bims-glecem 2023-12-24 papers

bims-glecem

Biomed News

on Glycogen metabolism in exercise, cancer and energy metabolism

Issue of 2023–12–24
nine papers selected by
Dipsikha Biswas, Københavns Universitet

Glycogen Storage Disease: Expert Opinion on Clinical Diagnosis Revisited after Molecular Testing.
Toward an Understanding of GSD5 (McArdle disease): How Do Individuals Learn to Live with the Metabolic Defect in Daily Life.
Severe perioperative lactic acidosis in a pediatric patient with glycogen storage disease type Ia: a case report.
Effects of osmolytes under crowding conditions on the properties of muscle glycogen phosphorylase b.
Glycogen plays a key role in survival of Salmonella Typhimurium on dry surfaces and in low-moisture foods.
Identification of New GSK3β Inhibitors through a Consensus Machine Learning-Based Virtual Screening.
Lafora Disease: A Case Report and Evolving Treatment Advancements.
Muscle diffusion MRI reveals autophagic buildup in a mouse model for Pompe disease.
The effects of high-intensity exercise training and detraining with and without active recovery on postexercise hypotension in young men.

Genes (Basel). 2023 Dec 15. pii: 2219. [Epub ahead of print]14(12):

Glycogen Storage Disease: Expert Opinion on Clinical Diagnosis Revisited after Molecular Testing.

Rafael de Marchi, Tatiele Nalin, Fernanda Sperb-Ludwig, Franciele Cabral Pinheiro, Ida Vanessa Doederlein Schwartz, Carlos Eduardo Steiner.

  This study sought to analyze whether an accurate diagnosis of the type and subtype of hepatic Glycogen Storage Diseases (GSDs) could be performed based on general clinical and biochemical aspects via comparing the proposed diagnostic hypotheses with the molecular results. Twelve physicians with experience in hepatic GSDs reviewed 45 real cases comprising a standardized summary of clinical and laboratory data. There was no relation between the hit rate and the time since graduation, the time of experience in GSD, and the number of patients treated during their careers. The average assertiveness was 47%, with GSD Ia and Ib being the best-identified types, while no expert correctly identified GSD IXc. Underage investigation for later manifestations, incomplete clinical description, and complementary analysis, the overvaluation of a specific clinical finding ("false positive") or the discarding of the diagnosis in the absence of it ("false negative"), as well as the lack of knowledge of the rarest GSD types, may have impacted the accuracy of the assessment. This study emphasized that characteristics considered as determinants in identifying the specific types or subtypes of GSD are not exclusive, thus becoming factors that may have induced the evaluators to misdiagnose.

Keywords:  Glycogen Storage Disease; clinical diagnosis; clinical manifestations; expert opinion; inherited errors of metabolism; next-generation sequencing; reverse phenotyping

DOI:  https://doi.org/10.3390/genes14122219
J Neuromuscul Dis. 2023 Dec 15.

Toward an Understanding of GSD5 (McArdle disease): How Do Individuals Learn to Live with the Metabolic Defect in Daily Life.

Walaa Karazi, Jacqueline Coppers, Daphne Maas, Edith Cup, Bart Bloemen, Nicole Voet, Jan T Groothuis, Tomàs Pinós, Ramon Marti Seves, Ros Quinlivan, Nicoline Løkken, John Vissing, Salman Bhai, Andrew Wakelin, Stacey Reason, Nicol C Voermans.

   BACKGROUND: Glycogen storage disease type 5 (GSD) is an autosomal recessive inherited metabolic myopathy caused by a deficiency of the enzyme muscle glycogen phosphorylase. Individuals with GSD5 experience physical activity intolerance.
OBJECTIVE: This patient-led study aimed to capture the daily life experiences of GSD5, with a focus on adapting to and coping with their physical activity intolerance.
METHODS: An online survey was composed in close collaboration with patient organizations. It consisted of customized and validated questionnaires on demographics, general health and comorbidities, physical activity, psychosocial well-being and functioning, pain, fatigue and adapting to and coping with GSD5.
RESULTS: One hundred sixty-two participants (16 countries) participated. The majority, n = 86 (69%) were from the Netherlands, USA or UK. We observed a high rate of misdiagnosis prior to GSD5 diagnosis (49%), surprisingly a relatively high proportion had not been diagnosed by DNA testing which is the gold standard. Being diagnosed had a strong impact on emotional status, daily life activities and important life choices. A large proportion had not received any rehabilitation (41%) nor medical treatment (57%) before diagnosis. Engagement in vigorous and moderate physical activity was reduced. Health related quality of life was low, most likely related to low physical health. The median Fatigue Severity Score was 4.3, indicating moderate to severe fatigue. Participants themselves had found various ways to adapt to and cope with their disability. The adaptations concerned all aspect of their life, including household chores, social and physical activities, and work. In addition to lack of support, participants reported limited availability of information sources.
CONCLUSION: Participants have provided guidance for newly diagnosed people, including the advice to accept one's limited abilities and maintain an active lifestyle. We conclude that adequate counseling on ways of adapting and coping is expected to increase both health-related quality of life and physical activity.

