which were effectively blunted by SLC2A1inhibitor BAY-876. In mechanism, BMP4 activated SMAD5 to regulate the promoter of SLC2A1to enhance its expression. The in vivo xenograft experiments revealed that BMP4 promoted glycogen accumulation and tumor growth, which were effectively diminished by BAY-876.
    CONCLUSION: These results demonstrate that BMP4 upregulates glycogen synthesis through the SMAD/SLC2A1 (GLUT1) signaling axis in HCC cells, which may be exploited as novel therapeutic targets for HCC treatment.
    Keywords:  BMP4; Glycogen synthesis; HCC; SLC2A1; Smad signal pathway
    DOI:  https://doi.org/10.1186/s40170-023-00310-6
  8. Polymers (Basel). 2023 Jun 22. pii: 2777. [Epub ahead of print]15(13):
    Alpha-1,4-transglycosylation Activity of GH57 Glycogen Branching Enzymes Is Higher in the Absence of a Flexible Loop with a Conserved Tyrosine Residue.
    Hilda Hubertha Maria Bax, Marc Jos Elise Cornelis van der Maarel, Edita Jurak.
      Starch-like polymers can be created through the use of enzymatic modification with glycogen branching enzymes (GBEs). GBEs are categorized in the glycoside hydrolase (GH) family 13 and 57. Both GH13 and GH57 GBEs exhibit branching and hydrolytic activity. While GH13 GBEs are also capable of α-1,4-transglycosylation, it is yet unknown whether GH57 share this capability. Among the four crystal structures of GH57 GBEs that have been solved, a flexible loop with a conserved tyrosine was identified to play a role in the branching activity. However, it remains unclear whether this flexible loop is also involved in α-1,4-transglycosylation activity. We hypothesize that GH57 GBEs with the flexible loop and tyrosine are also capable of α-1,4-transglycosylation, similar to GH13 GBEs. The aim of the present study was to characterize the activity of GH57 GBEs to investigate a possible α-1,4-transglycosylation activity. Three GH57 GBEs were selected, one from Thermococcus kodakarensis with the flexible loop and two beta-strands; one from Thermotoga maritima, missing the flexible loop and beta-strands; and one from Meiothermus sp., missing the flexible loop but with the two beta-strands. The analysis of chain length distribution over time of modified maltooctadecaose, revealed, for the first time, that all three GH57 GBEs can generate chains longer than the substrate itself, showing that α-1,4-transglycosylation activity is generally present in GH57 GBEs.
    Keywords:  alpha-1,4-transglycosylation; flexible loop; glycogen branching enzyme
    DOI:  https://doi.org/10.3390/polym15132777
  9. Int J Mol Sci. 2023 Jun 29. pii: 10870. [Epub ahead of print]24(13):
    GSK-3 Inhibitor Elraglusib Enhances Tumor-Infiltrating Immune Cell Activation in Tumor Biopsies and Synergizes with Anti-PD-L1 in a Murine Model of Colorectal Cancer.
    Kelsey E Huntington, Anna D Louie, Praveen R Srinivasan, Christoph Schorl, Shaolei Lu, David Silverberg, Daniel Newhouse, Zhijin Wu, Lanlan Zhou, Brittany A Borden, Francis J Giles, Mark Dooner, Benedito A Carneiro, Wafik S El-Deiry.
