bims-glecem 2022-01-30 papers

bims-glecem

Biomed News

on Glycogen metabolism in exercise, cancer and energy metabolism

Issue of 2022–01–30
nine papers selected by
Dipsikha Biswas, Københavns Universitet

Combined action of chemical chaperones on stability, aggregation and ologomeric state of muscle glycogen phosphorylase b.
Glycogen synthase downregulation rescues the amylopectinosis of murine RBCK1 deficiency.
[Genetic analysis of PYGL gene variants for a child with Glycogen storage disease VI].
Effect of acute swimming exercise at different intensities but equal total load over metabolic and molecular responses in swimming rats.
Efficacious Androgen Hormone Administration in Combination With AAV Vector-Mediated Gene Therapy in Female Mice With Pompe Disease.
Anti-adipogenic effect of the flavonoids through the activation of AMPK in palmitate (PA)-treated HepG2 cells.
The anti-fatigue effect of the Auxis thazard oligopeptide via modulation of the AMPK/PGC-1α pathway in mice.
Clues from the intestinal mucus proteome of Atlantic salmon to counter inflammation.
The Role of Fatty Acid Signaling in Islet Beta-Cell Adaptation to Normal Pregnancy.

Int J Biol Macromol. 2022 Jan 20. pii: S0141-8130(22)00121-0. [Epub ahead of print]

Combined action of chemical chaperones on stability, aggregation and ologomeric state of muscle glycogen phosphorylase b.

Tatiana B Eronina, Valeriya V Mikhaylova, Natalia A Chebotareva, Sergey Y Kleymenov, Anastasia V Pivovarova, Boris I Kurganov.

  Chemical chaperones are a class of small molecules, which enhance protein stability, folding, inhibit protein aggregation, and are used for long-term storage of therapeutic proteins. The combined action of chemical chaperones trehalose, betaine and lysine on stability, aggregation and oligomeric state of muscle glycogen phosphorylase b (Phb) has been studied. Dynamic light scattering data indicate that the affinity of trehalose to Phb increased in the presence of betaine or lysine at both stages (stage of nucleation and aggregate growth) of enzyme aggregation at 48 °C, in contrast, the affinity of betaine to the enzyme in the presence of lysine remained practically unchanged. According to differential scanning calorimetry and analytical ultracentrifugation data, the mixture of trehalose and betaine stabilized Phb stronger than either of them in total. Moreover, the destabilizing effect of lysine on the enzyme was almost completely compensated by trehalose and only partially by betaine. The main protective effect of the mixtures of osmolytes and lysine is associated with their influence on the dissociation/denaturation stage, which is the rate-limiting one of Phb aggregation. Thus, a pair of chaperones affects the stability, oligomeric state, and aggregation of Phb differently than individual chaperones.

Keywords:  Aggregation; Denaturation; Glycogen phosphorylase b; Mixture of chemical chaperones

DOI:  https://doi.org/10.1016/j.ijbiomac.2022.01.106
Brain. 2022 Jan 27. pii: awac017. [Epub ahead of print]

Glycogen synthase downregulation rescues the amylopectinosis of murine RBCK1 deficiency.

Silvia Nitschke, Mitchell A Sullivan, Sharmistha Mitra, Charlotte R Marchioni, Jennifer P Y Lee, Brandon H Smith, Saija Ahonen, Jun Wu, Erin E Chown, Peixiang Wang, Sara Petković, Xiaochu Zhao, Laura F DiGiovanni, Ami M Perri, Lori Israelian, Tamar R Grossman, Holly Kordasiewicz, Francisco Vilaplana, Kazuhiro Iwai, Felix Nitschke, Berge A Minassian.

