bims-glecem 2023-09-17 papers

bims-glecem

Biomed News

on Glycogen metabolism in exercise, cancer and energy metabolism

Issue of 2023–09–17
nine papers selected by
Dipsikha Biswas, Københavns Universitet

Differences in exercise capacity and muscle glycogen metabolism in C57BL/6J and BALB/cA mice.
Gys1 Antisense Therapy Prevents Disease-Driving Aggregates and Epileptiform Discharges in a Lafora Disease Mouse Model.
Development of hepatocellular adenomas in a patient with glycogen storage disease Ia treated with growth hormone therapy.
Endogenous glucose production in patients with glycogen storage disease type Ia estimated by oral d-[6,6-2H2]-glucose.
Clinical and Laboratory Findings on Glycogen Storage Disease Type V: Results from a Retrospective Observational Study in a Tertiary Hospital.
Opposite regulation of glycogen metabolism by cAMP produced in the cytosol and at the plasma membrane.
Differential G-Protein-Coupled Estrogen Receptor-1 Regulation of Counter-Regulatory Transmitter Marker and 5'-AMP-Activated Protein Kinase Expression in Ventrolateral versus Dorsomedial Ventromedial Hypothalamic Nucleus.
Diagnosis and management of children with McArdle Syndrome (GSD V) in New South Wales.
GSK-3β activation mediates apolipoprotein E4-associated cognitive impairment in type 2 diabetes mellitus: A multicenter, cross-sectional study.

Exp Anim. 2023 Sep 12.

Differences in exercise capacity and muscle glycogen metabolism in C57BL/6J and BALB/cA mice.

Tohru Miyata, Akira Shogatsudani, Ayaka Igarashi, Haruna Tsutiya, Kyouka Yoshida.

  This study compared differences in exercise capacity as well as muscle glycogen content and degradation, and mitochondrial enzyme activity between C57BL/6J and BALB/cA mice. In exercise tests, grip strength was higher in BALB/cA mice. In Rotarod and Inverted screen test, C57BL/6J mice had significantly longer exercise durations and showed differences in motor function and muscle endurance time. Glycogen in the liver and muscle of C57BL/6J mice was significantly decreased after 20 minutes of swimming. Muscle glycogen content in BALB/cA mice was higher than in C57BL/6J, but swimming induced no decrease in glycogen content. Glycogen phosphorylase in muscle was inactive in the absence of AMP, and its activity increased in a concentration-dependent manner with the addition of AMP in C57BL/6J mice. In BALB/cA mice, phosphorylase activity was increased by AMP, but not further increased by higher concentrations of AMP. The citrate synthase activity in muscle did not differ between C57BL/6J and BALB/cA mice. The results of this study suggested that the reactivity of muscle glycogen phosphorylase to AMP differs among strains of mice and affects glycogen availability during exercise.

Keywords:  exercise capacity; mouse strains; muscle glycogen metabolism

DOI:  https://doi.org/10.1538/expanim.23-0074
Neurotherapeutics. 2023 Sep 12.

Gys1 Antisense Therapy Prevents Disease-Driving Aggregates and Epileptiform Discharges in a Lafora Disease Mouse Model.

Katherine J Donohue, Bethany Fitzsimmons, Ronald C Bruntz, Kia H Markussen, Lyndsay E A Young, Harrison A Clarke, Peyton T Coburn, Laiken E Griffith, William Sanders, Jack Klier, Sara N Burke, Andrew P Maurer, Berge A Minassian, Ramon C Sun, Holly B Kordasiewisz, Matthew S Gentry.

