bims-glecem 2023-08-27 papers

bims-glecem

Biomed News

on Glycogen metabolism in exercise, cancer and energy metabolism

Issue of 2023–08–27
ten papers selected by
Dipsikha Biswas, Københavns Universitet

Methods for Studying Glycogen Metabolism.
Fluoride as a Potential Repressor of Glycogen Metabolism in Skeletal Muscle Cell Line CCL136.
An Unusual Case of Neonatal Hypotonia and Femur Fracture: Neuromuscular Variant of Glycogen Storage Disease Type IV.
Glycogen storage disease type IV without detectable polyglucosan bodies: importance of broad gene panels.
Systematic literature review of the epidemiology of glycogen storage disease type 1a.
GAA variants associated with reduced enzymatic activity but lack of Pompe-related symptoms, incidentally identified by exome sequencing.
Basidiomycota species in Drosophila gut are associated with host fat metabolism.
Glycerol 3-phosphate phosphatase/PGPH-2 counters metabolic stress and promotes healthy aging via a glycogen sensing-AMPK-HLH-30-autophagy axis in C. elegans.
Activated Lymphocyte-Derived DNA Drives Glucose Metabolic Adaptation for Inducing Macrophage Inflammatory Response in Systemic Lupus Erythematosus.
Genetics of enzymatic dysfunctions in metabolic disorders and cancer.

J Vis Exp. 2023 Mar 03.

Methods for Studying Glycogen Metabolism.

Bartholomew A Pederson.

ARTICLES DISCUSSED: Wilson, W. A. Spectrophotometric methods for the study of eukaryotic glycogen metabolism. Journal of Visualized Experiments. (174), e63046 (2021). Wang, J. J. et al. A non-degradative extraction method for molecular structure characterization of bacterial glycogen particles. Journal of Visualized Experiments. (180), e63016 (2022). Wang, Z., Liu, Q., Wang, L., Gilbert, R. G., Sullivan, M. A. The extraction of liver glycogen molecules for glycogen structure determination. Journal of Visualized Experiments. (180), e63088 (2022). Jensen, R., Ortenblad, N., di Benedetto, C., Qvortrup, K., Nielsen, J. Quantification of subcellular glycogen distribution in skeletal muscle fibers using transmission electron microscopy. Journal of Visualized Experiments. (180), e63347 (2022). Fermont, L., Szydlowski, N., Colleoni, C. Determination of glucan chain length distribution of glycogen using the fluorophore-assisted carbohydrate electrophoresis (FACE) method. Journal of Visualized Experiments. (181), e63392 (2022).

DOI: https://doi.org/10.3791/65023
Molecules. 2023 Aug 15. pii: 6065. [Epub ahead of print]28(16):

Fluoride as a Potential Repressor of Glycogen Metabolism in Skeletal Muscle Cell Line CCL136.

Izabela Gutowska, Agnieszka Maruszewska, Marta Skórka-Majewicz, Agnieszka Kempińska-Podhorodecka, Agnieszka Kolasa, Agata Wszołek, Irena Baranowska-Bosiacka, Wojciech Żwierełło.

  The exposure of humans to fluorine is connected with its presence in the air, food and water. It is well known that fluorides even at a low concentration but with long time exposure accumulate in the body and lead to numerous metabolic disorders. Fluoride is recognised as a factor modulating the energy metabolism of cells. This interaction is of particular importance in muscle cells, which are cells with high metabolic activity related to the metabolism of glucose and glycogen. In someone suffering from chronic fluoride poisoning, frequent symptoms are chronic fatigue not relieved by extra sleep or rest, muscular weakness, muscle spasms, involuntary twitching. The aim of this study was to examine the effect of fluorine at concentrations determined in blood of people environmentally exposed to fluorides on activity and expression of enzymes taking part in metabolism of muscle glycogen. CCL136 cells were cultured under standard conditions with the addition of NaF. The amount of ATP produced by the cells was determined using the HPLC method, the amount and expression of genes responsible for glycogen metabolism using WB and RT PCR methods and the amount of glycogen in cells using the fluorimetric and PAS methods. It has been shown that in CCL136 cells exposed to 1, 3 and 10 μM NaF there is a change in the energy state and expression pattern of enzymes involved in the synthesis and breakdown of glycogen. It was observed that NaF caused a decrease in ATP content in CCL136 cells. Fluoride exposure also increased glycogen deposition. These changes were accompanied by a decrease in gene expression and the level of enzymatic proteins related to glycogen metabolism: glycogen synthase, glycogen synthase kinase and glycogen phosphorylase. The results obtained shed new light on the molecular mechanisms by which fluoride acts as an environmental toxin.

