bims-glecem 2023-07-02 papers

bims-glecem

Biomed News

on Glycogen metabolism in exercise, cancer and energy metabolism

Issue of 2023–07–02
nine papers selected by
Dipsikha Biswas, Københavns Universitet

Development of Continuum of Care for McArdle disease: A practical tool for clinicians and patients.
GAA deficiency disrupts distal airway cells in Pompe disease.
Novel Expression of GLUT3, GLUT6 and GLUT10 in Equine Gluteal Muscle Following Glycogen-Depleting Exercise: Impact of Dietary Starch and Fat.
Elucidation of intermolecular interactions between chlorogenic acid and glucose-6-phosphate translocase: A step towards chemically induced glycogen storage disease type 1b model.
Glycogen synthase kinase 3β (GSK3β) and presenilin (PS) are key regulators of kinesin-1-mediated cargo motility within axons.
Fibroblast growth factor 15, induced by elevated bile acids, mediates the improvement of hepatic glucose metabolism after sleeve gastrectomy.
Dysregulation of Metabolism and Proteostasis in Skeletal Muscle of a Presymptomatic Pompe Mouse Model.
Deactivation of glycogen synthase kinase-3β by heat shock‑inducible tumor small protein attenuates hyperthermia‑induced pro‑migratory activity in colorectal cancer cells.
Toward countering muscle and bone loss with spaceflight: GSK3 as a potential target.

Neuromuscul Disord. 2023 Jun 12. pii: S0960-8966(23)00143-8. [Epub ahead of print]33(7): 575-579

Development of Continuum of Care for McArdle disease: A practical tool for clinicians and patients.

S L Reason, N Voermans, A Lucia, J Vissing, R Quinlivan, S Bhai, A Wakelin.

  McArdle disease (glycogen storage disease type V; GSDV) is a rare genetic disease caused by the inability to break down glycogen in skeletal muscle due to a deficiency in myophosphorylase. Glycolysis is only partially blocked in GSDV, as muscle fibres can take up circulating glucose and convert it to glucose-6-phosphate downstream of the metabolic block. Because skeletal muscle predominantly relies on anaerobic energy during the first few minutes of transition from rest to activity, and throughout more intense activities, individuals with GSDV experience muscle fatigue/pain, tachypnea, and tachycardia during these activities. If warning signs are not heeded, a muscle contracture may rapidly occur, and if significant, may lead to acute rhabdomyolysis. Without a cure or treatment, individuals with GSDV must be consistent in employing proper management techniques; however, this can be challenging due to the nuances inherent in this metabolic myopathy. The International Association for Muscle Glycogen Storage Disease collaborated with an international team of five expert clinicians to identify areas of learning to achieve an optimal state. A Continuum of Care model was developed that outlines five pivotal steps (diagnosis; understanding; acceptance; learning and exercise) to streamline assessments and more succinctly assist clinicians in determining patient-specific learning needs. This model serves as a translational tool to help optimize care for this patient population.

Keywords:  Clinical pathway; Continuum of Care; GSDV; McArdle disease; Patient Advocacy Organization

DOI:  https://doi.org/10.1016/j.nmd.2023.05.006
Am J Physiol Lung Cell Mol Physiol. 2023 Jun 27.

GAA deficiency disrupts distal airway cells in Pompe disease.

Léa El Haddad, Elias Lai, Preetish Kadur Lakshminarasimha Murthy, Debolina D Biswas, Rania Soufny, Angela L Roger, Purushothamarao Rao Tata, Mai K ElMallah.