Keywords:  GSD5; McArdle disease; adaptations; adjustments; international survey; physical activity; quality of life

DOI:  https://doi.org/10.3233/JND-230027
JA Clin Rep. 2023 Dec 20. 9(1): 91

Severe perioperative lactic acidosis in a pediatric patient with glycogen storage disease type Ia: a case report.

Tamayo Takahashi, Kana Oue, Eiji Imado, Mitsuru Doi, Yoshitaka Shimizu, Mitsuhiro Yoshida.

   BACKGROUND: Glycogen storage disease (GSD) is a group of rare inherited metabolic disorders caused by enzyme deficiencies in glycogen catabolism. GSD type Ia is a congenital deficiency of the enzyme responsible for the final step in glucose production by glycolysis, resulting in impaired carbohydrate metabolism.
CASE PRESENTATION: A 14-year-old boy with GSD type Ia was scheduled for a maxillary cystectomy under general anesthesia. He was taking oral sugars such as uncooked cornstarch regularly to prevent hypoglycemia. Perioperatively, glucose was administered via the peripheral vein for fasting; however, severe lactic acidosis occurred. He also developed hypercapnia because of intraoperative poor ventilation caused by hepatomegaly.
CONCLUSIONS: We experienced a child with GSD type Ia who developed severe lactic acidosis despite continuous glucose infusion. Further studies are required to determine appropriate perioperative management for patients with GSD, including fasting glucose administration.

Keywords:  Carbohydrate metabolism; Glycogen storage disease; Hepatomegaly; Hypoglycemia; Lactic acidosis

DOI:  https://doi.org/10.1186/s40981-023-00683-z
Biochimie. 2023 Dec 19. pii: S0300-9084(23)00328-0. [Epub ahead of print]

Effects of osmolytes under crowding conditions on the properties of muscle glycogen phosphorylase b.

Valeriya V Mikhaylova, Tatiana B Eronina.

  The study of the relationship between the activity and stability of enzymes under crowding conditions in the presence of osmolytes is important for understanding the functioning of a living cell. The effect of osmolytes (trehalose and betaine) on the secondary and tertiary structure and activity of muscle glycogen phosphorylase b (Phb) under crowding conditions created by PEG 2000 and PEG 20000 was investigated using dynamic light scattering, differential scanning calorimetry, circular dichroism spectroscopy, fluorimetry and enzymatic activity assay. At 25 °C PEGs increased Phb activity, but PEG 20000 to a greater extent. Wherein, PEG 20000 significantly destabilized its tertiary and secondary structure, in contrast to PEG 2000. Trehalose removed the effects of PEGs on Phb, while betaine significantly reduced the activating effect of PEG 20000 without affecting the action of PEG 2000. Under heat stress at 48 °C, the protective effect of osmolytes under crowding conditions was more pronounced than at room temperature, and the Phb activity in the presence of osmolytes was higher in these conditions than in diluted solutions. These results provide important insights into the complex mechanism, by which osmolytes affect the structure and activity of Phb under crowding conditions.

Keywords:  Crowding; Glycogen phosphorylase b; Osmolytes

DOI:  https://doi.org/10.1016/j.biochi.2023.12.005
Food Res Int. 2024 Jan;pii: S0963-9969(23)01262-0. [Epub ahead of print]175 113714

Glycogen plays a key role in survival of Salmonella Typhimurium on dry surfaces and in low-moisture foods.

Zejia Lin, Shaoqian Jiang, Ye Htut Zwe, Kexin Zhang, Dan Li.

