bims-glecem 2023-08-06 papers

bims-glecem

Biomed News

on Glycogen metabolism in exercise, cancer and energy metabolism

Issue of 2023–08–06
nine papers selected by
Dipsikha Biswas, Københavns Universitet

Glycogen phosphorylase inhibition improves cognitive function of aged mice.
Glycogen synthase kinase-3: A potential target for diabetes.
Intracellular glycogen accumulation by human gut commensals as a niche adaptation trait.
Treatment responsive glycogen storage myopathy in a patient with POEMS syndrome: A new monoclonal gammopathy-associated myopathy (MGAM).
Genotype, phenotype and treatment outcomes of 17 Malaysian patients with infantile-onset Pompe disease and the identification of 3 novel GAA variants.
Impaired cardiac glycolysis and glycogen depletion are linked to poor myocardial outcomes in juvenile male swine with metabolic syndrome and ischemia.
Effects of enzyme replacement therapy on bone density in late onset Pompe disease.
Hemizygous variants in protein phosphatase 1 regulatory subunit 3F (PPP1R3F) are associated with a neurodevelopmental disorder characterized by developmental delay, intellectual disability, and autistic features.
Anti-fatigue effect of tormentic acid through alleviating oxidative stress and energy metabolism-modulating property in C2C12 cells and animal models.

Aging Cell. 2023 Jul 31. e13928

Glycogen phosphorylase inhibition improves cognitive function of aged mice.

Dominika Drulis-Fajdasz, Adam Krzystyniak, Alicja Puścian, Agata Pytyś, Kinga Gostomska-Pampuch, Natalia Pudełko-Malik, Jerzy Ł Wiśniewski, Piotr Młynarz, Arkadiusz Miazek, Tomasz Wójtowicz, Jakub Włodarczyk, Kamila Duś-Szachniewicz, Agnieszka Gizak, Jacek R Wiśniewski, Dariusz Rakus.

  Inhibition of glycogen breakdown blocks memory formation in young animals, but it stimulates the maintenance of the long-term potentiation, a cellular mechanism of memory formation, in hippocampal slices of old animals. Here, we report that a 2-week treatment with glycogen phosphorylase inhibitor BAY U6751 alleviated memory deficits and stimulated neuroplasticity in old mice. Using the 2-Novel Object Recognition and Novel Object Location tests, we discovered that the prolonged intraperitoneal administration of BAY U6751 improved memory formation in old mice. This was accompanied by changes in morphology of dendritic spines in hippocampal neurons, and by "rejuvenation" of hippocampal proteome. In contrast, in young animals, inhibition of glycogen degradation impaired memory formation; however, as in old mice, it did not alter significantly the morphology and density of cortical dendritic spines. Our findings provide evidence that prolonged inhibition of glycogen phosphorolysis improves memory formation of old animals. This could lead to the development of new strategies for treatment of age-related memory deficits.

Keywords:  aging; behavioral tests; glycogen phosphorylase (Pyg); hippocampus; memory formation/deficits

DOI:  https://doi.org/10.1111/acel.13928
Bioorg Med Chem. 2023 Jul 06. pii: S0968-0896(23)00254-7. [Epub ahead of print]92 117406

Glycogen synthase kinase-3: A potential target for diabetes.

Divya M Teli, Anuradha K Gajjar.

  Elevated circulating glucose level due to β-cell dysfunction has been a key marker of Type-II diabetes. Glycogen synthase kinase-3 (GSK-3) has been recognized as an enzyme involved in the control of glycogen metabolism. Consequently, inhibitors of GSK-3 have been explored for anti-diabetic effects in vitro and in animal models. Further, the mechanisms governing the regulation of this enzyme have been elucidated by means of a combination of structural and cellular biological investigations. This review article examines the structural analysis of GSK-3 as well as molecular modeling reports from numerous researchers in the context of the design and development of GSK-3 inhibitors. This article centers on the signaling pathway of GSK-3 relevant to its potential as a target for diabetes and discusses advancements till date on different molecular modification approaches used by researchers in the development of novel GSK-3 inhibitors as potential therapeutics for the treatment of Type II diabetes.

