bims-glecem 2022-03-20 papers

bims-glecem

Biomed News

on Glycogen metabolism in exercise, cancer and energy metabolism

Issue of 2022‒03‒20
eleven papers selected by
Dipsikha Biswas, Københavns Universitet

MYCT1 alters the glycogen shunt by regulating selective translation of RACK1-mediated enzymes.
Live isolation of naïve ESCs via distinct glucose metabolism and stored glycogen.
Lipid-storage myopathy with glycogen storage disease gene mutations mimicking polymyositis: a case report and review of the literature.
PET imaging of glycogen synthase kinase-3 in pancreatic cancer xenograft mouse models.
Glycogen synthase kinase GSK3α promotes tumorigenesis by activating HIF1/VEGFA signaling pathway in NSCLC tumor.
One-step synthesis of glycogen-type polysaccharides from maltooctaose and its structural characteristics.
Oakmoss Exhibits Antihyperglycemic Activity in Streptozotocin-Induced Diabetic Rats.
Empagliflozin Inhibits Hepatic Gluconeogenesis and Increases Glycogen Synthesis by AMPK/CREB/GSK3β Signalling Pathway.
Mitochondrial depletion of glutaredoxin 2 induces metabolic dysfunction-associated fatty liver disease in mice.
GSK3 inhibition circumvents and overcomes acquired lorlatinib resistance in ALK-rearranged non-small-cell lung cancer.
Recent Trends in the Incidence of Clear Cell Adenocarcinoma and Survival Outcomes: A SEER Analysis.

iScience. 2022 Mar 18. 25(3): 103955

MYCT1 alters the glycogen shunt by regulating selective translation of RACK1-mediated enzymes.

Dong-Xue Ding, Yue Wang, Wei Yan, Wei-Neng Fu.

  MYCT1 has been shown to function as a tumor suppressor in various tumors, but its role in metabolism has never been reported. Here, we showed that global inactivation of Myct1 in mice led to progressive accumulation of glycogen in the liver, which was accompanied by aberrant changes in intermediates of the glycogen metabolic pathway. Mechanistically, MYCT1 appeared to promote translation efficiency of PGM1, UGP2 and GSK3A in hepatic cells in a RACK1-dependent manner. Consequently, upregulation of the three enzymes enhanced the glycogen shunt. Our data reveal a critical role of MYCT1 as a switch for the glycogen shunt in tumor cells.

Keywords:  Animal physiology; Molecular biology; Physiology

DOI:  https://doi.org/10.1016/j.isci.2022.103955
Metab Eng. 2022 Mar 10. pii: S1096-7176(22)00039-8. [Epub ahead of print]72 97-106

Live isolation of naïve ESCs via distinct glucose metabolism and stored glycogen.

Keun-Tae Kim, Ji-Young Oh, Seokwoo Park, Seong-Min Kim, Patterson Benjamin, In-Hyun Park, Kwang-Hoon Chun, Young-Tae Chang, Hyuk-Jin Cha.

  Naïve and primed pluripotent stem cells recapitulate the peri- and post-implantation development, respectively. Thus, investigation of distinct traits between each pluripotent stem cell type would shed light on early embryonic processes. Herein, by screening a fluorescent probe library, we found that intracellular glycogen led to specific reactivity to CDg4, a glycogen fluorescence sensor, in both human and mouse naïve embryonic stem cells (ESCs). The requirement of constant inhibition of Gsk3β as well as high oxidative phosphorylation (OxPHOS) in naïve compared to primed ESCs was closely associated to high level of intracellular glycogen in naïve ESCs. Both capacity of OxPHOS and stored glycogen, rescued naïve ESCs by transient inhibition of glycolysis, which selectively eliminated primed ESCs. Additionally, naïve ESCs with active OxPHOS were enriched from a mixture with primed ESCs by high reactivity to ATP-Red1, a mitochondrial ATP fluorescence probe. These results indicate the active OxPHOS and high intracellular glycogen as a novel "biomarker" delineating metabolic remodeling during the transition of naïve pluripotency.

Keywords:  Glucose metabolism; Glycogen; Mitochondrial ATP; Naïve pluripotency; Primed pluripotency

DOI:  https://doi.org/10.1016/j.ymben.2022.03.003
J Int Med Res. 2022 Mar;50(3): 3000605221084873

Lipid-storage myopathy with glycogen storage disease gene mutations mimicking polymyositis: a case report and review of the literature.

