bims-glecem 2023-05-21 papers

bims-glecem

Biomed News

on Glycogen metabolism in exercise, cancer and energy metabolism

Issue of 2023–05–21
seven papers selected by
Dipsikha Biswas, Københavns Universitet

Spatial metabolomics reveals glycogen as an actionable target for pulmonary fibrosis.
Stochastic modelling of a three-dimensional glycogen granule synthesis and impact of the branching enzyme.
Distribution of Exonic Variants in Glycogen Synthesis and Catabolism Genes in Late Onset Pompe Disease (LOPD).
A Systematic Review investigating the Effectiveness of Exercise training in Glycogen Storage Diseases.
Muscle-specific, liver-detargeted AAV gene therapy rescues Pompe phenotype in adult and neonate Gaa-/- mice.
Altered gut microbiota and microbial metabolism in children with hepatic glycogen storage disease: a case-control study.
Galectin-3 Mediates Tumor Progression in Astrocytoma by Regulating Glycogen Synthase Kinase-3β Activity.

Nat Commun. 2023 May 13. 14(1): 2759

Spatial metabolomics reveals glycogen as an actionable target for pulmonary fibrosis.

Lindsey R Conroy, Harrison A Clarke, Derek B Allison, Samuel Santos Valenca, Qi Sun, Tara R Hawkinson, Lyndsay E A Young, Juanita E Ferreira, Autumn V Hammonds, Jaclyn B Dunne, Robert J McDonald, Kimberly J Absher, Brittany E Dong, Ronald C Bruntz, Kia H Markussen, Jelena A Juras, Warren J Alilain, Jinze Liu, Matthew S Gentry, Peggi M Angel, Christopher M Waters, Ramon C Sun.

Matrix assisted laser desorption/ionization imaging has greatly improved our understanding of spatial biology, however a robust bioinformatic pipeline for data analysis is lacking. Here, we demonstrate the application of high-dimensionality reduction/spatial clustering and histopathological annotation of matrix assisted laser desorption/ionization imaging datasets to assess tissue metabolic heterogeneity in human lung diseases. Using metabolic features identified from this pipeline, we hypothesize that metabolic channeling between glycogen and N-linked glycans is a critical metabolic process favoring pulmonary fibrosis progression. To test our hypothesis, we induced pulmonary fibrosis in two different mouse models with lysosomal glycogen utilization deficiency. Both mouse models displayed blunted N-linked glycan levels and nearly 90% reduction in endpoint fibrosis when compared to WT animals. Collectively, we provide conclusive evidence that lysosomal utilization of glycogen is required for pulmonary fibrosis progression. In summary, our study provides a roadmap to leverage spatial metabolomics to understand foundational biology in pulmonary diseases.

DOI: https://doi.org/10.1038/s41467-023-38437-1
PLoS Comput Biol. 2023 May;19(5): e1010694

Stochastic modelling of a three-dimensional glycogen granule synthesis and impact of the branching enzyme.

Yvan Rousset, Oliver Ebenhöh, Adélaïde Raguin.

In humans, glycogen storage diseases result from metabolic inborn errors, and can lead to severe phenotypes and lethal conditions. Besides these rare diseases, glycogen is also associated to widely spread societal burdens such as diabetes. Glycogen is a branched glucose polymer synthesised and degraded by a complex set of enzymes. Over the past 50 years, the structure of glycogen has been intensively investigated. Yet, the interplay between the detailed three-dimensional glycogen structure and the related enzyme activity is only partially characterised and still to be fully understood. In this article, we develop a stochastic coarse-grained and spatially resolved model of branched polymer biosynthesis following a Gillespie algorithm. Our study largely focusses on the role of the branching enzyme, and first investigates the properties of the model with generic parameter values, before comparing it to in vivo experimental data in mice. It arises that the ratio of glycogen synthase over branching enzyme reaction rates drastically impacts the structure of the granule. We deeply investigate the mechanism of branching and parametrise it using distinct lengths. Not only do we consider various possible sets of values for these lengths, but also distinct rules to apply them. We show how combining various values for these lengths finely tunes glycogen macromolecular structure. Comparing the model with experimental data confirms that we can accurately reproduce glycogen chain length distributions in wild type mice. Additional granule properties obtained for this fit are also in good agreement with typically reported values in the experimental literature. Nonetheless, we find that the mechanism of branching must be more flexible than usually reported. Overall, our model provides a theoretical basis to quantify the effect that single enzymatic parameters, in particular of the branching enzyme, have on the chain length distribution. Our generic model and methods can be applied to any glycogen data set, and could in particular contribute to characterise the mechanisms responsible for glycogen storage disorders.