Keywords:  Diabetes; Glycogen metabolism; Glycogen synthase kinase-3; Inhibitors

DOI:  https://doi.org/10.1016/j.bmc.2023.117406
Gut Microbes. 2023 Jan-Dec;15(1):15(1): 2235067

Intracellular glycogen accumulation by human gut commensals as a niche adaptation trait.

Maria Esteban-Torres, Lorena Ruiz, Valerio Rossini, Ken Nally, Douwe van Sinderen.

  The human gut microbiota is a key contributor to host metabolism and physiology, thereby impacting in various ways on host health. This complex microbial community has developed many metabolic strategies to colonize, persist and survive in the gastrointestinal environment. In this regard, intracellular glycogen accumulation has been associated with important physiological functions in several bacterial species, including gut commensals. However, the role of glycogen storage in shaping the composition and functionality of the gut microbiota offers a novel perspective in gut microbiome research. Here, we review what is known about the enzymatic machinery and regulation of glycogen metabolism in selected enteric bacteria, while we also discuss its potential impact on colonization and adaptation to the gastrointestinal tract. Furthermore, we survey the presence of such glycogen biosynthesis pathways in gut metagenomic data to highlight the relevance of this metabolic trait in enhancing survival in the highly competitive and dynamic gut ecosystem.

Keywords:  bacteria-host interactions; carbohydrate-active enzymes; colonization factors; commensal bacteria; glycogen metabolism; gut microbiota; microbiome

DOI:  https://doi.org/10.1080/19490976.2023.2235067
Eur J Neurol. 2023 Jul 31.

Treatment responsive glycogen storage myopathy in a patient with POEMS syndrome: A new monoclonal gammopathy-associated myopathy (MGAM).

Pannathat Soontrapa, Jennifer A Tracy, Wilson I Gonsalves, Teerin Liewluck.

   BACKGROUND: Myopathies associated with monoclonal gammopathy are relatively uncommon and underrecognized, treatable myopathies, including sporadic late onset nemaline myopathy, light chain amyloid myopathy and a recently described vacuolar myopathy with monoclonal gammopathy and stiffness (VAMGS). Herein, we report a new subtype of monoclonal gammopathy-associated myopathy in a POEMS patient.
METHOD: Case report.
RESULTS: A 51-year-old woman presented with a 6-month history of progressive bilateral foot drop, lower limb edema and a 15-lb weight loss. She denied muscle stiffness. Neurologic exam showed severe distal weakness, mild proximal weakness, and length-dependent sensory deficits. Laboratory studies revealed biclonal gammopathy (IgG kappa and IgA lambda), thrombocytosis, and elevated vascular endothelial growth factor. Creatine kinase was normal. Electrodiagnostic studies identified mixed demyelinatnig and axonal polyradiculoneuropathy and a superimposed proximal myopathy. Gluteus medius biopsy demonstrated scattered fibers with glycogen-filled vacuoles, similar to VAMGS, with additional rare myofibers containing polyglucosan bodies. She was diagnosed with POEMS syndrome and concomitant glycogen storage myopathy. Next generation sequencing of glycogen storage and polyglucosan body myopathy-related genes was unrevealing. Proximal weakness resolved after autologous stem cell transplant.
CONCLUSION: This patient expands a spectrum of monoclonal gammopathy-associated myopathy (MGAM). Recognition of this condition and other subtypes of MGAM is utmost important because it is treatable.

Keywords:  POEMS syndrome; case report; glycogen storage disease; polyglucosan body; vacuolar myopathy

DOI:  https://doi.org/10.1111/ene.16008
Orphanet J Rare Dis. 2023 Aug 04. 18(1): 231

Genotype, phenotype and treatment outcomes of 17 Malaysian patients with infantile-onset Pompe disease and the identification of 3 novel GAA variants.

Mei-Yan Chan, Julaina Abdul Jalil, Yusnita Yakob, Siti Aishah Abdul Wahab, Ernie Zuraida Ali, Mohd Khairul Nizam Mohd Khalid, Huey-Yin Leong, Hui-Bein Chew, Jeya Bawani Sivabalakrishnan, Lock-Hock Ngu.