  Patients with Lafora disease have a mutation in EPM2A or EPM2B, resulting in dysregulation of glycogen metabolism throughout the body and aberrant glycogen molecules that aggregate into Lafora bodies. Lafora bodies are particularly damaging in the brain, where the aggregation drives seizures with increasing severity and frequency, coupled with neurodegeneration. Previous work employed mouse genetic models to reduce glycogen synthesis by approximately 50%, and this strategy significantly reduced Lafora body formation and disease phenotypes. Therefore, an antisense oligonucleotide (ASO) was developed to reduce glycogen synthesis in the brain by targeting glycogen synthase 1 (Gys1). To test the distribution and efficacy of this drug, the Gys1-ASO was administered to Epm2b-/- mice via intracerebroventricular administration at 4, 7, and 10 months. The mice were then sacrificed at 13 months and their brains analyzed for Gys1 expression, glycogen aggregation, and neuronal excitability. The mice treated with Gys1-ASO exhibited decreased Gys1 protein levels, decreased glycogen aggregation, and reduced epileptiform discharges compared to untreated Epm2b-/- mice. This work provides proof of concept that a Gys1-ASO halts disease progression of EPM2B mutations of Lafora disease.

Keywords:  Antisense oligonucleotide; Glycogen; Glycogen storage disease; Glycogen synthase; Lafora disease

DOI:  https://doi.org/10.1007/s13311-023-01434-9
JIMD Rep. 2023 Sep;64(5): 303-311

Development of hepatocellular adenomas in a patient with glycogen storage disease Ia treated with growth hormone therapy.

David G Jackson, Rebecca L Koch, Surekha Pendyal, Robert Benjamin, Priya S Kishnani.

  Glycogen storage disease Ia (GSD Ia), also known as von Gierke disease, is caused by pathogenic variants in the G6PC1 gene (OMIM 232200) which encodes glucose-6-phosphatase. Deficiency of glucose-6-phosphatase impairs the processes of gluconeogenesis and glycogenolysis by preventing conversion of glucose-6-phosphate to glucose. Clinical features include fasting hypoglycemia, lactic acidosis, hypertriglyceridemia, hyperuricemia, hepatomegaly, and development of hepatocellular adenomas (HCAs) with potential for malignant transformation. Additionally, patients with GSD Ia often exhibit short stature, in some instances due to growth hormone (GH) deficiency. Patients with short stature caused by GH deficiency typically receive GH injections. Here, we review the literature and describe a female with GSD Ia who had short stature, failure of growth progression, and suspected GH deficiency. This patient received GH injections from ages 11 to 14 years under careful monitoring of an endocrinologist and developed HCAs during that time. To date, there is no reported long-term follow up data on patients with GSD Ia who have received GH therapy, and therefore the clinical outcomes post-GH therapy are unclear.

Keywords:  glycogen storage disease; glycogen storage disease Ia; growth hormone therapy; hepatocellular adenoma; von Gierke disease

DOI:  https://doi.org/10.1002/jmd2.12381
J Clin Endocrinol Metab. 2023 Sep 10. pii: dgad537. [Epub ahead of print]

Endogenous glucose production in patients with glycogen storage disease type Ia estimated by oral d-[6,6-2H2]-glucose.

Alessandro Rossi, Maaike H Oosterveer, Theo H van Dijk, Aycha Bleeker, Martijn Koehorst, David A Weinstein, Barbara M Bakker, Terry G J Derks.

   CONTEXT: Glycogen storage disease type Ia (GSDIa) is an inborn metabolic disorder characterized by impaired endogenous glucose production (EGP). Monitoring of GSDIa patients is prioritized, because of ongoing treatment developments. Stable isotope tracers may enable reliable EGP monitoring.
OBJECTIVE: The aim of this study was to prospectively assessthe rate of appearance of endogenous glucose into the bloodstream (Ra) in GSDIa patients after a single oral d-[6,6-2H2]-glucose dose.
DESIGN: Ten adult GSDIa patients and ten age-, sex-, BMI-matched healthy volunteers (HV) were enrolled. For each participant, three oral glucose tracer tests were performed: 1) preprandial/fasted, 2) postprandial, and 3) randomly fed states. Dried blood spots were collected before d-[6,6-2H2]-glucose administration and 10, 20, 30, 40, 50, 60, 75, 90, 120 minutes thereafter.
RESULTS: Glucose Ra in fasted HV was consistent with previously reported data. The time-averaged glucose Ra was significantly higher in i) preprandial/fasted GSDIa patients than HV and ii) postprandial HV compared to fasted HV(p<0.05). A progressive decrease in glucose Ra was observed in preprandial/fasted GSDIa patients; the change in glucose Ra time-course was directly correlated with the change in capillary glucose (p<0.05).
CONCLUSIONS: This is the first study to quantify glucose Ra in GSDIa patients using oral d-[6,6-2H2] glucose. The test can reliably estimate EGP under conditions in which fasting tolerance is unaffected but does not discriminate between relative contributions of EGP (e.g., liver, kidney) and exogenous sources (e.g., dietary cornstarch). Future application is warranted for longitudinal monitoring after novel genome-based treatments in GSDIa patients in whom nocturnal dietary management can be discontinued.