Keywords:  fluoride (F-) toxicity; glycogen phosphorylase muscle isoform (PYGM); glycogen synthase (GYS); glycogen synthase kinase (GSK); muscle glycogen metabolism

DOI:  https://doi.org/10.3390/molecules28166065
Children (Basel). 2023 Aug 11. pii: 1375. [Epub ahead of print]10(8):

An Unusual Case of Neonatal Hypotonia and Femur Fracture: Neuromuscular Variant of Glycogen Storage Disease Type IV.

Handan Bezirganoglu, Kubra Adanur Saglam.

  Glycogen storage disease type IV (GSD IV) (OMIM #232500) is an autosomal recessive disorder caused by deficiency of the glycogen-branching enzyme. Here, we report a patient presenting with prematurity and severe hypotonia resulting from a complicated pregnancy with polyhydramnios. During her stay in the neonatal unit, the infant remained dependent on a ventilator, and her movements were mostly absent, except for occasional small movements of her fingers. A spontaneous fracture of femur shaft occurred in the postnatal fourth week. Whole-exome sequencing of DNA from the patient revealed a homozygous missense variant in the GBE1 gene (c.1693C>T, p.Arg565Trp). The variation detected in the index case was also confirmed by Sanger sequencing in the patient and respective parents. This study showed that the neuromuscular subtypes of GSD-IV should be considered as a possible differential diagnosis in severe neonatal hypotonia cases.

Keywords:  GSD-IV; neonatal fracture; neonatal hypotonia

DOI:  https://doi.org/10.3390/children10081375
Neuromuscul Disord. 2023 Jul 23. pii: S0960-8966(23)00172-4. [Epub ahead of print]

Glycogen storage disease type IV without detectable polyglucosan bodies: importance of broad gene panels.

Agata Oliwa, Gavin Langlands, Anna Sarkozy, Pinki Munot, Willie Stewart, Rahul Phadke, Ana Topf, Volker Straub, Roderick Duncan, Ralph Wigley, Richard Petty, Cheryl Longman, Maria Elena Farrugia.

  Glycogen storage disease type IV (GSD IV) is caused by mutations in the glycogen branching enzyme 1 (GBE1) gene and is characterized by accumulation of polyglucosan bodies in liver, muscle and other tissues. We report three cases with neuromuscular forms of GSD IV, none of whom had polyglucosan bodies on muscle biopsy. The first case had no neonatal problems and presented with delayed walking. The other cases presented at birth: one with arthrogryposis, hypotonia, and respiratory distress, the other with talipes and feeding problems. All developed a similar pattern of axial weakness, proximal upper limb weakness and scapular winging, and much milder proximal lower limb weakness. Our cases expand the phenotypic spectrum of neuromuscular GSD IV, highlight that congenital myopathy and limb girdle weakness can be caused by mutations in GBE1, and emphasize that GSD IV should be considered even in the absence of characteristic polyglucosan bodies on muscle biopsy.

Keywords:  GBE1; GSD IV; Glycogen branching enzyme 1; Glycogen storage disease type IV; Limb girdle weakness; Polyglucosan bodies; Polyglucosan body myopathy

DOI:  https://doi.org/10.1016/j.nmd.2023.07.004
J Pediatr Endocrinol Metab. 2023 Aug 25.

Systematic literature review of the epidemiology of glycogen storage disease type 1a.

Tamás Zelei, Sándor Kovács, Patrick Finn, Dávid Nagy, Vanja Sikirica, Katherine B Carlson, Zoltán Vokó.

  Glycogen storage disease (GSD) type 1a is an inherited autosomal recessive metabolic disease caused by a deficiency in glucose-6-phosphatase activity. The objectives of this research were to systematically review the published literature on the epidemiology of GSD 1a and to assess the performance of reported epidemiology measures in a simulation model. In this systematic literature review 2,539 record titles and abstracts were screened. Of these, only 11 studies contained relevant data on GSD 1a disease epidemiology. Reported disease frequency ranged from 0.085/100,000 to 10.3/100,000 newborns when considering all the GSD literature. When this was narrowed to GSD 1 and GSD 1a, the range was tightened to 0.25-3.02/100,000 and 0.085-4.9/100,000 newborns, respectively. Most of the identified studies counted the number of diagnoses in a defined period and related to the number of births in the same (Dx method) or different time period (DoB method). The simulation model results indicate that in most of the situations, the Dx method provides a closer estimate to the true disease incidence than the DoB method. Despite the scarcity of epidemiology data, the results of this systematic review strongly support that GSD 1a and its parent disease groups (GSD and GSD 1) are rare diseases.

Keywords:  GSD 1a; epidemiology; glycogen storage disease type 1a; prevalence; simulation modelling; systematic literature review

DOI:  https://doi.org/10.1515/jpem-2023-0127
Mol Genet Metab Rep. 2023 Sep;36 100997

GAA variants associated with reduced enzymatic activity but lack of Pompe-related symptoms, incidentally identified by exome sequencing.