   BACKGROUND: Pompe disease is a rare glycogen storage disorder caused by deficiency of the lysosomal enzyme acid alpha-glucosidase (GAA), leading to glycogen deposition in multiple tissues. Infantile-onset Pompe disease (IOPD) patients present within the first year of life with profound hypotonia and hypertrophic cardiomyopathy. Treatment with enzyme replacement therapy (ERT) has significantly improved survival for this otherwise lethal disorder. This study aims to describe the clinical and molecular spectrum of Malaysian IOPD patients, and to analyze their long term treatment outcomes.
METHODS: Seventeen patients diagnosed with IOPD between 2000 and 2020 were included in this retrospective cohort study. Clinical and biochemical data were collated and analyzed using descriptive statistics. GAA enzyme levels were performed on dried blood spots. Molecular analysis of the GAA gene was performed by polymerase chain reaction and Sanger sequencing. Structural modelling was used to predict the effect of the novel mutations on enzyme structure.
RESULTS: Our cohort had a median age of presentation of 3 months and median age of diagnosis of 6 months. Presenting features were hypertrophic cardiomyopathy (100%), respiratory insufficiency (94%), hypotonia (88%), failure to thrive (82%), feeding difficulties (76%), and hepatomegaly (76%). Fourteen different mutations in the GAA gene were identified, with three novel mutations, c.1552-14_1552-1del, exons 2-3 deletion and exons 6-10 deletion. The most common mutation identified was c.1935C > A p.(D645E), with an allele frequency of 33%. Sixteen patients received ERT at the median age of 7 months. Overall survival was 29%. Mean age of death was 17.5 months. Our longest surviving patient has atypical IOPD and is currently 20 years old.
CONCLUSIONS: This is the first study to analyze the genotype and phenotype of Malaysian IOPD patients, and has identified the c.1935C > A p.(D645E) as the most common mutation. The three novel mutations reported in this study expands the mutation spectrum for IOPD. Our low survival rate underscores the importance of early diagnosis and treatment in achieving better treatment outcomes.

Keywords:  Acid alpha-glucosidase; Enzyme replacement therapy; GAA; Infantile-onset Pompe disease; Lysosomal storage disease

DOI:  https://doi.org/10.1186/s13023-023-02848-6
Physiol Rep. 2023 Aug;11(15): e15742

Impaired cardiac glycolysis and glycogen depletion are linked to poor myocardial outcomes in juvenile male swine with metabolic syndrome and ischemia.

Mark Broadwin, Dwight D Harris, Sharif A Sabe, Elif Sengun, Amber J Sylvestre, Boian S Alexandrov, Frank W Selke, Anny Usheva.

  Obesity continues to rise in the juveniles and obese children are more likely to develop metabolic syndrome (MetS) and related cardiovascular disease. Unfortunately, effective prevention and long-term treatment options remain limited. We determined the juvenile cardiac response to MetS in a swine model. Juvenile male swine were fed either an obesogenic diet, to induce MetS, or a lean diet, as a control (LD). Myocardial ischemia was induced with surgically placed ameroid constrictor on the left circumflex artery. Physiological data were recorded and at 22 weeks of age the animals underwent a terminal harvest procedure and myocardial tissue was extracted for total metabolic and proteomic LC/MS-MS, RNA-seq analysis, and data underwent nonnegative matrix factorization for metabolic signatures. Significantly altered in MetS versus. LD were the glycolysis-related metabolites and enzymes. In MetS compared with LD Glycogen synthase 1 (GYS1)-glycogen phosphorylases (PYGM/PYGL) expression disbalance resulted in a loss of myocardial glycogen. Our findings are consistent with the concept that transcriptionally driven myocardial changes in glycogen and glucose metabolism-related enzymes lead to a deficiency of their metabolite products in MetS. This abnormal energy metabolism provides insight into the pathogenesis of the juvenile heart in MetS. This study reveals that MetS and ischemia diminishes ATP availability in the myocardium via altering the glucose-G6P-pyruvate axis at the level of metabolites and gene expression of related enzymes. The observed severe glycogen depletion in MetS coincides with disbalance in expression of GYS1 and both PYGM and PYGL. This altered energy substrate metabolism is a potential target of pharmacological agents for improving juvenile myocardial function in MetS and ischemia.