  Pompe disease is an autosomal recessive glycogen storage disease caused by mutations in the gene that encodes acid alpha-glucosidase (GAA) - an enzyme responsible for hydrolyzing lysosomal glycogen. GAA deficiency results in systemic lysosomal glycogen accumulation and cellular disruption. Glycogen accumulation in skeletal muscle, motor neurons, and airway smooth muscle cells are known to contribute to respiratory insufficiency in Pompe disease. However, the impact of GAA deficiency on the distal alveolar type 1 and type 2 cells (AT1 and AT2) has not been evaluated. AT1 cells rely on lysosomes for cellular homeostasis so that they can maintain a thin barrier for gas exchange, while AT2 cells depend on lysosome-like structures (lamellar bodies) for surfactant production. Using a mouse model of Pompe disease, the Gaa-/- mouse, we investigated the consequences of GAA deficiency on AT1 and AT2 cells using histology, pulmonary function and mechanics, and transcriptional analysis. Histological analysis revealed increased accumulation of lysosomal associated membrane protein 1 (LAMP1) in the Gaa-/- mice lungs. Further, ultrastructural examination showed extensive intracytoplasmic vacuoles enlargement and lamellar body engorgement. Respiratory dysfunction was confirmed using whole body plethysmography and forced oscillometry. Finally, transcriptomic analysis demonstrated dysregulation of surfactant proteins in AT2 cells, specifically reduced levels of surfactant protein D in the Gaa-/-mice. We conclude that GAA enzyme deficiency leads to glycogen accumulation in the distal airway cells that disrupts surfactant homeostasis and contributes to respiratory impairments in Pompe disease.

Keywords:  Distal airway cells; Pompe disease; Respiratory dysfunction; Surfactant proteins

DOI:  https://doi.org/10.1152/ajplung.00032.2023
Metabolites. 2023 Jun 01. pii: 718. [Epub ahead of print]13(6):

Novel Expression of GLUT3, GLUT6 and GLUT10 in Equine Gluteal Muscle Following Glycogen-Depleting Exercise: Impact of Dietary Starch and Fat.

Stephanie J Valberg, Deborah Velez-Irizarry, Zoe J Williams, Joe D Pagan, Vanesa Mesquita, Brian Waldridge, Hailey Maresca-Fichter.

  Horses have a slow rate of muscle glycogen repletion relative to other species for unknown reasons. Our aim was to determine the expression of glucose transporters (GLUT) and genes impacting GLUT4 expression and translocation in the gluteal muscle. Five fit Thoroughbred horses performed glycogen-depleting exercises on high-starch (HS, 2869 g starch/day) and low-starch, high-fat diets (LS-HF, 358 g starch/d) with gluteal muscle biopsies obtained before and after depletion and during repletion. Muscle glycogen declined by ≈30% on both diets with little increase during repletion on LS-HF. Transcriptomic analysis identified differential expression (DE) of only 2/12 genes impacting GLUT4 translocation (two subunits of AMP protein kinase) and only at depletion on LS-HF. Only 1/13 genes encoding proteins that promote GLUT4 transcription had increased DE (PPARGC1A at depletion LS-HF). GLUT4 comprised ≈30% of total GLUT mRNA expression at rest. Remarkably, by 72 h of repletion expression of GLUT3, GLUT6 and GLUT10 increased to ≈25% of total GLUT mRNA. Expression of GLUT6 and GLUT10 lagged from 24 h of repletion on HS to 72 h on LS-HF. Lacking an increase in GLUT4 gene expression in response to glycogen-depleting exercise, equine muscle increases GLUT3, GLUT6 and GLUT10 expression potentially to enhance glucose transport, resembling responses observed in resistance trained GLUT4-null mice.

Keywords:  carbohydrates; glucose transport; horse; nutrition; training

DOI:  https://doi.org/10.3390/metabo13060718
3 Biotech. 2023 Jul;13(7): 250

Elucidation of intermolecular interactions between chlorogenic acid and glucose-6-phosphate translocase: A step towards chemically induced glycogen storage disease type 1b model.

Santosh B Patil, Pramod C Gadad.