  Longer glucan chains tend to precipitate. Glycogen, by far the largest mammalian glucan and the largest molecule in the cytosol with up to 55,000 glucoses, does not, due to a highly regularly branched spherical structure that allows it to be perfused with cytosol. Aberrant construction of glycogen leads it to precipitate, accumulate into polyglucosan bodies (PBs) that resemble plant starch amylopectin, and cause disease. This pathology, amylopectinosis, is caused by mutations in a series of single genes whose functions are under active study toward understanding the mechanisms of proper glycogen construction. Concurrently, we are characterizing the physicochemical particularities of glycogen and polyglucosans associated with each gene. These genes include GBE1, EPM2A and EPM2B, which respectively encode the glycogen branching enzyme, the glycogen phosphatase laforin and the laforin-interacting E3 ubiquitin ligase malin for which an unequivocal function is not yet known. Mutations in GBE1 cause a motor neuron disease (Adult Polyglucosan Body Disease, APBD), and mutations in EPM2A or EPM2B a fatal progressive myoclonus epilepsy (Lafora disease, LD). RBCK1 deficiency (RD) causes an amylopectinosis with fatal skeletal and cardiac myopathy (Polyglucosan Body Myopathy 1, PGBM1, OMIM# 615895). RBCK1 is a component of the linear ubiquitin chain assembly complex (LUBAC), with unique functions including generating linear ubiquitin chains and ubiquitinating hydroxyl (versus canonical amine) residues, including of glycogen. In a mouse model we now show (1) that the amylopectinosis of RD like in APBD and LD affects the brain, (2) that RD glycogen like in APBD and LD has overlong branches, (3) that unlike APBD but like LD, RD glycogen is hyperphosphorylated, and finally (4) that unlike laforin-deficient LD but like malin-deficient LD RD's glycogen hyperphosphorylation is limited to precipitated polyglucosans. In summary, the fundamental glycogen pathology of RD recapitulates that of malin-deficient LD. Additionally, we uncover sex and genetic background effects in RD on organ and brain region specific amylopectinoses, and in the brain on consequent neuroinflammation and behavioral deficits. Finally, we exploit the portion of the basic glycogen pathology that is common to APBD, both forms of LD, and RD, namely overlong branches, to show that a unified approach based on downregulating glycogen synthase, the enzyme that elongates glycogen branches, can rescue all four diseases.

Keywords:  PGBM1 (Polyglucosan body myopathy 1); RBCK1/HOIL1; antisense oligonucleotide (ASO) therapy; glycogen synthase; neuroinflammation

DOI:  https://doi.org/10.1093/brain/awac017
Zhonghua Yi Xue Yi Chuan Xue Za Zhi. 2022 Feb 10. 39(2): 209-212

[Genetic analysis of PYGL gene variants for a child with Glycogen storage disease VI].

Yucan Zheng, Guiping Kong, Guorui Hu, Bixia Zheng, Mei Li.

OBJECTIVE: To explore the clinical features and genetic basis of a patient with glycogen storage disease type VI (GSD-VI).
METHODS: Clinical data of the patient was collected. Genomic DNA was extracted from peripheral blood samples of the proband and his parents. Genetic variants were detected by using whole exome sequencing. Candidate variants were verified by Sanger sequencing followed by bioinformatics analysis.
RESULTS: The proband presented fasting hypoglycemia, hepatomegaly, growth retardation, transaminitis, metabolic acidosis and hyperlactatemia. Liver biopsy indicated GSD. Novel compound heterozygous PYGL gene variants (c.2089A>G/c.158_160delACT) were detected in the proband. Compound heterozygosity was confirmed by Sanger sequencing of the patient's genomic DNA. Provean and MutationTaster predicted the two variants as deleterious and the variant sites are highly conserved.
CONCLUSION: The compound heterozygous variants (c.2089A>G/c.158_160delACT) of PYGL gene probably underlay the GSD in the patient. The two novel variants have expanded the spectrum of PYGL gene variants and provided the basis for genetic counseling of the family.

DOI: https://doi.org/10.3760/cma.j.cn511374-20201225-00913
J Muscle Res Cell Motil. 2022 Jan 27.

Effect of acute swimming exercise at different intensities but equal total load over metabolic and molecular responses in swimming rats.

Lucas Dantas Maia Forte, Natália de Almeida Rodrigues, André Vitor Cordeiro, Thais de Fante, Laís Angélica de Paula Simino, Adriana de Souza Torsoni, Márcio Alberto Torsoni, Claudio Alexandre Gobatto, Fúlvia Barros Manchado-Gobatto.

