bims-glecem 2023-04-16 papers

bims-glecem

Biomed News

on Glycogen metabolism in exercise, cancer and energy metabolism

Issue of 2023–04–16
eleven papers selected by
Dipsikha Biswas, Københavns Universitet

Design and Synthesis of 3-(β-d-Glucopyranosyl)-4-amino/4-guanidino Pyrazole Derivatives and Analysis of Their Glycogen Phosphorylase Inhibitory Potential.
A quantitative analysis method for a new glycogen synthase kinase - 3 inhibitor and its pharmacokinetics in rats.
The Liver and Glycogen: In Sickness and in Health.
Novel AGL variants in a patient with glycogen storage disease type IIIb and pulmonary hypertension caused by pulmonary veno-occlusive disease: A case report.
Estimation of Health Utility Scores for Glycogen Storage Disease Type Ia.
Tumor-targeted glycogen nanoparticles loaded with hemin and glucose oxidase to promote tumor synergistic therapy.
Advances in the Therapeutic Potential of Inhibitors Targeting Glycogen Synthase Kinase 3 in Inflammatory Diseases.
Hepatic IDH2 regulates glycolysis and gluconeogenesis.
Exercise training impacts skeletal muscle remodelling induced by metabolic syndrome in ZSF1 rats through metabolism regulation.
The role of ChREBP in carbohydrate sensing and NAFLD development.
Can muscle typology explain the inter-individual variability in resistance training adaptations?

Molecules. 2023 Mar 28. pii: 3005. [Epub ahead of print]28(7):

Design and Synthesis of 3-(β-d-Glucopyranosyl)-4-amino/4-guanidino Pyrazole Derivatives and Analysis of Their Glycogen Phosphorylase Inhibitory Potential.

Sándor Kun, Rachel T Mathomes, Tibor Docsa, László Somsák, Joseph M Hayes.

  Glycogen phosphorylase (GP) is a key regulator of glucose levels and, with that, an important target for the discovery of novel treatments against type 2 diabetes. β-d-Glucopyranosyl derivatives have provided some of the most potent GP inhibitors discovered to date. In this regard, C-β-d-glucopyranosyl azole type inhibitors proved to be particularly effective, with 2- and 4-β-d-glucopyranosyl imidazoles among the most potent designed to date. His377 backbone C=O hydrogen bonding and ion-ion interactions of the protonated imidazole with Asp283 from the 280s loop, stabilizing the inactive state, were proposed as crucial to the observed potencies. Towards further exploring these features, 4-amino-3-(β-d-glucopyranosyl)-5-phenyl-1H-pyrazole (3) and 3-(β-d-glucopyranosyl)-4-guanidino-5-phenyl-1H-pyrazole (4) were designed and synthesized with the potential to exploit similar interactions. Binding assay experiments against rabbit muscle GPb revealed 3 as a moderate inhibitor (IC50 = 565 µM), but 4 displayed no inhibition at 625 µM concentration. Towards understanding the observed inhibitions, docking and post-docking molecular mechanics-generalized Born surface area (MM-GBSA) binding free energy calculations were performed, together with Monte Carlo and density functional theory (DFT) calculations on the free unbound ligands. The computations revealed that while 3 was predicted to hydrogen bond with His377 C=O in its favoured tautomeric state, the interactions with Asp283 were not direct and there were no ion-ion interactions; for 4, the most stable tautomer did not have the His377 backbone C=O interaction and while ion-ion interactions and direct hydrogen bonding with Asp283 were predicted, the conformational strain and entropy loss of the ligand in the bound state was significant. The importance of consideration of tautomeric states and ligand strain for glucose analogues in the confined space of the catalytic site with the 280s loop in the closed position was highlighted.

Keywords:  C-glycosyl pyrazole; MM-GBSA; glucose analogues; glycogen phosphorylase inhibitor; ligand strain; tautomers; type 2 diabetes

DOI:  https://doi.org/10.3390/molecules28073005
Biomed Chromatogr. 2023 Apr 13. e5649

A quantitative analysis method for a new glycogen synthase kinase - 3 inhibitor and its pharmacokinetics in rats.