DOI: https://doi.org/10.1371/journal.pcbi.1010694
Curr Issues Mol Biol. 2023 Apr 01. 45(4): 2847-2860

Distribution of Exonic Variants in Glycogen Synthesis and Catabolism Genes in Late Onset Pompe Disease (LOPD).

Paola De Filippi, Edoardo Errichiello, Antonio Toscano, Tiziana Mongini, Maurizio Moggio, Sabrina Ravaglia, Massimiliano Filosto, Serenella Servidei, Olimpia Musumeci, Fabio Giannini, Alberto Piperno, Gabriele Siciliano, Giulia Ricci, Antonio Di Muzio, Miriam Rigoldi, Paola Tonin, Michele Giovanni Croce, Elena Pegoraro, Luisa Politano, Lorenzo Maggi, Roberta Telese, Alberto Lerario, Cristina Sancricca, Liliana Vercelli, Claudio Semplicini, Barbara Pasanisi, Bruno Bembi, Andrea Dardis, Ilaria Palmieri, Cristina Cereda, Enza Maria Valente, Cesare Danesino.

  Pompe disease (PD) is a monogenic autosomal recessive disorder caused by biallelic pathogenic variants of the GAA gene encoding lysosomal alpha-glucosidase; its loss causes glycogen storage in lysosomes, mainly in the muscular tissue. The genotype-phenotype correlation has been extensively discussed, and caution is recommended when interpreting the clinical significance of any mutation in a single patient. As there is no evidence that environmental factors can modulate the phenotype, the observed clinical variability in PD suggests that genetic variants other than pathogenic GAA mutations influence the mechanisms of muscle damage/repair and the overall clinical picture. Genes encoding proteins involved in glycogen synthesis and catabolism may represent excellent candidates as phenotypic modifiers of PD. The genes analyzed for glycogen synthesis included UGP2, glycogenin (GYG1-muscle, GYG2, and other tissues), glycogen synthase (GYS1-muscle and GYS2-liver), GBE1, EPM2A, NHLRC1, GSK3A, and GSK3B. The only enzyme involved in glycogen catabolism in lysosomes is α-glucosidase, which is encoded by GAA, while two cytoplasmic enzymes, phosphorylase (PYGB-brain, PGL-liver, and PYGM-muscle) and glycogen debranching (AGL) are needed to obtain glucose 1-phosphate or free glucose. Here, we report the potentially relevant variants in genes related to glycogen synthesis and catabolism, identified by whole exome sequencing in a group of 30 patients with late-onset Pompe disease (LOPD). In our exploratory analysis, we observed a reduced number of variants in the genes expressed in muscles versus the genes expressed in other tissues, but we did not find a single variant that strongly affected the phenotype. From our work, it also appears that the current clinical scores used in LOPD do not describe muscle impairment with enough qualitative/quantitative details to correlate it with genes that, even with a slightly reduced function due to genetic variants, impact the phenotype.

Keywords:  exonic variants; genetic modifiers; genotype–phenotype correlates; glycogen catabolism; glycogen synthesis; late-onset Pompe disease (LOPD)

DOI:  https://doi.org/10.3390/cimb45040186
Ther Adv Rare Dis. 2022 Jan-Dec;3:3 26330040221076497

A Systematic Review investigating the Effectiveness of Exercise training in Glycogen Storage Diseases.

Claire Bordoli, Elaine Murphy, Ian Varley, Graham Sharpe, Philip Hennis.