      Glycogen synthase kinase-3 (GSK-3) is a serine/threonine kinase that has been implicated in numerous oncogenic processes. GSK-3 inhibitor elraglusib (9-ING-41) has shown promising preclinical and clinical antitumor activity across multiple tumor types. Despite promising early-phase clinical trial results, there have been limited efforts to characterize the potential immunomodulatory properties of elraglusib. We report that elraglusib promotes immune cell-mediated tumor cell killing of microsatellite stable colorectal cancer (CRC) cells. Mechanistically, elraglusib sensitized CRC cells to immune-mediated cytotoxicity and enhanced immune cell effector function. Using western blots, we found that elraglusib decreased CRC cell expression of NF-κB p65 and several survival proteins. Using microarrays, we discovered that elraglusib upregulated the expression of proapoptotic and antiproliferative genes and downregulated the expression of cell proliferation, cell cycle progression, metastasis, TGFβ signaling, and anti-apoptotic genes in CRC cells. Elraglusib reduced CRC cell production of immunosuppressive molecules such as VEGF, GDF-15, and sPD-L1. Elraglusib increased immune cell IFN-γ secretion, which upregulated CRC cell gasdermin B expression to potentially enhance pyroptosis. Elraglusib enhanced immune effector function resulting in augmented granzyme B, IFN-γ, TNF-α, and TRAIL production. Using a syngeneic, immunocompetent murine model of microsatellite stable CRC, we evaluated elraglusib as a single agent or combined with immune checkpoint blockade (anti-PD-1/L1) and observed improved survival in the elraglusib and anti-PD-L1 group. Murine responders had increased tumor-infiltrating T cells, augmented granzyme B expression, and fewer regulatory T cells. Murine responders had reduced immunosuppressive (VEGF, VEGFR2) and elevated immunostimulatory (GM-CSF, IL-12p70) cytokine plasma concentrations. To determine the clinical significance, we then utilized elraglusib-treated patient plasma samples and found that reduced VEGF and BAFF and elevated IL-1 beta, CCL22, and CCL4 concentrations correlated with improved survival. Using paired tumor biopsies, we found that tumor-infiltrating immune cells had a reduced expression of inhibitory immune checkpoints (VISTA, PD-1, PD-L2) and an elevated expression of T-cell activation markers (CTLA-4, OX40L) after elraglusib treatment. These results address a significant gap in knowledge concerning the immunomodulatory mechanisms of GSK-3 inhibitor elraglusib, provide a rationale for the clinical evaluation of elraglusib in combination with immune checkpoint blockade, and are expected to have an impact on additional tumor types, besides CRC.
    Keywords:  9-ING-41; GSK-3; elraglusib; immune checkpoint blockade; immunotherapy
    DOI:  https://doi.org/10.3390/ijms241310870
  10. J Inflamm (Lond). 2023 Jul 13. 20(1): 24
    Inhibition of GSK3β activity alleviates acute liver failure via suppressing multiple programmed cell death.
    Danmei Zhang, Chunxia Shi, Qingqi Zhang, Yukun Wang, Jin Guo, Zuojiong Gong.
       BACKGROUND: Acute liver failure (ALF) is one of the most common life-threatening diseases in adults without previous liver disease. Glycogen synthase kinase 3β (GSK3β) is a serine/threonine protein kinase that is widely distributed in the cells. Inhibition of its activity can inhibit cell death and promote autophagy through various pathways, thus providing a protective effect. In this study, we aimed to investigate the effect on ALF after inhibition of GSK3β and its potential mechanisms.
    METHODS: D- galactosamine(D-Gal) in combination with lipopolysaccharide(LPS) was used to induce ALF in vitro and in vivo. And then GSK3β inhibitor TDZD-8 was used to explore the protective effect against ALF. After TDZD-8 treatment TUNEL staining and flow techniques were used to detect the proportion of apoptosis in liver tissues and cells respectively, while western blotting and immunofluorescence assays were performed to detect the expression levels of apoptosis, pyroptosis and necroptosis-related proteins in tissues and cells. In addition, western blotting was performed to explore the specific mechanism of hepatoprotective effect after GSK3β inhibition to detect the expression levels of TAK1, TRAF6 and HDAC3 after TRAF6 and HDAC3 inhibition alone. The co-localization of TRAF6 and HDAC3 in vitro was detected by immunofluorescence, while the interaction between TRAF6 and HDAC3 was detected by immunoprecipitation assay.
    RESULTS: Both in vivo and in vitro experiments, GSK3β inhibitor TDZD-8 can significantly alleviate the progression of ALF. Inhibition of GSK3β activity could significantly reduce the level of hepatocyte apoptosis, pyroptosis, necroptosis and improve liver dysfunction and tissue damage. Furthermore, we found that hepatocyte TAK1 and TRAF6 levels decreased and HDAC3 levels increased in ALF, whereas inhibition of GSK3β upregulated TAK1 and TRAF6 levels and decreased HDAC3 expression.
    CONCLUSION: GSK3β inhibitor TDZD-8 can prevent the progression of ALF, and its action may involve the TRAF6/HDAC3/TAK1 pathway.
    Keywords:  Acute liver failure; GSK3β; HDAC3; Programmed cell death; TAK1; TRAF6
    DOI:  https://doi.org/10.1186/s12950-023-00350-1
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