  Acute metabolic and molecular response to exercise may vary according to exercise's intensity and duration. However, there is a lack regarding specific tissue alterations after acute exercise with aerobic or anaerobic predominance. The present study investigated the effects of acute exercise performed at different intensities, but with equal total load on molecular and physiological responses in swimming rats. Sixty male rats were divided into a control group and five groups performing an acute bout of swimming exercise at different intensities (80, 90, 100, 110 and 120% of anaerobic threshold [AnT]). The exercise duration of each group was balanced so all groups performed at the same total load. Gene expression (HIF-1α, PGC-1α, MCT1 and MCT4 mRNA), blood biomarkers and tissue glycogen depletion were analyzed after the exercise session. ANOVA One-Way was used to indicate statistical mean differences considering 5% significance level. Blood lactate concentration was the only biomarker sensitive to acute exercise, with a significant increase in rats exercised above AnT intensities (p < 0.000). Glycogen stores of gluteus muscle were significantly reduced in all exercised animals in comparison to control group (p = 0.02). Hepatic tissue presented significant reduction in glycogen in animals exercised above AnT (p = 0.000, as well as reduced HIF-1α mRNA and increased MCT1 mRNA, especially at the highest intensity (p = 0.002). Physiological parameters did not alter amongst groups for most tissues. Our results indicate the hepatic tissue alterations (glycogen stores and gene expressions) in response to different exercise intensities of exercise, even with the total load matched.

Keywords:  Anaerobic threshold; Exercise; Hypoxia-inducible factor 1; Monocarboxylic acid transporters; Peroxisome proliferator-activated receptor gamma coactivator 1-alpha; Physiological stress

DOI:  https://doi.org/10.1007/s10974-022-09614-4
Hum Gene Ther. 2022 Jan 26.

Efficacious Androgen Hormone Administration in Combination With AAV Vector-Mediated Gene Therapy in Female Mice With Pompe Disease.

Sangoh Han, Dorothy Brooke Gheorghiu, Alex Chang, Sweet Hope Mapatano, Songtao Li, Elizabeth D Brooks, Dwight Koeberl.

Pompe disease is an autosomal recessive lysosomal storage disorder caused by deficiency of acid α-glucosidase (GAA), resulting in skeletal muscle weakness and cardiomyopathy that progresses despite currently available therapy in some patients. The development of gene therapy with adeno-associated virus (AAV) vectors revealed a sex-dependent decrease in efficacy in female mice with Pompe disease. This study evaluated the effect of testosterone on gene therapy with an AAV2/8 vector containing a liver-specific promoter to drive expression of GAA (AAV2/8-LSPhGAA) in female GAA-knockout (KO) mice that were implanted with pellets containing testosterone propionate prior to vector administration. Six weeks following treatment, neuromuscular function and muscle strength were improved as demonstrated by increased Rotarod and wirehang latency for female mice treated with testosterone and vector, in comparison with vector alone. Biochemical correction improved following the addition of testosterone as demonstrated by increased GAA activity and decreased glycogen content in the skeletal muscles of female mice treated with testosterone and vector, in comparison with vector alone. An alternative androgen, oxandrolone, was evaluated similarly to reveal increased GAA in the diaphragm and EDL of female GAA-KO mice following oxandrolone administration; however, glycogen content was unchanged by oxandrolone treatment. The efficacy of androgen hormone treatment in females correlated with increased mannose-6-phosphate receptor in skeletal muscle. These data confirmed the benefits of brief treatment with an androgen hormone in mice with Pompe disease during gene therapy.

DOI: https://doi.org/10.1089/hum.2021.218
J Vet Sci. 2022 Jan;23(1): e4

Anti-adipogenic effect of the flavonoids through the activation of AMPK in palmitate (PA)-treated HepG2 cells.

Priyanka Rajan, Premkumar Natraj, Sachithra S Ranaweera, Lakshi A Dayarathne, Young Jae Lee, Chang-Hoon Han.