Keywords:  diet; glycogen storage disease type Ia; monitoring; precision medicine; stable isotopes

DOI:  https://doi.org/10.1210/clinem/dgad537
Endocr Metab Immune Disord Drug Targets. 2023 Sep 14.

Clinical and Laboratory Findings on Glycogen Storage Disease Type V: Results from a Retrospective Observational Study in a Tertiary Hospital.

Ângela Pereira, Jorge Diogo da Silva, Ana Rita Soares, Arlindo Guimas, Sara Rocha, Márcio Cardoso, Cristina Garrido, Célia Azevedo Soares, Isabel Nunes, Ana Maria Fortuna, Dulce Quelhas, Sónia Figueiroa, Rosa Ribeiro, Manuela Santos, Esmeralda Martins, Nataliya Tkachenko.

  Introduction - Glycogen storage disease type V (GSDV, MIM #232600) is an autosomal recessive metabolic myopathy caused by pathogenic variants in the PYGM gene. The characteristic symptoms of exercise intolerance, myalgia, and cramps, which improve after a few minutes of rest, are frequently unrecognized in affected children. When there is clinical suspicion, the initial approach with a forearm exercise test has diagnostic value by detecting low post-exercise plasma lactate-to-ammonia ratio values. The diagnostic algorithm is followed by genetic testing if the results suggest myophosphorylase deficiency. Methods - This was a retrospective observational study conducted based on reviewing medical records of patients with GSDV in a tertiary hospital. We assessed demographic variables, including the timing of onset and diagnosis, relevant clinical characteristics, and whether genetic testing was performed, including its results. Results/Case Report - Our goal was to review the GSDV cases in our center to assess our cohort's diagnostic timing and clinical and genetic characteristics. We identified 28 patients from 24 families, three with consanguinity. The mean age at the time of the study was 43 years. While most (26/28; 93%) recalled their first symptoms in childhood/adolescence, only 25% (7/28) were diagnosed then. All patients had exercise intolerance and CK elevation, while about half reported the second wind phenomenon. Genetic testing was performed in 22 patients, revealing biallelic PYGM variants (9 homozygous, 13 compound heterozygous) as the most common (p.R50*). Conclusion - GSDV is rare and presents in the pediatric age, with subtle manifestations often underestimated for decades. A late diagnosis may negatively impact the psychosocial development of affected children. It is essential to recognize some unique features that facilitate diagnosis: history of exercise intolerance, the second wind sign, and high resting serum CK levels. Identifying the disease-causing variants in PYGM is currently the gold standard for diagnosis as it is less invasive than performing a muscle biopsy, and may promptly diagnose the condition and avoid wrongful labelling of patients.

Keywords:  Creatine Kinase; Exercise intolerance; Glycogen storage disease type V; PYGM

DOI:  https://doi.org/10.2174/1871530323666230914122936
Biochim Biophys Acta Mol Cell Res. 2023 Sep 13. pii: S0167-4889(23)00158-1. [Epub ahead of print] 119585

Opposite regulation of glycogen metabolism by cAMP produced in the cytosol and at the plasma membrane.

Paulo F V Bizerra, Eduardo H Gilglioni, H L Li, Simei Go, Ronald P J Oude Elferink, Arthur J Verhoeven, Jung-Chin Chang.