   Introduction: Glycogen storage diseases (GSDs) are rare inborn errors of carbohydrate metabolism typically with skeletal muscle and liver involvement. In those with skeletal muscle involvement, the majority display symptoms of exercise intolerance which can cause profound exercise limitation and impair everyday living and quality of life (QoL). There are no curative treatments for GSDs, thus therapeutic options, such as exercise training, are aimed at improving QoL by alleviating signs and symptoms. In order to investigate the effectiveness of exercise training in adults with GSDs, we systematically reviewed the literature.
Methods: In this review we conducted searches within SCOPUS and MEDLINE to identify potential papers for inclusion. These papers were independently assessed for inclusion and quality by two authors. We identified 23 studies which included aerobic training, strength training or respiratory muscle training in patients with McArdles (n = 41) and Pompe disease (n = 139).
Results: In McArdle disease, aerobic exercise training improved aerobic capacity (VO2 peak) by 14-111% with further benefits to functional capacity and well-being. Meanwhile, strength training increased muscle peak power by 100-151% and reduced disease severity. In Pompe disease, a combination of aerobic and strength training improved VO2 peak by 9-10%, muscle peak power by 64%, functional capacity and well-being. Furthermore, respiratory muscle training (RMT) improved respiratory muscular strength [maximum inspiratory pressure (MIP) increased by up to 65% and maximum expiratory pressure (MEP) by up to 70%], with additional benefits shown in aerobic capacity, functional capacity and well-being.
Conclusion: This adds to the growing body of evidence which suggests that supervised exercise training is safe and effective in improving aerobic capacity and muscle function in adults with McArdle or Pompe disease. However, the literature base is limited in quality and quantity with a dearth of literature regarding exercise training in other GSD subtypes.

Keywords:  endurance training; exercise; glycogen storage disease; respiratory training; review; strength training

DOI:  https://doi.org/10.1177/26330040221076497
J Inherit Metab Dis. 2023 May 19.

Muscle-specific, liver-detargeted AAV gene therapy rescues Pompe phenotype in adult and neonate Gaa-/- mice.

P Sellier, P Vidal, B Bertin, E Gicquel, Bertil-Froidevaux, C Georger, L van Wittenberghe, A Miranda, N Daniele, I Richard, D A Gross, F Mingozzi, F Collaud, G Ronzitti.

Pompe disease (PD) is a neuromuscular disorder caused by acid α-glucosidase (GAA) deficiency. Reduced GAA activity leads to pathological glycogen accumulation in cardiac and skeletal muscles responsible for severe heart impairment, respiratory defects, and muscle weakness. Enzyme replacement therapy with recombinant human GAA is the standard-of-care treatment for PD, however, its efficacy is limited due to poor uptake in muscle and the development of an immune response. Multiple clinical trials are ongoing in PD with adeno-associated virus (AAV) vectors based on liver- and muscle-targeting. Current gene therapy approaches are limited by liver proliferation, poor muscle targeting and the potential immune response to the hGAA transgene. To generate a treatment tailored to infantile-onset PD, we took advantage of a novel AAV capsid able to increase skeletal muscle targeting compared to AAV9 while reducing liver overload. When combined with a liver-muscle tandem promoter (LiMP), and despite the extensive liver-detargeting, this vector had limited immune response to the hGAA transgene. This combination of capsid and promoter with improved muscle expression and specificity allowed for glycogen clearance in cardiac and skeletal muscles of Gaa-/- adult mice. In neonate Gaa-/- , complete rescue of glycogen content and muscle strength was observed six months after AAV vector injection. Our work highlights the importance of residual liver expression to control the immune response toward a potentially immunogenic transgene expressed in muscle. In conclusion, the demonstration of the efficacy of a muscle-specific AAV capsid-promoter combination for the full rescue of PD manifestation in both neonate and adult Gaa-/- provides a potential therapeutic avenue for the infantile-onset form of this devastating disease. This article is protected by copyright. All rights reserved.

DOI: https://doi.org/10.1002/jimd.12625
Transl Pediatr. 2023 Apr 29. 12(4): 572-586

Altered gut microbiota and microbial metabolism in children with hepatic glycogen storage disease: a case-control study.

Yizhong Wang, Honghong Liu, Fang Dong, Yongmei Xiao, Fangfei Xiao, Ting Ge, Dan Li, Guangjun Yu, Ting Zhang.