  Salmonella enterica is known to survive in desiccate environments and is often associated with low-moisture foods (LMFs). In this work, S. Typhimurium ATCC 14028 was found to survive better by achieving the least reductions (3.17 ± 0.20 Log CFU reduction) compared to S. Tennessee ATCC 10722 (3.82 ± 0.13 Log CFU reduction) and S. Newport ATCC 6962 (6.03 ± 0.36 Log CFU reduction) after 30 days on surfaces with a relative humidity of 49% at ambient temperature. A metabolomic analysis revealed that S. Typhimurium was still active in energy metabolism after 24 h in the desiccate environment and glycogen, an energy reserve, was drastically reduced. We followed up on the glycogen levels over 30 days and found indeed a sharp decline on the first day. However, the glycogens detected on day 7 were significantly higher (P < 0.05) and thereafter remained stable above the original levels until day 30. The expression levels of both glycogen anabolism- and catabolism-related genes (csrA, glgA, glgC, glgX) were significantly up-regulated at all tested points (P < 0.05). The glgA and glgC insertion mutants displayed weaker survivability on both dry surfaces and in representative LMFs (flour and milk powder) compared to the wild-type strain. This work highlights the role of glycogen during different periods of desiccation, which may bring novel insight into mitigating Salmonella by disrupting glycogen metabolism.

Keywords:  Desiccation; Dry food-contact surface; Foodborne pathogen; Glycogen; LMFs

DOI:  https://doi.org/10.1016/j.foodres.2023.113714
Int J Mol Sci. 2023 Dec 07. pii: 17233. [Epub ahead of print]24(24):

Identification of New GSK3β Inhibitors through a Consensus Machine Learning-Based Virtual Screening.

Salvatore Galati, Miriana Di Stefano, Simone Bertini, Carlotta Granchi, Antonio Giordano, Francesca Gado, Marco Macchia, Tiziano Tuccinardi, Giulio Poli.

  Glycogen synthase kinase-3 beta (GSK3β) is a serine/threonine kinase that plays key roles in glycogen metabolism, Wnt/β-catenin signaling cascade, synaptic modulation, and multiple autophagy-related signaling pathways. GSK3β is an attractive target for drug discovery since its aberrant activity is involved in the development of neurodegenerative diseases such as Alzheimer's and Parkinson's disease. In the present study, multiple machine learning models aimed at identifying novel GSK3β inhibitors were developed and evaluated for their predictive reliability. The most powerful models were combined in a consensus approach, which was used to screen about 2 million commercial compounds. Our consensus machine learning-based virtual screening led to the identification of compounds G1 and G4, which showed inhibitory activity against GSK3β in the low-micromolar and sub-micromolar range, respectively. These results demonstrated the reliability of our virtual screening approach. Moreover, docking and molecular dynamics simulation studies were employed for predicting reliable binding modes for G1 and G4, which represent two valuable starting points for future hit-to-lead and lead optimization studies.

Keywords:  GSK3B; kinase; machine learning; virtual screening

DOI:  https://doi.org/10.3390/ijms242417233
Brain Sci. 2023 Dec 06. pii: 1679. [Epub ahead of print]13(12):

Lafora Disease: A Case Report and Evolving Treatment Advancements.

Carola Rita Ferrari Aggradi, Martina Rimoldi, Gloria Romagnoli, Daniele Velardo, Megi Meneri, Davide Iacobucci, Michela Ripolone, Laura Napoli, Patrizia Ciscato, Maurizio Moggio, Giacomo Pietro Comi, Dario Ronchi, Stefania Corti, Elena Abati.

  Lafora disease is a rare genetic disorder characterized by a disruption in glycogen metabolism. It manifests as progressive myoclonus epilepsy and cognitive decline during adolescence. Pathognomonic is the presence of abnormal glycogen aggregates that, over time, produce large inclusions (Lafora bodies) in various tissues. This study aims to describe the clinical and histopathological aspects of a novel Lafora disease patient, and to provide an update on the therapeutical advancements for this disorder. A 20-year-old Libyan boy presented with generalized tonic-clonic seizures, sporadic muscular jerks, eyelid spasms, and mental impairment. Electroencephalography showed multiple discharges across both brain hemispheres. Brain magnetic resonance imaging was unremarkable. Muscle biopsy showed increased lipid content and a very mild increase of intermyofibrillar glycogen, without the polyglucosan accumulation typically observed in Lafora bodies. Despite undergoing three lines of antiepileptic treatment, the patient's condition showed minimal to no improvement. We identified the homozygous variant c.137G>A, p.(Cys46Tyr), in the EPM2B/NHLRC1 gene, confirming the diagnosis of Lafora disease. To our knowledge, the presence of lipid aggregates without Lafora bodies is atypical. Lafora disease should be considered during the differential diagnosis of progressive, myoclonic, and refractory epilepsies in both children and young adults, especially when accompanied by cognitive decline. Although there are no effective therapies yet, the development of promising new strategies prompts the need for an early and accurate diagnosis.