   BACKGROUND: Flavonoids are natural polyphenols found widely in citrus fruit and peel that possess anti-adipogenic effects. On the other hand, the detailed mechanisms for the anti-adipogenic effects of flavonoids are unclear.
OBJECTIVES: The present study observed the anti-adipogenic effects of five major citrus flavonoids, including hesperidin (HES), narirutin (NAR), nobiletin (NOB), sinensetin (SIN), and tangeretin (TAN), on AMP-activated protein kinase (AMPK) activation in palmitate (PA)-treated HepG2 cells.
METHODS: The intracellular lipid accumulation and triglyceride (TG) contents were quantified by Oil-red O staining and TG assay, respectively. The glucose uptake was assessed using 2-[N-(7-Nitrobenz-2-oxa-1,3-diazol-4-yl)amino]-2-deoxy-d-glucose (2-NBDG) assay. The levels of AMPK, acetyl-CoA carboxylase (ACC), and glycogen synthase kinase 3 beta (GSK3β) phosphorylation, and levels of sterol regulatory element-binding protein 2 (SREBP-2) and 3-hydroxy-3-methylglutaryl-CoA reductase (HMGCR) expression were analyzed by Western blot analysis. The potential interaction between the flavonoids and the γ-subunit of AMPK was investigated by molecular docking analysis.
RESULTS: The flavonoid treatment reduced both intracellular lipid accumulation and TG content in PA-treated HepG2 cells significantly. In addition, the flavonoids showed increased 2-NBDG uptake in an insulin-independent manner in PA-treated HepG2 cells. The flavonoids increased the AMPK, ACC, and GSK3β phosphorylation levels and decreased the SREBP-2 and HMGCR expression levels in PA-treated HepG2 cells. Molecular docking analysis showed that the flavonoids bind to the CBS domains in the regulatory γ-subunit of AMPK with high binding affinities and could serve as potential AMPK activators.
CONCLUSION: The overall results suggest that the anti-adipogenic effect of flavonoids on PA-treated HepG2 cells results from the activation of AMPK by flavonoids.

Keywords:  AMP-activated protein kinase; Adipogenesis; HepG2 cells; flavonoids; molecular docking

DOI:  https://doi.org/10.4142/jvs.21256
Food Funct. 2022 Jan 26.

The anti-fatigue effect of the Auxis thazard oligopeptide via modulation of the AMPK/PGC-1α pathway in mice.

Yushan Qu, Hongwu Ji, Wenkui Song, Shuo Peng, Suhong Zhan, Liuyi Wei, Ming Chen, Di Zhang, Shucheng Liu.

The Auxis thazard oligopeptide (ATO) was obtained by papain digestion and ultrafiltration membrane separation, and its anti-fatigue effects and mechanisms were evaluated using animal experiments on Kunming mice. Compared with the negative control group, the ATO extended the time to exhaustion in mice in a forced swim test by 0.81-1.62 times. Liver glycogen levels were significantly increased by 0.6-1.63 times and muscle glycogen levels were increased by 9.52-10.02%; the levels of lactic acid (16.46-17.21%) and urea nitrogen (34.88-41.91%) decreased. The ATO also increased antioxidant activity, reduced malondialdehyde levels (18.00-35.79%) in the liver and myocardium, and increased the gene and protein expression of AMPK and PGC-1α in fatigued mice. These results indicate that the ATO exerts an anti-fatigue effect via improving energy metabolism and decreasing oxidative stress.

DOI: https://doi.org/10.1039/d1fo03320d
J Proteomics. 2022 Jan 19. pii: S1874-3919(22)00010-0. [Epub ahead of print] 104487

Clues from the intestinal mucus proteome of Atlantic salmon to counter inflammation.

Viswanath Kiron, Purushothaman Kathiresan, Jorge M O Fernandes, Mette Sørensen, Ghana K Vasanth, Lin Qingsong, Qifeng Lin, Lim Teck Kwang, Dalia Dahle, Jorge Dias, Viviane Verlhac Trichet.

  Intestinal inflammation in Atlantic salmon was studied by profiling the intestine mucus proteome, employing iTRAQ and 2D LC-MS/MS approach. Two fish groups were fed soy saponin-containing (inflammation inducer, SO and SP) diets and two control fish groups were fed diets devoid of soy saponin (CO and CP) for 36 days. The CP and SP groups were fed diets with a health additive. Inflammation characteristics in the intestine were milder in the SP-fed fish compared to the SO-fed fish. The SO group was characterised by alterations of many proteins. KEGG pathways such as phagosome and lipid binding were possibly affected in the SO group due to the higher abundant proteins like Integrin beta 2 precursor, Coronin 1A, Cathepsin S precursor, Vesicle-trafficking protein, and Neutrophil cytosol factors. On the other hand, the SP group had fewer altered proteins and inflammation characteristics; aminoacyl-tRNA biosynthesis and ribosome in the fish group were plausibly aberrated due to the higher abundance of many large and small subunit of ribosomes. Elevation of the abundance of ribosomal proteins, aminoacyl-tRNA ligases, and appropriate abundance of Glycogen phosphorylase and Glutamine synthetase could alleviate intestinal inflammation. Data are available via ProteomeXchange with identifier PXD027922 and PXD029849. SIGNIFICANCE: Intestinal inflammation, caused by dietary factors, can be considered as a non-infectious disease. Hence, researchers are gathering clues to avert the associated health issues. The present study was conducted to infer the alterations in the intestine mucus proteome induced by a dietary health additive to counter intestinal inflammation in farmed Atlantic salmon. The reduction in the number of affected proteins and their alterations point to mechanisms evoked by the premix. Our knowledge on inflammation associated proteome in fish is limited and the present study not only highlights the changes, but also opens the possibility to avert the dysfunction of the organ through a dietary approach.