   Background: Accumulating evidence has demonstrated that gut microbiota dysbiosis correlated with altered metabolism are implicated in liver metabolic diseases. However, data on pediatric hepatic glycogen storage disease (GSD) are limited. Here, we aimed to investigate the features of the gut microbiota and metabolites in hepatic GSD children from China.
Methods: Totals of 22 hepatic GSD patients and 16 age- and gender-matched healthy children were enrolled from the Shanghai Children's Hospital, China. Pediatric GSD patients were confirmed as having hepatic GSD via genetic diagnosis and/or liver biopsy pathology. The control group comprised children without any history of chronic diseases or clinically relevant GSD or symptoms of any other metabolic diseases. The baseline characteristics of the two groups were gender- and age-matched matched using chi-squared test and the Mann-Whitney U test, respectively. The gut microbiota, bile acids (BAs), and short chain fatty acids (SCFAs) were determined from the feces using 16S ribosomal RNA (rRNA) gene sequencing, ultra-high performance liquid chromatography-tandem mass spectrometry (UHPLC-MS/MS), and gas chromatography-mass spectrometry (GC-MS), respectively.
Results: The alpha diversity of fecal microbiome was significantly lower in hepatic GSD patients [observed species richness (Sobs): P=0.011; abundance-based coverage estimator (ACE): P=0.011; Chao: P=0.011; Shannon: P<0.001], and their microbial community was more distanced from that of the control [principal coordinate analysis (PCoA) on genus level, unweighted UniFrac: P=0.011]. Relative abundances of phyla Firmicutes (P=0.030) and Bacteroidetes (P=0.029), families Lachnospiraceae (P=0.012), Ruminococcaceae (P=0.008), and Peptostreptococcaceare (P=0.031), genera Blautia (P=0.017), Eubacterium_hallii_group (P=0.032), and Faecalibacterium (P=0.017) were decreased, whereas phyla Actinobacteria (P=0.033), Proteobacteria (P=0.049), families Bifidobacteriaceae (P=0.030), Lactobacillaceae (P=0.034), and Veillonellaceae (P=0.033), genera Lactobacillus (P=0.011), Enterobater (P=0.034), and Veillonella (P=0.014) were increased in hepatic GSD. Altered microbial metabolisms were characterized by increased abundances of primary BAs (P=0.009) and decreased concentrations of SCFAs in hepatic GSD children. Furthermore, the altered bacterial genera were correlated with the changes of both fecal BAs and SCFAs.
Conclusions: The hepatic GSD patients in this study presented with gut microbiota dysbiosis which correlated with altered BAs metabolism and fecal SCFAs changes. Further studies are needed to investigate the driver of these changes mediated by either the genetic defect, disease status, or diet therapy.

Keywords:  Glycogen storage disease (GSD); bile acids (BAs); gut microbiota; metabolism; short chain fatty acids (SCFAs)

DOI:  https://doi.org/10.21037/tp-22-293
Curr Issues Mol Biol. 2023 Apr 19. 45(4): 3591-3602

Galectin-3 Mediates Tumor Progression in Astrocytoma by Regulating Glycogen Synthase Kinase-3β Activity.

Hung-Pei Tsai, Chien-Ju Lin, Ann-Shung Lieu, Yi-Ting Chen, Tzu-Ting Tseng, Aij-Lie Kwan, Joon-Khim Loh.

  Numerous studies have considered galectin-3 or Glycogen synthase kinase 3 beta (GSK3B) as a potential prognosis marker for various cancers. However, the correlation between the protein expression of galectin-3/GSK3B and the clinical parameters of astrocytoma has not been reported. This study aims to validate the correlation between the clinical outcomes and protein expression of galectin-3/GSK3B in astrocytoma. Immunohistochemistry staining was performed to detect galectin-3/GSK3B protein expression in patients with astrocytoma. The Chi-square test, Kaplan-Meier evaluation, and Cox regression analysis were used to determine the correlation between clinical parameters and galectin-3/GSK3B expression. Cell proliferation, invasion, and migration were compared between a non-siRNA group and a galectin-3/GSK3B siRNA group. Protein expression in galectin-3 or GSK3B siRNA-treated cells was evaluated using western blotting. Galectin-3 and GSK3B protein expression were significantly positively correlated with the World Health Organization (WHO) astrocytoma grade and overall survival time. Multivariate analysis revealed that WHO grade, galectin-3 expression, and GSK3B expression were independent prognostic factors for astrocytoma. Galectin-3 or GSK3B downregulation induced apoptosis and decreased cell numbers, migration, and invasion. siRNA-mediated gene silencing of galectin-3 resulted in the downregulation of Ki-67, cyclin D1, VEGF, GSK3B, p-GSK3B Ser9 (p-GSK3B S9), and β-catenin. In contrast, GSK3B knockdown only decreased Ki-67, VEGF, p-GSK3B S9, and β-catenin protein expression but did not affect cyclin D1 and galectin-3 protein expression. The siRNA results indicated that GSK3B is downstream of the galectin-3 gene. These data support that galectin-3 mediated tumor progression by upregulating GSK3B and β-catenin protein expression in glioblastoma. Therefore, galectin-3 and GSK3B are potential prognostic markers, and their genes may be considered to be anticancer targets for astrocytoma therapy.

Keywords:  GSK3B; astrocytoma; galectin-3

DOI:  https://doi.org/10.3390/cimb45040234