Xiaoli Pan, Yuan Yuan, Bangcui Wu, Wendan Zheng, Mei Tian.

  A 26-year-old Asian woman with persistent muscle weakness was diagnosed with polymyositis based on biopsy findings at another hospital 11 years ago. However, her symptoms fluctuated repeatedly under treatment with prednisone and immunosuppressive agents, and worsened 2 months prior to the current presentation. A second muscle biopsy suggested metabolic myopathy, and genetic testing revealed a novel c.1074C > T variant in the glycogen synthase 1 gene (GYS1), which is implicated in muscle glycogen storage disease type 0. However, no abnormalities in glycogen deposition were found by biopsy; rather, muscle fibers exhibited large intracellular lipid droplets. Furthermore, muscle strength was greatly restored and circulating levels of creatine kinase indicative of muscle degeneration greatly reduced by vitamin B2 treatment. Therefore, the final diagnosis was lipid storage myopathy.

Keywords:  GYS1; Lipid storage myopathy; case report; glycogen storage disease type 0; polymyositis muscle; vitamin B2

DOI:  https://doi.org/10.1177/03000605221084873
Am J Nucl Med Mol Imaging. 2022 ;12(1): 1-14

PET imaging of glycogen synthase kinase-3 in pancreatic cancer xenograft mouse models.

Amanda J Boyle, Andrea Narvaez, Melissa Chassé, Neil Vasdev.

Glycogen synthase kinase-3 (GSK-3) contributes to tumorigenesis in pancreatic cancer by modulating cell proliferation and survival. This study evaluated the lead GSK-3 targeted PET radiotracers for neuro-PET imaging, [11C]PF-367 and [11C]OCM-44, in pancreatic cancer xenograft mice. Immunohistochemistry showed that GSK-3α and GSK-3β were overexpressed in PANC-1 xenografts. In autoradiography studies, higher specific binding was observed for [3H]PF-367 compared to [3H]OCM-44 when co-incubated with unlabeled PF-367 (59.2±1.8% vs 22.6±3.75%, respectively). Co-incubation of [11C]OCM-44 with OCM-44 did not improve the specific binding (25.5±30.2%). In dynamic PET imaging of PANC-1 xenograft mouse models, tumors were not visualized with [11C]PF-367 but were well visualized with [11C]OCM-44. Time-activity curves revealed no difference in accumulation in PANC-1 tumor tissue compared to muscle tissue in [11C]PF-367 baseline studies, while a significant difference was observed for [11C]OCM-44 with a tumor-to-muscle ratio of 1.6. Tumor radioactivity accumulation following injection with [11C]OCM-44 was not displaced by pre-treatment with unlabeled PF-367. Radiometabolite analysis showed that intact [11C]PF-367 accounted for 7.5% of tumor radioactivity, with >30% in plasma, at 40 min post-injection of the radiotracer, and that intact [11C]OCM-44 accounted for 20% of tumor radioactivity, with >60% in plasma. [11C]OCM-44 is superior to [11C]PF-367 for detecting lesions in preclinical mouse models of pancreatic cancer, however, both radiotracers undergo rapid metabolism in vivo. GSK-3 PET radiotracers with improved in vivo stability are needed for clinical translation. To our knowledge this work represents the first PET imaging study of GSK-3 in oncology.

Keywords: GSK-3; Glycogen synthase kinase-3; PET; carbon-11; oncology; pancreatic cancer
Cell Commun Signal. 2022 Mar 15. 20(1): 32

Glycogen synthase kinase GSK3α promotes tumorigenesis by activating HIF1/VEGFA signaling pathway in NSCLC tumor.

Xiaonian Cao, Wei Wu, Dao Wang, Wei Sun, Senyan Lai.