Dan Wu, Xue Bai, Jiasi Yu, Linli Guo, Yanan Zhao, Ping Liu.

  Alzheimer's disease (AD), as a chronic and frequent neurodegenerative disease in the elderly population, has caused a huge economic burden to society, family, and other aspects. (E)-N-(4-(((2-amino-5-phenylpyridin-3-yl) imino) methyl) pyridine-2-yl) cyclopropanecarboxamide (PIMPC), a new glycogen synthase kinase-3 (GSK-3) inhibitor, has been designed and synthesized as a potential anti-AD compound with antioxidant and metal chelating properties. In this study, we established a high-performance liquid chromatography (HPLC) method for the determination of PIMPC, which has high accuracy, good sensitivity, and repeatability. This method determined the plasma PIMPC content in rats at different time points after intragastric administration to understand the pharmacokinetics (PK) process of PIMPC in rats. In addition, we preliminarily evaluated the effect of PIMPC on the liver and kidney in rats at pharmacodynamic doses. In conclusion, we have established a quantitative analysis method for PIMPC with excellent performance. And the PK process of PIMPC in rats, which was characterized by fast absorption, rapid distribution, and rapid elimination, conformed to the characteristics of the two-compartment model. In addition, long-term administration of PIMPC at therapeutic doses would not affect liver and kidney function. These studies have a certain reference for the development and research of PIMPC as a potential anti-AD drug.

Keywords:  alzheimer's disease; glycogen synthase kinase-3 inhibitor; high-performance liquid chromatography; method; pharmacokinetics

DOI:  https://doi.org/10.1002/bmc.5649
Int J Mol Sci. 2023 Mar 24. pii: 6133. [Epub ahead of print]24(7):

The Liver and Glycogen: In Sickness and in Health.

Gwyneth S T Soon, Michael Torbenson.

  The liver is a major store of glycogen and is essential in maintaining systemic glucose homeostasis. In healthy individuals, glycogen synthesis and breakdown in the liver are tightly regulated. Abnormal glycogen metabolism results in prominent pathological changes in the liver, often manifesting as hepatic glycogenosis or glycogen inclusions. This can occur in genetic glycogen storage disease or acquired conditions with insulin dysregulation such as diabetes mellitus and non-alcoholic fatty liver disease or medication effects. Some primary hepatic tumors such as clear cell hepatocellular carcinoma also demonstrate excessive glycogen accumulation. This review provides an overview of the pathological manifestations and molecular mechanisms of liver diseases associated with abnormal glycogen accumulation.

Keywords:  Mauriac syndrome; clear cell hepatocellular carcinoma; glycogenic hepatopathy; hepatic glycogenosis; pathology; pseudoground glass

DOI:  https://doi.org/10.3390/ijms24076133
Front Genet. 2023 ;14 1148067

Novel AGL variants in a patient with glycogen storage disease type IIIb and pulmonary hypertension caused by pulmonary veno-occlusive disease: A case report.

Akito Shindo, Kazutaka Ueda, Shun Minatsuki, Yukiteru Nakayama, Satoshi Hatsuse, Kanna Fujita, Seitaro Nomura, Masaru Hatano, Norifumi Takeda, Hiroshi Akazawa, Issei Komuro.

  Glycogen storage disease type III (GSD-III) is an autosomal recessive metabolic disorder caused by mutations in the AGL gene, and may develop various types of pulmonary hypertension (PH). Here, we report a case of 24-year-old man with GSD-IIIb with two novel null variants in AGL (c.2308 + 2T>C and c.3045_3048dupTACC). He developed multi-drug-resistant pulmonary veno-occlusive disease (PVOD) and was registered as a candidate for lung transplantation. No pathogenic variants were detected in previously known causative genes for pulmonary hypertension and the underlying mechanism of coincidence of two rare diseases was unknown. We discuss the association of the loss of glycogen-debranching enzyme with incident PVOD.