Keywords:  EPM2A; EPM2B; Lafora bodies; Lafora disease; laforin; malin; therapeutic strategies; tonic–clonic seizures

DOI:  https://doi.org/10.3390/brainsci13121679
Sci Rep. 2023 Dec 20. 13(1): 22822

Muscle diffusion MRI reveals autophagic buildup in a mouse model for Pompe disease.

Marlena Rohm, Gabriele Russo, Xavier Helluy, Martijn Froeling, Vincent Umathum, Nicolina Südkamp, Denise Manahan-Vaughan, Robert Rehmann, Johannes Forsting, Frank Jacobsen, Andreas Roos, Yoon Shin, Anne Schänzer, Matthias Vorgerd, Lara Schlaffke.

Quantitative muscle MRI is increasingly important in the non-invasive evaluation of neuromuscular disorders and their progression. Underlying histopathotological alterations, leading to changes in qMRI parameters are incompletely unraveled. Early microstructural differences of unknown origin reflected by Diffusion MRI in non-fat infiltrated muscles were detected in Pompe patients. This study employed a longitudinal approach with a Pompe disease mouse model to investigate the histopathological basis of these changes. Monthly scans of Pompe (Gaa6neo/6neo) and wildtype mice (age 1-8 months) were conducted using diffusion MRI, T2-mapping, and Dixon-based water-fat imaging on a 7 T scanner. Immunofluorescence studies on quadriceps muscles were analyzed for lysosomal accumulations and autophagic buildup and correlated with MRI outcome measures. Fat fraction and water-T2 did not differ between groups and remained stable over time. In Pompe mice, fractional anisotropy increased, while mean diffusivity (MD) and radial diffusivity (RD) decreased in all observed muscles. Autophagic marker and muscle fibre diameter revealed significant negative correlations with reduced RD and MD, while lysosomal marker did not show any change or correlation. Using qMRI, we showed diffusion changes in muscles of presymptomatic Pompe mice without fat-infiltrated muscles and correlated them to autophagic markers and fibre diameter, indicating diffusion MRI reveals autophagic buildup.

DOI: https://doi.org/10.1038/s41598-023-49971-9
Physiol Rep. 2023 Dec;11(24): e15862

The effects of high-intensity exercise training and detraining with and without active recovery on postexercise hypotension in young men.

Tze-Huan Lei, Naoto Fujii, Xiao Zhang, Faming Wang, Toby Mündel, I-Lin Wang, Yi-Ming Chen, Takeshi Nishiyasu, Tatsuro Amano, Kohei Dobashi, Lin Wang, Tzu-Shao Yeh, Narihiko Kondo, Richie P Goulding.

  Whether high-intensity exercise training and detraining combined with skeletal muscle pump (MP) could alter the magnitude of postexercise hypotension has not been investigated. We therefore sought to determine whether the combination of MP (unloaded back-pedaling) with 4 weeks of high-intensity exercise training and detraining could alter the magnitude of postexercise hypotension. Fourteen healthy men underwent 4 weeks of high-intensity exercise training (5 consecutive days per week for 15 min per session at 40% of the difference between the gas exchange threshold and maximal oxygen uptake [i.e., Δ40%]) followed by detraining for 4 weeks. Assessments were conducted at Pre-training (Pre), Post-training (Post) and after Detraining with (MP) and without MP (Con). The exercise test in the Pre, Post and the Detraining consisted of 15 min exercise at Δ40% followed by 1 h of recovery. At all time-points, the postexercise reduction in mean arterial pressure (MAP) was reduced in MP compared to Con (all p < 0.01). Four weeks of high-intensity exercise training resulted in a reduction in the magnitude of postexercise hypotension (i.e., the change in MAP from baseline was mitigated) across both trials (All p < 0.01) when compared to Pre and Detraining. Following Detraining, the reduction of MAP from baseline was reduced compared to Pre, but was not different from Post. We conclude that high-intensity exercise training combined with skeletal MP reduces the magnitude of postexercise hypotension, and this effect is partially retained for 4 weeks following the complete cessation of high-intensity exercise training.

Keywords:  arterial baroreflex; physical training and detraining; postexercise hypotension

DOI:  https://doi.org/10.14814/phy2.15862