  Glucose-6-phosphate translocase enzyme, encoded by SLC37A4 gene, is a crucial enzyme involved in transporting glucose-6-phosphate into the endoplasmic reticulum. Inhibition of this enzyme can cause Von-Gierke's/glycogen storage disease sub-type 1b. The current study dealt to elucidate the intermolecular interactions to assess the inhibitory activity of Chlorogenic acid (CGA) against SLC37A4 was assessed by molecular docking and dynamic simulation. The alpha folded model of SLC37A4 and CGA 3D structure were optimized using CHARMM force field, using energy minimization protocol in the Discovery Studio software. Glucose-6-phosphate (G6P) and CGA molecular docking, Molecular dynamics (MD) simulation, analysis of binding free energy of G6P-SLC37A4 and CGA-SLC37A4 complexes was performed for 100 ns using GROMACS, followed by principal component analysis (PCA). The docking score of the CGA-SLC37A4 complex exhibited a higher docking score (- 8.2 kcal/mol) when compared to the G6P-SLC37A4 complex (- 6.5 kcal/mol), suggesting a stronger binding interaction between CGA and SLC37A4. Further, the MD simulation demonstrated a stable backbone and complex Root Mean Square Deviation (RMSD), the least RMS fluctuation, and stable active site residue interactions throughout the 100 ns production run. The CGA complex with SLC37A4 exhibits higher compactness and formed 8 hydrogen bonds to achieve stability. The binding free energy of the G6P-SLC37A4 and CGA-SLC37A4 complex was found to be - 12.73 and - 31.493 kcal/mol. Lys29 formed stable contact for both G6P (- 4.73 kJ/mol) and SLC37A4 (- 2.18 kJ/mol). This study imparts structural insights into the competitive inhibition of SLC37A4 by CGA. CGA shows potential as a candidate to induce manifestations of GSD1b by inhibiting glycogenolysis, and gluconeogenesis.
Supplementary Information: The online version contains supplementary material available at 10.1007/s13205-023-03661-5.

Keywords:  Chlorogenic acid; Glucose-6-phosphate exchanger; Glycogen storage disease type 1; Molecular docking; Molecular dynamics; SLC37A4

DOI:  https://doi.org/10.1007/s13205-023-03661-5
Front Cell Dev Biol. 2023 ;11 1202307

Glycogen synthase kinase 3β (GSK3β) and presenilin (PS) are key regulators of kinesin-1-mediated cargo motility within axons.

Rupkatha Banerjee, Shermali Gunawardena.

  It has been a quarter century since the discovery that molecular motors are phosphorylated, but fundamental questions still remain as to how specific kinases contribute to particular motor functions, particularly in vivo, and to what extent these processes have been evolutionarily conserved. Such questions remain largely unanswered because there is no cohesive strategy to unravel the likely complex spatial and temporal mechanisms that control motility in vivo. Since diverse cargoes are transported simultaneously within cells and along narrow long neurons to maintain intracellular processes and cell viability, and disruptions in these processes can lead to cancer and neurodegeneration, there is a critical need to better understand how kinases regulate molecular motors. Here, we review our current understanding of how phosphorylation can control kinesin-1 motility and provide evidence for a novel regulatory mechanism that is governed by a specific kinase, glycogen synthase kinase 3β (GSK3β), and a scaffolding protein presenilin (PS).

Keywords:  GSK3β; axonal transport; kinesin-1; phosphorylation; presenilin

DOI:  https://doi.org/10.3389/fcell.2023.1202307
World J Gastroenterol. 2023 Jun 07. 29(21): 3280-3291

Fibroblast growth factor 15, induced by elevated bile acids, mediates the improvement of hepatic glucose metabolism after sleeve gastrectomy.

Meng Wei, Wei-Bo Cao, Ru-Dong Zhao, Dan-Ping Sun, Yi-Ze Liang, Ya-Di Huang, Ze-Wei Cheng, Jun Ouyang, Wen-Shuo Yang, Wen-Bin Yu.