Keywords:  AGL; PVOD; glycogen storage disease; pulmonary hypertension; pulmonary veno-occlusive disease

DOI:  https://doi.org/10.3389/fgene.2023.1148067
Pharmacoecon Open. 2023 Apr 11.

Estimation of Health Utility Scores for Glycogen Storage Disease Type Ia.

Eliza Kruger, Daniel Aggio, Hayley de Freitas, Andrew Lloyd.

BACKGROUND: Glycogen Storage Disease Type Ia (GSDIa) is a rare genetic metabolic disorder characterized by hypoglycemia, hepatomegaly, growth failure, and possible seizures/death. Patients frequently consume cornstarch to maintain blood glucose. Evidence demonstrating the impact of GSDIa on health-related quality of life (HRQoL) is lacking. This study aims to understand the burden of GSDIa by obtaining utility values for economic appraisals.
METHODS: A targeted literature review and interviews with experts (n = 4) and caregivers (n = 4) informed the development of health state vignettes describing different GSDIa severities by age and level of hypothetical treatment (i.e., gene therapy) response. Health states reflecting caregivers' experiences were also developed. A convenience sample of the UK general public completed a time trade-off (TTO) exercise. Scores conceptually varied from 0 (dead) to 1 (full health). States were also rated using a visual analog scale (VAS) and the EQ-5D-5L. Data were descriptively summarized.
RESULTS: One hundred participants completed the exercise (male: 48%; mean age: 42 years). Scores were lowest for the adolescent pre-treatment state (TTO = 0.38). Large increments in HRQoL were observed for the response (adult: TTO = 0.86; child: TTO = 0.84) and complete response (adult and child: TTO = 0.94) hypothetical treatment response states. Caregiver values were lowest for the pre-treatment state (TTO = 0.57) and highest for the complete response state (TTO = 0.95). VAS and EQ-5D-5L scores followed a similar pattern.
CONCLUSION: This study found an HRQoL burden on GSDIa patients and caregivers, with potential large improvement from a hypothetical treatment. These findings may be useful for families, clinicians, regulatory agencies, and in therapy economic evaluations.

DOI: https://doi.org/10.1007/s41669-023-00397-z
Int J Biol Macromol. 2023 Apr 07. pii: S0141-8130(23)01257-6. [Epub ahead of print] 124363

Tumor-targeted glycogen nanoparticles loaded with hemin and glucose oxidase to promote tumor synergistic therapy.

Lipeng Qiu, Junze Wang, Mariana Conceição, Shenhuan Liu, Meiyang Yang, Weijun Chen, Miaomiao Long, Xian Cheng, Matthew J A Wood, Jinghua Chen.

  Strategies which are used to address the low levels of intracellular hydrogen peroxide and the development of biocompatible catalysts still need to be fulfilled in tumor chemodynamic therapy. Therefore, a novel tumor-targeted glycogen-based nanoparticle system (GN/He/GOx/HA) was developed to co-deliver hemin (He) and GOx, which can self-supply glucose formed upon degradation of glycogen by α-glycosidase in the lysosome environment, in order to achieve synergistic antitumor therapy. Hyaluronic acid (HA) was selected as the outer shell to protect the activity of GOx, and to increase the uptake by tumor cells via CD44 receptor-mediated endocytosis. GN/He/GOx/HA NPs had a good stability in the blood circulation, but fast release of the therapeutic cargos upon intracellular uptake. Hemin had a cascade catalytic reaction with GOx. Furthermore, GN/He/GOx/HA NPs had the strongest cytotoxicity in Hela cells in a glucose concentration dependent manner. The NPs could efficiently produce reactive oxygen species in tumor cells, resulting in a decrease in the mitochondrial membrane potential and apoptosis of tumor cells. The in vivo results showed that the drug-loaded nanoparticles had good safety, biocompatibility, and efficacious antitumor effect. Therefore, the glycogen-based nanoparticle delivery system provides potential application for self-enhancing CDT, which can be used for effective antitumor therapy.