Keywords:  myocardial metabolomics; nonnegative matrix factorization; proteomics; swine model of metabolic syndrome

DOI:  https://doi.org/10.14814/phy2.15742
Mol Genet Metab. 2023 Jun 28. pii: S1096-7192(23)00274-3. [Epub ahead of print]140(3): 107644

Effects of enzyme replacement therapy on bone density in late onset Pompe disease.

Mahima Avanti, Angela Martin, Rod Carlo Columbres, Tahseen Mozaffar, Virginia Kimonis.

  Pompe disease is an autosomal recessive disorder caused by a deficiency of α-glucosidase, resulting in the accumulation of glycogen in smooth, cardiac, and skeletal muscles, leading to skeletal muscle dysfunction, proximal muscle weakness, and early respiratory insufficiency. Although many patients exhibit decreased bone mineral density (BMD) and increased fractures, there is currently no official protocol for surveillance and management of osteoporosis and osteopenia in late onset Pompe disease (LOPD). Enzyme replacement therapy (ERT) has therapeutic effects on muscle function; however, very few studies report on the effect of ERT on bone mineralization in LOPD patients. Our study included 15 Pompe patients from 25 to 76 years of age on ERT for variable durations. Progressive impact of ERT on BMD of the hips and spine, and the frequency of osteopenia or osteoporosis was studied using DEXA scanning, and correlations were made with age of initiation of ERT, duration of ERT and six-minute walk test. We found a significant positive correlation between the age of ERT initiation and age of the subject, with increases in the Z-scores for the femur and lumbar region. Females had a significantly higher risk for developing osteoporosis compared to males. These results highlight the significance of ERT on reducing progression of osteoporosis in LOPD patients.

Keywords:  Alglucosidase alpha; Bone mineral density; DEXA; Dual energy X-ray absorptiometry; Enzyme replacement therapy; Late-onset Pompe disease

DOI:  https://doi.org/10.1016/j.ymgme.2023.107644
Hum Mol Genet. 2023 Aug 02. pii: ddad124. [Epub ahead of print]

Hemizygous variants in protein phosphatase 1 regulatory subunit 3F (PPP1R3F) are associated with a neurodevelopmental disorder characterized by developmental delay, intellectual disability, and autistic features.

Zhigang Liu, Baozhong Xin, Iris N Smith, Valerie Sency, Julia Szekely, Anna Alkelai, Alan Shuldiner, Stephanie Efthymiou, Farrah Rajabi, Stephanie Coury, Catherine A Brownstein, Sabine Rudnik-Schöneborn, Ange-Line Bruel, Julien Thevenon, Shimriet Zeidler, Parul Jayakar, Axel Schmidt, Kirsten Cremer, Hartmut Engels, Sophia O Peters, Maha S Zaki, Ruizhi Duan, Changlian Zhu, Yiran Xu, Chao Gao, Tania Sepulveda-Morales, Reza Maroofian, Issam A Alkhawaja, Mariam Khawaja, Hunaida Alhalasah, Henry Houlden, Jill A Madden, Valentina Turchetti, Dana Marafi, Pankaj B Agrawal, Ulrich Schatz, Ari Rotenberg, Joshua Rotenberg, Grazia M S Mancini, Somayeh Bakhtiari, Michael Kruer, Isabelle Thiffault, Steffen Hirsch, Maja Hempel, Lara G Stühn, Tobias B Haack, Jennifer E Posey, James R Lupski, Hyunpil Lee, Nicholas B Sarn, Charis Eng, Claudia Gonzaga-Jauregui, Bin Zhang, Heng Wang.