   BACKGROUND: Fibroblast growth factor (FGF) 15/19, which is expressed in and secreted from the distal ileum, can regulate hepatic glucose metabolism in an endocrine manner. The levels of both bile acids (BAs) and FGF15/19 are elevated after bariatric surgery. However, it is unclear whether the increase in FGF15/19 is induced by BAs. Moreover, it remains to be understood whether FGF15/19 elevations contribute to improvements in hepatic glucose metabolism after bariatric surgery.
AIM: To investigate the mechanism of improvement of hepatic glucose metabolism by elevated BAs after sleeve gastrectomy (SG).
METHODS: By calculating and comparing the changes of body weight after SG with SHAM group, we examined the weight-loss effect of SG. The oral glucose tolerance test (OGTT) test and area under the curve of OGTT curves were used to assess the anti-diabetic effects of SG. By detecting the glycogen content, expression and activity of glycogen synthase as well as the glucose-6-phosphatase (G6Pase) and phosphoenolpyruvate carboxykinase (Pepck), we evaluated the hepatic glycogen content and gluconeogenesis activity. We examined the levels of total BA (TBA) together with the farnesoid X receptor (FXR)-agonistic BA subspecies in systemic serum and portal vein at week 12 post-surgery. Then the histological expression of ileal FXR and FGF15 and hepatic FGF receptor 4 (FGFR4) with its corresponding signal pathways involved in glucose metabolism were detected.
RESULTS: After surgery, food intake and body weight gain of SG group was decreased compare with the SHAM group. The hepatic glycogen content and glycogen synthase activity was significantly stimulated after SG, while the expression of the key enzyme for hepatic gluconeogenesis: G6Pase and Pepck, were depressed. TBA levels in serum and portal vein were both elevated after SG, the FXR-agonistic BA subspecies: Chenodeoxycholic acid (CDCA), lithocholic acid (LCA) in serum and CDCA, DCA, LCA in portal vein were all higher in SG group than that in SHAM group. Consequently, the ileal expression of FXR and FGF15 were also advanced in SG group. Moreover, the hepatic expression of FGFR4 was stimulated in SG-operated rats. As a result, the activity of its corresponding pathway for glycogen synthesis: FGFR4-Ras-extracellular signal regulated kinase pathway was stimulated, while the corresponding pathway for hepatic gluconeogenesis: FGFR4- cAMP regulatory element-binding protein- peroxisome proliferator-activated receptor γ coactivator-1α pathway was suppressed.
CONCLUSION: Elevated BAs after SG induced FGF15 expression in distal ileum by activating their receptor FXR. Furthermore, the promoted FGF15 partly mediated the improving effects on hepatic glucose metabolism of SG.

Keywords:  Bile acids; Fibroblast growth factor 15; Hepatic glucose metabolism; Sleeve gastrectomy; Type 2 diabetes mellitus

DOI:  https://doi.org/10.3748/wjg.v29.i21.3280
Cells. 2023 06 11. pii: 1602. [Epub ahead of print]12(12):

Dysregulation of Metabolism and Proteostasis in Skeletal Muscle of a Presymptomatic Pompe Mouse Model.

Marlena Rohm, Leon Volke, Lara Schlaffke, Robert Rehmann, Nicolina Südkamp, Andreas Roos, Anne Schänzer, Andreas Hentschel, Matthias Vorgerd.

  Pompe disease is a rare genetic metabolic disorder caused by mutations in acid-alpha glucoside (GAA) leading to pathological lysosomal glycogen accumulation associated with skeletal muscle weakness, respiratory difficulties and cardiomyopathy, dependent from the GAA residual enzyme activity. This study aimed to investigate early proteomic changes in a mouse model of Pompe disease and identify potential therapeutic pathways using proteomic analysis of skeletal muscles from pre-symptomatic Pompe mice. For this purpose, quadriceps samples of Gaa6neo/6neo mutant (Pompe) and wildtype mice, at the age of six weeks, were studied with three biological replicates for each group. The data were validated with skeletal muscle morphology, immunofluorescence studies and western blot analysis. Proteomic profiling identified 538 significantly upregulated and 16 significantly downregulated proteins in quadriceps muscles derived from Pompe animals compared to wildtype mice. The majority of significantly upregulated proteins were involved in metabolism, translation, folding, degrading and vesicular transport, with some having crucial roles in the etiopathology of other neurological or neuromuscular diseases. This study highlights the importance of the early diagnosis and treatment of Pompe disease and suggests potential add-on therapeutic strategies targeting protein dysregulations.