Keywords:  Chemodynamic therapy; Glucose oxidase; Glycogen

DOI:  https://doi.org/10.1016/j.ijbiomac.2023.124363
Mini Rev Med Chem. 2023 Apr 12.

Advances in the Therapeutic Potential of Inhibitors Targeting Glycogen Synthase Kinase 3 in Inflammatory Diseases.

Yifan Zhu, Hui Wang, Yueyue Guo, Jie Cao, Huanqiu Li.

  Glycogen synthase kinase-3 (GSK3) is one of the important serine/threonine protein kinases and has two isoforms, namely, GSK3α and GSK3β. GSK3 inhibits glycogen synthase activity through phosphorylation. It plays a key role in various pathophysiological processes, such as differentiation, immunity, metabolism, cell death, and cell survival. Therefore, GSK3 has evolved as an important therapeutic target for treating neurological diseases, inflammatory diseases, and cancer. In addition, GSK3 regulates inflammatory processes through NF-κB-induced expression of various cytokines, including tumor necrosis factor-α (TNF-α), interleukin (IL)-1β, and IL-6. Moreover, GSK3 is reported to participate in many signaling pathways related to disease pathology, including PI3K/Akt, Wnt, Hedgehog, cyclic adenosine monophosphate, mitogen-activated protein kinase, and transforming growth factor-β (TGF-β). GSK3 has become a therapeutic target against some inflammatory diseases, including the inclusion body myositis, sepsis, and inflammatory bowel disease. Hence, several GSK3 inhibitors have been under evaluation as new therapeutic strategies in recent years. Two drugs targeting GSK3 have already entered clinical studies, including tideglusib and lithium carbonate. In this study, we analyzed nearly 30 different small-molecule GSK3 inhibitors reported in the past 4 years and classified them into four categories (thiazole, pyridine, F-substituted benzene, and others) according to their structure to conduct further literature research. Moreover, we summarized the optimal compounds and described the process of transformation from the lead compound to the optimal compound. In addition, we aimed to summarize the role of GSK3 in the pathogenesis of inflammatory diseases, with insights into the recent progress in the discovery of GSK3 inhibitors.

Keywords:  GSK3?; Glycogen synthase kinase-3; inflammatory diseases; inhibitors; small-molecule compound; structure activity relationship.

DOI:  https://doi.org/10.2174/1389557523666230412083123
Metabolism. 2023 Apr 10. pii: S0026-0495(23)00162-2. [Epub ahead of print] 155559

Hepatic IDH2 regulates glycolysis and gluconeogenesis.

Huawei Wang, Qing Xiong, Guangzhen He, Jun Tang, Li Sun, Siyuan Cheng, Mengting Ke, Shangyu Chen, Yong Hu, Jieyuan Feng, Linyang Song, Beier Tong, Zhengwei Zhang, Zhe Dai, Yancheng Xu.

   BACKGROUND AND AIMS: The liver plays a central role in controlling glucose and lipid metabolism. IDH2, a mitochondrial protein, controls TCA cycle flux. However, its role in regulating metabolism in obesity is still unclear. This study intends to investigate the impact of hepatic IDH2 expression on overnutrition-regulated glucose and lipid metabolism.
METHODS: Hepatic IDH2 was knocked-out in mice by the approach of CRISPR-Cas9. Mice were subjected to starvation and refeeding for hepatic glucose and lipid studies in vivo. Primary hepatocytes and mouse normal liver cell line, AML12 cells were used for experiments in vitro.
RESULTS: This study found that IDH2 protein levels were elevated in the livers of obese people and mice with high-fat diet consumption or hepatic steatosis. Liver IDH2-deletion mice (IDH2LKO) were resistant to high-fat diet-induced body weight gain, with lower serum glucose and TG levels, increased insulin sensitivity, and higher FGF21 secretion, despite the higher TG content in the liver. Consistently, overexpression of IDH2 in hepatocytes promoted gluconeogenesis and enhanced glycogenesis. By performing mass spectrometry and proteomics analyses, we further demonstrated that IDH2-deficiency in hepatocytes accelerated ATP production by increasing forward TCA cycle flux, thus promoting glycolysis pathway and decreasing glycogen synthesis at refeeding state, and inhibiting hepatic gluconeogenesis, increasing β-oxidation during starvation. Moreover, experiments in vivo demonstrated that IDH2-knockout might not exacerbate hepatic inflammatory responses in the NASH model.
CONCLUSIONS: Elevated hepatic IDH2 under over-nutrition state contributes to elevated gluconeogenesis and glycogen synthesis. Inhibition of IDH2 in the liver could be a potential therapeutic target for obesity and diabetes.