Keywords:  Aminoacyl-tRNA ligases; Atlantic salmon; Glutamine synthetase; Glycogen phosphorylase; Intestinal inflammation; Mucus proteome; Ribosomal proteins; Soy saponin

DOI:  https://doi.org/10.1016/j.jprot.2022.104487
Front Endocrinol (Lausanne). 2021 ;12 799081

The Role of Fatty Acid Signaling in Islet Beta-Cell Adaptation to Normal Pregnancy.

Jee-Hye Kim, Viviane Delghingaro-Augusto, Jeng Yie Chan, D Ross Laybutt, Joseph Proietto, Christopher J Nolan.

   Background: Maintenance of a normal fetal nutrient supply requires major adaptations in maternal metabolic physiology, including of the islet beta-cell. The role of lipid signaling processes in the mechanisms of islet beta-cell adaptation to pregnancy has been minimally investigated.
Objective: To determine the effects of pregnancy on islet fatty acid (FA) metabolic partitioning and FA augmentation of glucose-stimulated insulin secretion (GSIS).
Methods: Age matched virgin, early pregnant (gestational day-11, G11) and late pregnant (G19) Sprague-Dawley rats were studied. Fasted and fed state biochemistry, oral glucose tolerance tests (OGTT), and fasted and post-OGTT liver glycogen, were determined to assess in vivo metabolic characteristics. In isolated islets, FA (BSA-bound palmitate 0.25 mmol/l) augmentation of GSIS, FA partitioning into esterification and oxidation processes using metabolic tracer techniques, lipolysis by glycerol release, triacylglycerols (TG) content, and the expression of key beta-cell genes were determined.
Results: Plasma glucose in pregnancy was lower, including during the OGTT (glucose area under the curve 0-120 min (AUC0-120); 655±24 versus 849±13 mmol.l-1.min; G19 vs virgin; P<0.0001), with plasma insulin concentrations equivalent to those of virgin rats (insulin AUC0-120; 97±7 versus 83±7 ng.ml-1.min; G19 vs virgin; not significant). Liver glycogen was depleted in fasted G19 rats with full recovery after oral glucose. Serum TG increased during pregnancy (4.4±0.4, 6.7±0.5; 17.1±1.5 mmol/l; virgin, G11, G19, P<0.0001), and islet TG content decreased (147±42, 172±27, 73±13 ng/µg protein; virgin, G11, G19; P<0.01). GSIS in isolated islets was increased in G19 compared to virgin rats, and this effect was augmented in the presence of FA. FA esterification into phospholipids, monoacylglycerols and TG were increased, whereas FA oxidation was reduced, in islets of pregnant compared to virgin rats, with variable effects on lipolysis dependent on gestational age. Expression of Ppargc1a, a key regulator of mitochondrial metabolism, was reduced by 51% in G11 and 64% in G19 pregnant rat islets compared to virgin rat islets (P<0.001).
Conclusion: A lowered set-point for islet and hepatic glucose homeostasis in the pregnant rat has been confirmed. Islet adaptation to pregnancy includes increased FA esterification, reduced FA oxidation, and enhanced FA augmentation of glucose-stimulated insulin secretion.

Keywords:  Ppargc1a; Sprague-Dawley rat; fatty acid metabolism; fatty acid signaling; hyperlipidemia; insulin secretion; pancreatic islet beta-cell; pregnancy

DOI:  https://doi.org/10.3389/fendo.2021.799081