  Cyclic AMP is produced in cells by two different types of adenylyl cyclases: at the plasma membrane by the transmembrane adenylyl cyclases (tmACs, ADCY1~ADCY9) and in the cytosol by the evolutionarily more conserved soluble adenylyl cyclase (sAC, ADCY10). By employing high-resolution extracellular flux analysis in HepG2 cells to study glycogen breakdown in real time, we showed that cAMP regulates glycogen metabolism in opposite directions depending on its location of synthesis within cells and the downstream cAMP effectors. While the canonical tmAC-cAMP-PKA signaling promotes glycogenolysis, we demonstrate here that the non-canonical sAC-cAMP-Epac1 signaling suppresses glycogenolysis. Mechanistically, suppression of sAC-cAMP-Epac1 leads to Ser-15 phosphorylation and thereby activation of the liver-form glycogen phosphorylase to promote glycogenolysis. Our findings highlight the importance of cAMP microdomain organization for distinct metabolic regulation and establish sAC as a novel regulator of glycogen metabolism.

Keywords:  Cyclic AMP; Exchange protein directly activated by cAMP (Epac); Glycogen breakdown; Glycogenolysis; Soluble adenylyl cyclase; cAMP signaling microdomains

DOI:  https://doi.org/10.1016/j.bbamcr.2023.119585
Neuroendocrinology. 2023 Sep 12.

Differential G-Protein-Coupled Estrogen Receptor-1 Regulation of Counter-Regulatory Transmitter Marker and 5'-AMP-Activated Protein Kinase Expression in Ventrolateral versus Dorsomedial Ventromedial Hypothalamic Nucleus.

Khaggeswar Bheemanapally, Karen P Briski.

The ventromedial hypothalamic nucleus (VMN) is an estrogen receptor (ER)-rich structure that regulates glucostasis. The role of nuclear, but not membrane G-protein-coupled ER-1 (GPER) in that function has been studied. Gene silencing and laser-catapult-microdissection/immunoblot tools were used to examine whether GPER regulates transmitter and energy sensor function in dorsomedial (VMNdm) and/or ventrolateral (VMNvl) VMN counter-regulatory nitrergic and -aminobutyric acid (GABA) neurons. Intra-VMN GPER siRNA administration to euglycemic animals did not affect VMNdm or -vl nitrergic neuron neuron nitric oxide synthase (nNOS), but up-regulated (VMNdm) or lacked influence on (VMNvl) GABA nerve cell glutamate decarboxylase65/67 (GAD) protein. Insulin-induced hypoglycemia (IIH) caused GPER knockdown-reversible augmentation of nNOS, 5'-AMP-activated protein kinase (AMPK), and phosphoAMPK proteins in VMNvl nitrergic neurons. IIH had dissimilar effects on VMNvl (unchanged) versus VMNdm (increased) GABAergic neuron GAD levels, yet GPER knockdown affected these profiles. GPER siRNA prevented hypoglycemic up-regulation of VMNvl and -dm GABA neuron AMPK without altering pAMPK expression. Outcomes infer that GPER exerts differential control of VMNdm versus -vl GABA transmission during glucostasis, and is required for hypoglycemic up-regulated nitrergic (VMNdm and -vl) and GABA (VMNdm) signaling. Glycogen metabolism is reported to regulate VMN nNOS and GAD proteins. Data show that GPER limits VMNvl glycogen phosphorylase (GP) protein expression and glycogen buildup during euglycemia, but mediates hypoglycemic augmentation of VMNvl GP protein and glycogen content; VMNdm glycogen mass is refractory to GPER control. GPER regulation of VMNvl glycogen metabolism infers that this receptor may govern local counter-regulatory transmission in part by astrocyte metabolic coupling.

DOI: https://doi.org/10.1159/000533627
JIMD Rep. 2023 Sep;64(5): 327-336

Diagnosis and management of children with McArdle Syndrome (GSD V) in New South Wales.

Louisa Adams, Arthavan Selvanathan, Kiera J Batten, Nancy van Doorn, Susan Thompson, Ashleigh Mitchell, Hugo Sampaio, Troy Dalkeith, Jacqui Russell, Carolyn J Ellaway, Michelle Farrar, Carolyn Broderick, Kaustuv Bhattacharya.