Keywords:  Gluconeogenesis; Glycolysis; IDH2; Over-nutrition; TCA cycle

DOI:  https://doi.org/10.1016/j.metabol.2023.155559
Biochim Biophys Acta Mol Basis Dis. 2023 Apr 06. pii: S0925-4439(23)00075-3. [Epub ahead of print] 166709

Exercise training impacts skeletal muscle remodelling induced by metabolic syndrome in ZSF1 rats through metabolism regulation.

Rita Nogueira-Ferreira, Inês Santos, Rita Ferreira, Dulce Fontoura, Cláudia Sousa-Mendes, Inês Falcão-Pires, André Lourenço, Adelino Leite-Moreira, Iola F Duarte, Daniel Moreira-Gonçalves.

  Metabolic syndrome (MetS), characterized by a set of conditions that include obesity, hypertension, and dyslipidemia, is associated with increased cardiovascular risk. Exercise training (EX) has been reported to improve MetS management, although the underlying metabolic adaptations that drive its benefits remain poorly understood. This work aims to characterize the molecular changes induced by EX in skeletal muscle in MetS, focusing on gastrocnemius metabolic remodelling. 1H NMR metabolomics and molecular assays were employed to assess the metabolic profile of skeletal muscle tissue from lean male ZSF1 rats (CTL), obese sedentary male ZSF1 rats (MetS-SED), and obese male ZF1 rats submitted to 4 weeks of treadmill EX (5 days/week, 60 min/day, 15 m/min) (MetS-EX). EX did not counteract the significant increase of body weight and circulating lipid profile, but had an anti-inflammatory effect and improved exercise capacity. The decreased gastrocnemius mass observed in MetS was paralleled with glycogen degradation into small glucose oligosaccharides, with the release of glucose-1-phosphate, and an increase in glucose-6-phosphate and glucose levels. Moreover, sedentary MetS animals' muscle exhibited lower AMPK expression levels and higher amino acids' metabolism such as glutamine and glutamate, compared to lean animals. In contrast, the EX group showed changes suggesting an increase in fatty acid oxidation and oxidative phosphorylation. Additionally, EX mitigated MetS-induced fiber atrophy and fibrosis in the gastrocnemius muscle. EX had a positive effect on gastrocnemius metabolism by enhancing oxidative metabolism and, consequently, reducing susceptibility to fatigue. These findings reinforce the importance of prescribing EX programs to patients with MetS.

Keywords:  Gastrocnemius; Metabolic syndrome; Metabolism; Metabolomics; Treadmill exercise

DOI:  https://doi.org/10.1016/j.bbadis.2023.166709
Nat Rev Endocrinol. 2023 Apr 13.

The role of ChREBP in carbohydrate sensing and NAFLD development.

Marion Régnier, Thaïs Carbinatti, Lucia Parlati, Fadila Benhamed, Catherine Postic.