Keywords:  Gaa6neo/6neo mouse; Pompe disease; muscular disease; proteomics

DOI:  https://doi.org/10.3390/cells12121602
Int J Oncol. 2023 Aug;pii: 92. [Epub ahead of print]63(2):

Deactivation of glycogen synthase kinase-3β by heat shock‑inducible tumor small protein attenuates hyperthermia‑induced pro‑migratory activity in colorectal cancer cells.

Keita Koizumi, Takahiro Domoto, Toshinari Minamoto, Kazuhito Satomura, Hideo Nakajima.

  Hyperthermia is a promising approach for improving cancer treatment in combination with chemotherapy, radiotherapy and/or immunotherapy; however, its molecular mechanisms remain unclear. Although heat shock proteins (HSPs) are involved in hyperthermia via antigen presentation and immune activation, major HSPs including HSP90 are associated with cancer progression via tumor cell migration and metastasis. The present study showed that heat shock‑inducible tumor small protein (HITS) could counteract the pro‑migratory effects of HSPs in colorectal cancer (CRC) cells, which represents a novel function. Western blotting analysis revealed that overexpression of HITS increased the protein level of glycogen synthase kinase‑3β (GSK3β) phosphorylated (p) at the serine 9 (pGSK3βS9; inactive form) in HCT 116, RKO and SW480 CRC cells. GSK3βS9 phosphorylation was reported to suppress migration in some cancer types; therefore, by using the wound healing assay, the present study revealed that HITS overexpression decreased the migration activity of CRC cells. Induction of HITS transcription was observed at 12 and 18 h after heat shock (HS) by using semi‑quantitative reverse transcription‑PCR analysis, followed by increased levels of pGSK3βS9 protein at 24 and 30 h in CRC cells in western blotting. Thus, HS induced not only HSPs to promote cell migration, but also HITS to counteract the migratory activity of these HSPs in CRC cells. HITS knockdown in CRC cells subject to HS showed increased cell migration in wound healing assay, which was decreased by the GSK3β inhibitor AR‑A014418, confirming the anti‑migratory effect of HITS via the deactivation of GSK3β. The present findings indicated that the deactivation of GSK3β sufficiently offset the pro‑migratory effect of hyperthermia via major HSPs in CRC.

Keywords:  colorectal cancer; glycogen synthase kinase-3β; heat shock protein 90; heat shock‑inducible tumor small protein (HITS); hyperthermia; migration

DOI:  https://doi.org/10.3892/ijo.2023.5540
iScience. 2023 Jul 21. 26(7): 107047

Toward countering muscle and bone loss with spaceflight: GSK3 as a potential target.

Ryan W Baranowski, Jessica L Braun, Briana L Hockey, Jenalyn L Yumol, Mia S Geromella, Colton J F Watson, Nigel Kurgan, Holt N Messner, Kennedy C Whitley, Adam J MacNeil, Guillemette Gauquelin-Koch, Fabrice Bertile, William Gittings, Rene Vandenboom, Wendy E Ward, Val A Fajardo.

  We examined the effects of ∼30 days of spaceflight on glycogen synthase kinase 3 (GSK3) content and inhibitory serine phosphorylation in murine muscle and bone samples from four separate missions (BION-M1, rodent research [RR]1, RR9, and RR18). Spaceflight reduced GSK3β content across all missions, whereas its serine phosphorylation was elevated with RR18 and BION-M1. The reduction in GSK3β was linked to the reduction in type IIA fibers commonly observed with spaceflight as these fibers are particularly enriched with GSK3. We then tested the effects of inhibiting GSK3 before this fiber type shift, and we demonstrate that muscle-specific Gsk3 knockdown increased muscle mass, preserved muscle strength, and promoted the oxidative fiber type with Earth-based hindlimb unloading. In bone, GSK3 activation was enhanced after spaceflight; and strikingly, muscle-specific Gsk3 deletion increased bone mineral density in response to hindlimb unloading. Thus, future studies should test the effects of GSK3 inhibition during spaceflight.

Keywords:  Musculoskeletal medicine; Space medicine

DOI:  https://doi.org/10.1016/j.isci.2023.107047