Anna Malekkou, Athina Theodosiou, Angelos Alexandrou, Ioannis Papaevripidou, Carolina Sismani, Edwin H Jacobs, George J G Ruijter, Violetta Anastasiadou, Sofia Ourani, Emilia Athanasiou, Anthi Drousiotou, Olga Grafakou, Petros P Petrou.

  Pompe disease is a rare metabolic myopathy caused by pathogenic variants affecting the activity of the lysosomal glycogen-degrading enzyme acid alpha-glucosidase (GAA). Impaired GAA function results in the accumulation of undegraded glycogen within lysosomes in multiple tissues but predominantly affects the skeletal, smooth and cardiac muscle. The degree of residual enzymatic activity appears to roughly correlate with the age of onset and the severity of the clinical symptoms. Here, we report four siblings in which the GAA variants NM_000152.5:c.2237G > C p.(Trp746Ser) and NM_000152.5:c.266G > A p.(Arg89His) were identified as an incidental finding of clinical exome sequencing. These variants are listed in the ClinVar and the Pompe disease GAA variant databases but are reported here for the first time in compound heterozygosity. All four siblings displayed normal urine tetrasaccharide levels and no clinical manifestations related to Pompe disease. Nevertheless, GAA enzymatic activity was within the range for late onset Pompe patients. Our report shows an association between a novel genotype and attenuated GAA enzymatic activity. The clinical significance can only be established by the regular monitoring of these individuals. The study highlights the major challenges for clinical care arising from incidental findings of next generation sequencing.

Keywords:  Acid alpha glucosidase; Case report; Exome sequencing; Glycogen storage disorder; Pompe disease; Variants

DOI:  https://doi.org/10.1016/j.ymgmr.2023.100997
Sci Rep. 2023 Aug 23. 13(1): 13807

Basidiomycota species in Drosophila gut are associated with host fat metabolism.

Berkay Bozkurt, Gamze Terlemez, Efe Sezgin.

The importance of bacterial microbiota on host metabolism and obesity risk is well documented. However, the role of fungal microbiota on host storage metabolite pools is largely unexplored. We aimed to investigate the role of microbiota on D. melanogaster fat metabolism, and examine interrelatedness between fungal and bacterial microbiota, and major metabolic pools. Fungal and bacterial microbiota profiles, fat, glycogen, and trehalose metabolic pools are measured in a context of genetic variation represented by whole genome sequenced inbred Drosophila Genetic Reference Panel (DGRP) samples. Increasing Basidiomycota, Acetobacter persici, Acetobacter pomorum, and Lactobacillus brevis levels correlated with decreasing triglyceride levels. Host genes and biological pathways, identified via genome-wide scans, associated with Basidiomycota and triglyceride levels were different suggesting the effect of Basidiomycota on fat metabolism is independent of host biological pathways that control fungal microbiota or host fat metabolism. Although triglyceride, glycogen and trehalose levels were highly correlated, microorganisms' effect on triglyceride pool were independent of glycogen and trehalose levels. Multivariate analyses suggested positive interactions between Basidiomycota, A. persici, and L. brevis that collectively correlated negatively with fat and glycogen pools. In conclusion, fungal microbiota can be a major player in host fat metabolism. Interactions between fungal and bacterial microbiota may exert substantial control over host storage metabolite pools and influence obesity risk.

DOI: https://doi.org/10.1038/s41598-023-41027-2
Nat Commun. 2023 Aug 25. 14(1): 5214

Glycerol 3-phosphate phosphatase/PGPH-2 counters metabolic stress and promotes healthy aging via a glycogen sensing-AMPK-HLH-30-autophagy axis in C. elegans.

Elite Possik, Laura-Lee Klein, Perla Sanjab, Ruyuan Zhu, Laurence Côté, Ying Bai, Dongwei Zhang, Howard Sun, Anfal Al-Mass, Abel Oppong, Rasheed Ahmad, Alex Parker, S R Murthy Madiraju, Fahd Al-Mulla, Marc Prentki.

Metabolic stress caused by excess nutrients accelerates aging. We recently demonstrated that the newly discovered enzyme glycerol-3-phosphate phosphatase (G3PP; gene Pgp), which operates an evolutionarily conserved glycerol shunt that hydrolyzes glucose-derived glycerol-3-phosphate to glycerol, counters metabolic stress and promotes healthy aging in C. elegans. However, the mechanism whereby G3PP activation extends healthspan and lifespan, particularly under glucotoxicity, remained unknown. Here, we show that the overexpression of the C. elegans G3PP homolog, PGPH-2, decreases fat levels and mimics, in part, the beneficial effects of calorie restriction, particularly in glucotoxicity conditions, without reducing food intake. PGPH-2 overexpression depletes glycogen stores activating AMP-activate protein kinase, which leads to the HLH-30 nuclear translocation and activation of autophagy, promoting healthy aging. Transcriptomics reveal an HLH-30-dependent longevity and catabolic gene expression signature with PGPH-2 overexpression. Thus, G3PP overexpression activates three key longevity factors, AMPK, the TFEB homolog HLH-30, and autophagy, and may be an attractive target for age-related metabolic disorders linked to excess nutrients.