  BACKGROUND: Lung cancer is one of the most common cancers and the leading cause of cancer-related death. Glycogen synthase kinase-3 (GSK-3) α, a member of the glycogen synthase kinase-3 family, reportedly plays a role in tumorigenesis. However, its biological function in tumorigenesis requires deeper exploration. Hypoxia is a major feature of solid tumor, along with decreasing availability of oxygen, inducing treatment resistance, and tumor progress.METHODS: Levels of GSK3α expression in clinical samples were detected using western blot and IHC assays, while its biological function and underlying mechanism of action in tumor progression were investigated using western blot, CCK8, cell cycle, colony formation, Transwell, ELISA and tube formation assays. Furthermore, we investigated the relationship between GSK3α expression and the HIF1α/VEGFA signaling pathway in vivo using a mouse xenograft model.
RESULTS: GSK3α was significantly upregulated in NSCLC patients with cases that exhibited high GSK3α levels recording shorter survival times. Moreover, GSK3α overexpression promoted proliferation, migration, invasion and clone formation ability of NSCLC cells, while its silencing resulted in an opposite phenomenon. Moreover, GSK3α not only activated the HIF1α/VEGFA signaling pathway, but also regulated HIF1α stabilization independently via the PHDs-pVHL signaling pathway. Moreover, GSK3α-mediated tumor angiogenesis depended on HIF1α expression both in vitro and in vivo.
CONCLUSION: GSK3α functioned as an oncogene in NSCLC tumorigenesis by regulating the HIF1/VEGFA signaling pathway in an independent manner through the PHDs-pVHL signaling pathway. These findings were expected to provide novel sights to guide future development of therapies for effective treatment of NSCLC. Video abstract.

Keywords:  GSK3α; HIF1α; Tumor angiogenesis

DOI:  https://doi.org/10.1186/s12964-022-00825-3
Carbohydr Polym. 2022 May 15. pii: S0144-8617(22)00079-0. [Epub ahead of print]284 119175

One-step synthesis of glycogen-type polysaccharides from maltooctaose and its structural characteristics.

Phuong Lan Tran, Yan An, Goo-Yeong Jeong, So-Young Ban, Phu Cuong Nguyen, Euijeon Woo, SangGuan You, Jong-Tae Park.

  The one-step synthesis of glycogen-type polysaccharides from maltooctaose (G8) was accomplished based on the new findings of the catalytic mechanism of glycogen branching enzymes (GBEs) from Vibrio vulnificus, Deinococcus geothermalis, and Escherichia coli. GBEs from D. geothermalis and E. coli used maltononaose and maltotridecaose as the minimum, respectively, while V. vulnificus GBE (VvGBE) catalyzed the surprisingly small substrate, G8, into polysaccharides. Intriguingly, all three GBEs catalyzed α-1,4-transglycosylation at the early reaction stage of transglycosylation. VvGBE successfully converted the smallest substrate (G8) into two highly branched polysaccharides (HBP), in which the big polysaccharide (1.49 × 105 Da) exhibited structural properties similar to glycogen. Both HBPs had similar side chain distribution with a very short average degree of polymerization compared with mussel glycogen. As a molecular biology reagent, these nucleotide-free HBPs significantly increased the mRNA extraction efficiency of mammalian cells. Our results provide a new approach to the synthesis of novel polysaccharides.

Keywords:  Glycogen branching enzyme; Glycogen-type polysaccharide; Maltooctaose; Polysaccharide synthesis; α-1,4-Transglycosylation

DOI:  https://doi.org/10.1016/j.carbpol.2022.119175
Cardiovasc Hematol Disord Drug Targets. 2022 Mar 16.

Oakmoss Exhibits Antihyperglycemic Activity in Streptozotocin-Induced Diabetic Rats.

Ayoub Amssayef, Ismail Bouadid, Mohamed Eddouks.

  AIMS: The study aimed to assess the antidiabetic effect of Oakmoss.BACKGROUND: Lichens species are dual organisms consisting of a mycobiont (Fungi) and a photoautotrophic partner (Algae). They are widely used in traditional medicine as a treatment against diabetes.
OBJECTIVE: This study was designed to assess the antihyperglycemic activity as well as the antihyperlipidemic capacity of Oakmoss (Evernia prunastri (L.)) in normal and streptozotocin(STZ)-induced diabetic rats.
METHODS: This study has evaluated the effects of aqueous extract of Oakmoss at a dose of 60 mg/kg on blood glucose levels and lipid profile in normal and STZ-induced diabetic rats. Histopathological examination of liver, determination of glycogen content in liver and skeletal muscles (EDL and soleus), antioxidant activity, and phytochemical investigation were also performed.
RESULTS: Both single and repeated oral doses of Oakmoss (60 mg/kg) produced a significant reduction of blood glucose, triglycerides and very low-density lipoprotein (VLDL) levels in diabetic rats. Furthermore, repeated oral administration of Oakmoss during 7 days ameliorated the liver function by increasing its glycogen content and improving its histological architecture in treated diabetic rats. In addition, the aqueous extract of Oakmoss exhibited an antioxidant activity and showed richness in certain phytochemicals especially in phenolic acids and flavonoids.
CONCLUSION: Oakmoss, a lichen species, exhibits a potential effect on improving hyperglycemia and hypertriglyceridemia in diabetic rats.