  PPP1R3F (R3F) is a member of the glycogen targeting subunits (GTSs), which belong to the large group of regulatory subunits of protein phosphatase 1 (PP1), a major eukaryotic serine/threonine protein phosphatase that regulates diverse cellular processes. Here, we describe the identification of hemizygous variants in PPP1R3F associated with a novel X-linked recessive neurodevelopmental disorder in 13 unrelated individuals. This disorder is characterized by developmental delay, mild intellectual disability, neurobehavioral issues such as autism spectrum disorder, seizures, and other neurological findings including tone, gait, and cerebellar abnormalities. PPP1R3F variants segregated with disease in affected hemizygous males that inherited the variants from their heterozygous carrier mothers. We show that R3F is predominantly expressed in brain astrocytes and localizes to the endoplasmic reticulum in cells. Glycogen content in PPP1R3F knockout astrocytoma cells appears to be more sensitive to fluxes in extracellular glucose levels than in wild-type cells, suggesting that R3F functions in maintaining steady brain glycogen levels under changing glucose conditions. We performed functional studies on nine of the identified variants and observed defects in PP1 binding, protein stability, subcellular localization, and regulation of glycogen metabolism in most of them. Collectively, the genetic and molecular data indicate that deleterious variants in PPP1R3F are associated with a new X-linked disorder of glycogen metabolism, highlighting the critical role of GTSs in neurological development. This research expands our understanding of neurodevelopmental disorders and the role of PP1 in brain development and proper function.

Keywords:  PPP1R3F; X-linked; autism; developmental delay; glycogen metabolism; intellectual disability; protein phosphatase 1; seizure

DOI:  https://doi.org/10.1093/hmg/ddad124
Nutr Res Pract. 2023 Aug;17(4): 670-681

Anti-fatigue effect of tormentic acid through alleviating oxidative stress and energy metabolism-modulating property in C2C12 cells and animal models.

Ho-Geun Kang, Jin-Ho Lim, Hee-Yun Kim, Hyunyong Kim, Hyung-Min Kim, Hyun-Ja Jeong.

   BACKGROUND/OBJECTIVES: Oxidative stress is caused by reactive oxygen species and free radicals that accelerate inflammatory responses and exacerbate fatigue. Tormentic acid (TA) has antioxidant and anti-inflammatory properties. Thus, the aim of present study is to determine the fatigue-regulatory effects of TA in H2O2-stimulated myoblast cell line, C2C12 cells and treadmill stress test (TST) and forced swimming test (FST) animal models.
MATERIALS/METHODS: In the in vitro study, C2C12 cells were pretreated with TA before stimulation with H2O2. Then, malondialdehyde (MDA), lactate dehydrogenase (LDH), creatine kinase (CK) activity, tumor necrosis factor (TNF)-α, interleukin (IL)-6, superoxide dismutase (SOD), catalase (CAT), glycogen, and cell viability were analyzed. In the in vivo study, the ICR male mice were administered TA or distilled water orally daily for 28 days. FST and TST were then performed on the last day. In addition, biochemical analysis of the serum, muscle, and liver was performed.
RESULTS: TA dose-dependently alleviated the levels of MDA, LDH, CK activity, TNF-α, and IL-6 in H2O2-stimulated C2C12 cells without affecting the cytotoxicity. TA increased the SOD and CAT activities and the glycogen levels in H2O2-stimulated C2C12 cells. In TST and FST animal models, TA decreased the FST immobility time significantly while increasing the TST exhaustion time without weight fluctuations. The in vivo studies showed that the levels of SOD, CAT, citrate synthase, glycogen, and free fatty acid were increased by TA administration, whereas TA significantly reduced the levels of glucose, MDA, LDH, lactate, CK, inflammatory cytokines, alanine transaminase, aspartate transaminase, blood urea nitrogen, and cortisol compared to the control group.
CONCLUSIONS: TA improves fatigue by modulating oxidative stress and energy metabolism in C2C12 cells and animal models. Therefore, we suggest that TA can be a powerful substance in healthy functional foods and therapeutics to improve fatigue.

Keywords:  Fatigue; cytokine; oxidative stress; superoxide dismutase; tormentic acid

DOI:  https://doi.org/10.4162/nrp.2023.17.4.670