  Glycogen storage type V (GSD V-McArdle Syndrome) is a rare neuromuscular disorder characterised by severe pain early after the onset of physical activity. A recent series indicated a diagnostic delay of 29 years; hence reports of children affected by the disorder are uncommon (Lucia et al., 2021, Neuromuscul Disord, 31, 1296-1310). This paper presents eight patients with a median onset age of 5.5 years and diagnosis of 9.5 years. Six patients had episodes of rhabdomyolysis with creatine kinase elevations >50 000 IU/L. Most episodes occurred in relation to eccentric non-predicted activities rather than regular exercise. One of the patients performed a non-ischaemic forearm test. One patient was diagnosed subsequent to a skeletal muscle biopsy, and all had confirmatory molecular genetic diagnosis. Three were homozygous for the common PYGM:c.148C > T (p.Arg50*) variant. All but one patient had truncating variants. All patients were managed with structured exercise testing to help them identify 'second-wind', and plan an exercise regimen. In addition all also had an exercise test with 25 g maltodextrin which had statistically significant effect on ameliorating ratings of perceived exertion. GSD V is under-recognised in paediatric practice. Genetic testing can readily diagnose the condition. Careful identification of second-wind symptomatology during exercise with the assistance of a multi-disciplinary team, allows children to manage activities and tolerate exercise. Maltodextrin can be used for structured exercise, but excessive utilisation may lead to weight gain. Early intervention and education may improve outcomes into adult life.

Keywords:  McArdle; VO2 max; aerobic; exercise; glycogen storage; rhabdomyolysis; sports physiology

DOI:  https://doi.org/10.1002/jmd2.12389
J Diabetes. 2023 Sep 12.

GSK-3β activation mediates apolipoprotein E4-associated cognitive impairment in type 2 diabetes mellitus: A multicenter, cross-sectional study.

Yang Gao, Haitao Yu, Yanchao Liu, Zhipeng Xu, Benrong He, Honghai Liu, Yuying Wang, Yao Zhang, Yi Liang, Ying Yang, Jie Zheng, Jian-Zhi Wang.

   AIM: Both the activation of glycogen synthase kinase-3β (GSK-3β) and the presence of ApoE ε4 genotype have been found to respectively correlate with cognitive decline in patients with type 2 diabetes mellitus (T2DM), who further show a high incidence of developing Alzheimer's disease. However, the relationship between ApoE ε4 and GSK-3β in the cognitive impairment of T2DM patients remains unclear.
METHODS: ApoE genotypes and platelet GSK-3β level were measured in 1139 T2DM patients recruited from five medical centers in Wuhan, China. Cognitive functions were assessed by Mini-Mental State Examination (MMSE). The association and the relationships among apolipoprotein E (ApoE) genotypes, GSK-3β activity and cognitive function were analyzed by regression and mediating effect analyses, respectively.
RESULTS: T2DM patients with ApoE ε4 but not ApoE ε2 haplotype showed poorer cognitive function and elevated platelet GSK-3β activity, when using ApoE ε3 as reference. The elevation of GSK-3β activity was positively correlated the diabetes duration, as well as plasma glycated hemoglobin (HbA1c) and glucose levels. Moreover, correlation and regression analysis also revealed significant pairwise correlations among GSK-3β activity, ApoE gene polymorphism and cognitive function. Lastly, using Baron and Kenny modeling, we unveiled a mediative role of GSK-3β activity between ApoE ε4 and cognitive impairment.
CONCLUSION: We reported here that the upregulation of GSK-3β activity mediates the exacerbation of cognitive impairment by ApoE ε4-enhanced cognitive impairment in T2DM patients, suggesting GSK-3β inhibitors as promising drugs for preserving cognitive function in T2DM patients, especially to those with ApoE ε4 genotype.

Keywords:  ApoE; gene polymorphism; glycogen synthase kinase-3β; mediation analyses; mild cognitive impairment; type 2 diabetes mellitus

DOI:  https://doi.org/10.1111/1753-0407.13470