Keywords:  Diabetic rats; Glycogen; Hyperglycemia; Hypertriglyceridemia; Oakmoss.; Streptozotocin

DOI:  https://doi.org/10.2174/1871529X22666220316100022
Front Physiol. 2022 ;13 817542

Empagliflozin Inhibits Hepatic Gluconeogenesis and Increases Glycogen Synthesis by AMPK/CREB/GSK3β Signalling Pathway.

Xiaochen Yu, Ziyu Meng, Ting Fang, Xiaohuan Liu, Ying Cheng, Linxin Xu, Xiangyang Liu, Xiaoyu Li, Mei Xue, Ting Li, Bei Sun, Liming Chen.

  Increases in glucose production and decreases in hepatic glycogen storage induce glucose metabolic abnormalities in type 2 diabetes (T2DM). Empagliflozin, a sodium-dependent glucose transporter 2 (SGLT2) inhibitor, is an effective hypoglycemic drug; however, the effects of empagliflozin on hepatic gluconeogenesis and glycogenesis are still unclear. In this study, we investigated the effects and mechanisms of empagliflozin on hepatic gluconeogenesis and glycogenesis in vivo and in vitro. Empagliflozin was administered via gavage to db/db mice for 8 weeks, and human hepatocyte HL7702 cells were treated with empagliflozin after palmitic acid (PA) stimulation. Compared with the control db/db mice, empagliflozin-treated mice showed a significant reduction in urine glucose levels, blood glucose levels, body weight and intraperitoneal glucose tolerance test (IPGTT) blood glucose levels. Moreover, the expression levels and activities of key gluconeogenesis enzymes PEPCK and G6Pase were dramatically reduced in the empagliflozin-treated mice, and the protein expression levels of AMPK/CREB/GSK3β signalling pathway-related molecules were significantly changed. In HL7702 cells, empagliflozin ameliorated glucose production and PEPCK and G6Pase expression and activity. Empagliflozin could also prevent the decreases in glycogen content and regulate the protein expression levels of AMPK/CREB/GSK3β signalling pathway-related molecules. Then, we selected the AMPK agonist AICAR and inhibitor compound C to further verify the effects of the AMPK signalling pathway on hepatic gluconeogenesis and glycogen synthesis. The results of the 5-Aminoimidazole-4-carboxamide1-β-D-ribofuranoside (AIACR) intervention in HL7702 cells were consistent with those of empagliflozin treatment, and the effects of empagliflozin were abolished by compound C. In summary, empagliflozin could maintain glucose homoeostasis by reducing gluconeogenesis and increasing glycogenesis through the AMPK/CREB/GSK3β signalling pathway.

Keywords:  AMPK/CREB/GSK3β signalling pathway; SGLT2 inhibitor; empagliflozin; gluconeogenesis; glycogenesis

DOI:  https://doi.org/10.3389/fphys.2022.817542
Redox Biol. 2022 Mar 02. pii: S2213-2317(22)00049-0. [Epub ahead of print]51 102277

Mitochondrial depletion of glutaredoxin 2 induces metabolic dysfunction-associated fatty liver disease in mice.

Valeria Scalcon, Alessandra Folda, Maria Giovanna Lupo, Federica Tonolo, Naixuan Pei, Ilaria Battisti, Nicola Ferri, Giorgio Arrigoni, Alberto Bindoli, Arne Holmgren, Lucia Coppo, Maria Pia Rigobello.

  Glutaredoxin 2 (Grx2) is a glutathione-dependent oxidoreductase that facilitates glutathionylation/de-glutathionylation of target proteins. The main variants of Grx2 are the mitochondrial Grx2a and the cytosolic Grx2c. The aim of this study was to investigate the specific role of mitochondrial Grx2 in vivo using a mitochondrial Grx2 depleted (mGD) mouse model. mGD mice displayed an altered mitochondrial morphology and functioning. Furthermore, the lack of Grx2 in the mitochondrial compartment is responsible for increased blood lipid levels under a normal diet, a metabolic dysfunction-associated fatty liver disease (MAFLD) phenotype and a decreased glycogen storage capacity. In addition, depleting Grx2a leads to an alteration in abundance and in glutathionylation pattern of different mitochondrial enzymes, highlighting the selective role of Grx2 in the regulation of metabolic pathways. Overall, our findings identify the involvement of mitochondrial Grx2a in the regulation of cell metabolism and highlight a previously unknown association between Grx2 and MAFLD.