DOI: https://doi.org/10.1038/s41467-023-40857-y
Cells. 2023 Aug 18. pii: 2093. [Epub ahead of print]12(16):

Activated Lymphocyte-Derived DNA Drives Glucose Metabolic Adaptation for Inducing Macrophage Inflammatory Response in Systemic Lupus Erythematosus.

Hanqing Zhao, Zhenke Wen, Sidong Xiong.

  Activated lymphocyte-derived DNA (ALD-DNA) has been reported to drive the polarization of macrophages toward M2b, producing inflammatory cytokines and inducing inflammation, correspondingly playing an essential role in the development of systemic lupus erythematosus (SLE). Recently, accumulating evidence has pinpointed metabolic adaptation as the crucial cell-intrinsic determinant for inflammatory response, in which glucose metabolism is the key event. However, whether and how glucose metabolism was involved in ALD-DNA-induced macrophage inflammatory response and SLE development remains unclear. Herein, we performed glucose metabolomic analyses of ALD-DNA-stimulated macrophages and uncovered increased glycolysis and diminished pentose phosphate pathway (PPP), as well as enhanced glycogenesis. In ALD-DNA-stimulated macrophages, increased glycolysis resulted in higher lactate production, whereas diminished PPP efficiently led to lower levels of nicotinamide adenine dinucleotide phosphate (NADPH) with higher levels of reactive oxygen species (ROS). While blockade of lactate generation exerted no significant effect on macrophage inflammation in response to ALD-DNA, scavenging ROS fundamentally inhibited the inflammatory response of ALD-DNA-stimulated macrophages. Further, cyclic adenosine monophosphate (cAMP), a master for regulating glycogen metabolism, was downregulated by ALD-DNA in macrophages, which subsequently imbalanced glycogen metabolism toward glycogenesis but not glycogenolysis. Administration of cAMP effectively restored glycogenolysis and enhanced PPP, which correspondingly reduced ROS levels and inhibited the inflammatory response of ALD-DNA-stimulated macrophages. Finally, blocking glucose metabolism using 2-deoxy-D-glucose (2-DG) efficiently restricted macrophage inflammatory response and alleviated ALD-DNA-induced lupus disease. Together, our findings demonstrate that ALD-DNA drives the adaptation of glucose metabolism for inducing macrophage inflammatory response in SLE, which might further our understanding of disease pathogenesis and provide clues for interventive explorations.

Keywords:  ALD-DNA; SLE; cAMP; glucose metabolism; macrophage inflammatory response

DOI:  https://doi.org/10.3390/cells12162093
Front Oncol. 2023 ;13 1230934

Genetics of enzymatic dysfunctions in metabolic disorders and cancer.

Mélanie Mahé, Tiffany J Rios-Fuller, Andrea Karolin, Robert J Schneider.

  Inherited metabolic disorders arise from mutations in genes involved in the biogenesis, assembly, or activity of metabolic enzymes, leading to enzymatic deficiency and severe metabolic impairments. Metabolic enzymes are essential for the normal functioning of cells and are involved in the production of amino acids, fatty acids and nucleotides, which are essential for cell growth, division and survival. When the activity of metabolic enzymes is disrupted due to mutations or changes in expression levels, it can result in various metabolic disorders that have also been linked to cancer development. However, there remains much to learn regarding the relationship between the dysregulation of metabolic enzymes and metabolic adaptations in cancer cells. In this review, we explore how dysregulated metabolism due to the alteration or change of metabolic enzymes in cancer cells plays a crucial role in tumor development, progression, metastasis and drug resistance. In addition, these changes in metabolism provide cancer cells with a number of advantages, including increased proliferation, resistance to apoptosis and the ability to evade the immune system. The tumor microenvironment, genetic context, and different signaling pathways further influence this interplay between cancer and metabolism. This review aims to explore how the dysregulation of metabolic enzymes in specific pathways, including the urea cycle, glycogen storage, lysosome storage, fatty acid oxidation, and mitochondrial respiration, contributes to the development of metabolic disorders and cancer. Additionally, the review seeks to shed light on why these enzymes represent crucial potential therapeutic targets and biomarkers in various cancer types.

Keywords:  cancer; enzymatic dysregulation; fatty acid oxidation; glycogen storage; inherited metabolic disorders; lysosome storage; mitochondrial respiration; urea cycle

DOI:  https://doi.org/10.3389/fonc.2023.1230934