Excessive sugar consumption and defective glucose sensing by hepatocytes contribute to the development of metabolic diseases including type 2 diabetes mellitus (T2DM) and nonalcoholic fatty liver disease (NAFLD). Hepatic metabolism of carbohydrates into lipids is largely dependent on the carbohydrate-responsive element binding protein (ChREBP), a transcription factor that senses intracellular carbohydrates and activates many different target genes, through the activation of de novo lipogenesis (DNL). This process is crucial for the storage of energy as triglycerides in hepatocytes. Furthermore, ChREBP and its downstream targets represent promising targets for the development of therapies for the treatment of NAFLD and T2DM. Although lipogenic inhibitors (for example, inhibitors of fatty acid synthase, acetyl-CoA carboxylase or ATP citrate lyase) are currently under investigation, targeting lipogenesis remains a topic of discussion for NAFLD treatment. In this Review, we discuss mechanisms that regulate ChREBP activity in a tissue-specific manner and their respective roles in controlling DNL and beyond. We also provide in-depth discussion of the roles of ChREBP in the onset and progression of NAFLD and consider emerging targets for NAFLD therapeutics.

DOI: https://doi.org/10.1038/s41574-023-00809-4
J Physiol. 2023 Apr 11.

Can muscle typology explain the inter-individual variability in resistance training adaptations?

Kim Van Vossel, Julie Hardeel, Freek Van de Casteele, Thibaux Van der Stede, Anneleen Weyns, Jan Boone, Silvia Blemker, Eline Lievens, Wim Derave.

  Considerable inter-individual heterogeneity exists in the muscular adaptations to resistance training. It has been proposed that fast-twitch fibers are more sensitive to hypertrophic stimuli and thus that variation in muscle fiber type composition is a contributing factor to the magnitude of training response. This study investigated if the inter-individual variability in resistance training adaptations is determined by muscle typology and if the most appropriate weekly training frequency depends on muscle typology. In strength-training novices, 11 slow (ST) and 10 fast typology (FT) individuals were selected by measuring muscle carnosine with proton magnetic resonance spectroscopy. Participants trained both upper arm and leg muscles to failure at 60% 1RM for 10 weeks, whereby one arm and leg trained 3x/week, the contralateral arm and leg 2x/week. Muscle volume (MRI-based 3D segmentation), maximal dynamic strength (one-repetition maximum, 1RM) and fiber-type specific cross-sectional area (vastus lateralis biopsies) were evaluated. The training response for total muscle volume (+3 to +14%), fiber size (-19 to +22%) and strength (+17 to +47%) showed considerable inter-individual variability, but these could not be attributed to differences in muscle typology. However, ST individuals performed a significantly higher training volume to gain these similar adaptations as FT individuals. The limb that trained 3x/week had generally more pronounced hypertrophy than the limb that trained 2x/week, and there was no interaction with muscle typology. In conclusion, muscle typology cannot explain the high variability in resistance training adaptations when training is performed to failure at 60% of 1RM. KEY POINTS: This study investigated the influence of muscle typology ( = muscle fiber type composition) on the variability in resistance training adaptations and on its role in the individualization of resistance training frequency. We demonstrate that an individual's muscle typology cannot explain the inter-individual variability in resistance training induced increases in muscle volume, maximal dynamic strength and fiber cross-sectional area when repetitions are performed to failure. Importantly, slow typology individuals performed a significantly higher training volume to obtain similar adaptations compared to fast typology individuals. Muscle typology does not determine the most appropriate resistance training frequency. However, regardless of muscle typology, an additional weekly training (3x/week vs 2x/week) increases muscle hypertrophy but not maximal dynamic strength. These findings expand on our understanding of the underlying mechanisms for the large inter-individual variability in resistance training adaptations. Abstract figure legend This study investigated if muscle typology can explain the high variability in resistance training adaptations. Slow and fast typology resistance training novices were selected to participate in this study by the non-invasive measurement of muscle carnosine with proton magnetic resonance spectroscopy. After the chronic training period a high inter-individual variability was observed in changes in muscle volume, maximal dynamic strength and fiber cross-sectional area. However, this high inter-individual variability could not be explained by muscle typology for any of the outcomes. Visual abstract created with BioRender. This article is protected by copyright. All rights reserved.

Keywords:  blood flow; dynamic strength; fiber cross-sectional area; hypertrophy; muscle typology; resistance training; resistance training frequency; resistance training volume

DOI:  https://doi.org/10.1113/JP284442