Keywords:  Glutaredoxin 2; Lipid metabolism; MAFLD; Mitochondria; Mouse model; ROS production

DOI:  https://doi.org/10.1016/j.redox.2022.102277
NPJ Precis Oncol. 2022 Mar 17. 6(1): 16

GSK3 inhibition circumvents and overcomes acquired lorlatinib resistance in ALK-rearranged non-small-cell lung cancer.

Yuki Shimizu, Koutaroh Okada, Jun Adachi, Yuichi Abe, Ryohei Narumi, Ken Uchibori, Noriko Yanagitani, Sumie Koike, Satoshi Takagi, Makoto Nishio, Naoya Fujita, Ryohei Katayama.

Anaplastic lymphoma kinase (ALK) fusion is found in ~3%-5% of patients with non-small-cell lung cancers (NSCLCs). Although the third-generation ALK tyrosine kinase inhibitor (TKI) lorlatinib shows high clinical efficacy in ALK-positive NSCLC, most of the patients eventually relapse with acquired resistance. Recently, drug-tolerant persister (DTP) cells have been considered an important seed of acquired resistance cells. In this study, we established lorlatinib intermediate resistant cells from a patient-derived cell model. Glycogen synthase kinase 3 (GSK3) inhibitions significantly suppressed lorlatinib intermediate resistant cell growth. GSK3 inhibition also sensitized acquired resistance cells derived from alectinib-treated patients with or without secondary mutations to lorlatinib. Therefore, GSK3 plays a crucial role in developing acquired resistance against lorlatinib in ALK-positive NSCLC mediated by lorlatinib intermediate resistant cells and could be a potential molecular target to prevent acquired lorlatinib resistance and overcome ALK-TKI resistance.

DOI: https://doi.org/10.1038/s41698-022-00260-0
Front Endocrinol (Lausanne). 2022 ;13 762589

Recent Trends in the Incidence of Clear Cell Adenocarcinoma and Survival Outcomes: A SEER Analysis.

Yadong Guo, Anil Shrestha, Niraj Maskey, Xiaohui Dong, Zongtai Zheng, Fuhan Yang, Ruiliang Wang, Wenchao Ma, Ji Liu, Cheng Li, Wentao Zhang, Shiyu Mao, Aihong Zhang, Shenghua Liu, Xudong Yao.

  Background: Clear cell adenocarcinoma (CCA) is considered a relatively rare tumor with a glycogen-rich phenotype. The prognosis of CCA patients is unclear. In this study, recent trends in the epidemiological and prognostic factors of CCA were comprehensively investigated.Methods: Patients with CCA from years 2000 to 2016 were identified from the Surveillance, Epidemiological, and End Results (SEER) database. Relevant population data were used to analyze the rates age-adjusted incidence, age-standardized 3-year and 5-year relative survivals, and overall survival (OS).
Results: The age-adjusted incidence of CCA increased 2.7-fold from the year 2000 (3.3/100,000) to 2016 (8.8/100,000). This increase occurred across all ages, races, stages, and grades. Of all these subgroups, the increase was largest in the grade IV group. The age-standardized 3-year and 5-year relative survivals increased during this study period, rising by 9.1% and 9.5% from 2000 to 2011, respectively. Among all the stages and grades, the relative survival increase was greatest in the grade IV group. According to multivariate analysis of all CCA patients, predictors of OS were: age, gender, year of diagnosis, marital status, race, grade, stage, and primary tumor site (P < 0.001). The OS of all CCA patients during the period 2008 to 2016 was significantly higher than that from 2000 to 2007 (P < 0.001).
Conclusions: The incidence of CCA and survival of these patients improved over time. In particular, the highest increases were reported for grade IV CCA, which may be due to an earlier diagnosis and improved treatment.

Keywords:  SEER database; clear cell adenocarcinoma; glycogen-rich phenotype; incidence; survival

DOI:  https://doi.org/10.3389/fendo.2022.762589