bims-glecem 2022-11-27 papers

bims-glecem

Biomed News

on Glycogen metabolism in exercise, cancer and energy metabolism

Issue of 2022‒11‒27
eleven papers selected by
Dipsikha Biswas, Københavns Universitet

Case report: Familial glycogen storage disease type IV caused by novel compound heterozygous mutations in a glycogen branching enzyme 1 gene.
Infantile Pompe disease with intrauterine onset: a case report and literature review.
Glycogen Synthase Kinase 3β: A True Foe in Pancreatic Cancer.
Screening chimeric GAA variants in preclinicalstudy results in hematopoietic stem cell genetherapy candidate vectors for Pompe disease.
GSK-3β phosphorylation of DHX33 leads to its ubiquitination mediated protein degradation.
G-Protein-Coupled Lactate Receptor GPR81 Control of VMNvl Glucoregulatory Neurotransmitter and 5'-AMP-Activated Protein Kinase Expression.
Outcome of liver transplantation in hepatic glycogen storage disease: A systematic review and meta-analysis.
Integration of Liver Glycogen and Triglyceride NMR Isotopomer Analyses Provides a Comprehensive Coverage of Hepatic Glucose and Fructose Metabolism.
Generation of the First Human In Vitro Model for McArdle Disease Based on iPSC Technology.
The dysfunction of hormone-sensitive lipase induces lipid deposition and reprogramming of nutrient metabolism.
Right Ventricle Involvement by Glycogen Storage Cardiomyopathy (PRKAG2): Standard and Advanced Echocardiography Analyses.

Front Genet. 2022 ;13 1033944

Case report: Familial glycogen storage disease type IV caused by novel compound heterozygous mutations in a glycogen branching enzyme 1 gene.

Yiyang Li, Chuan Tian, Si Huang, Weijie Zhang, Qiuyu Liutang, Yajun Wang, Guoda Ma, Riling Chen.

  Glycogen storage disease type IV (GSD IV), caused by a mutation in the glycogen branching enzyme 1 (GBE1) gene, is a rare metabolic disorder with an autosomal recessive inheritance that involves the liver, neuromuscular, and cardiac systems. Here, we reported a case of familial GSD IV induced by novel compound heterozygous mutations in GBE1. The proband (at age 1) and her younger brother (at age 10 months) manifested hepatosplenomegaly, liver dysfunction, and growth retardation at onset, followed by progressive disease deterioration to liver cirrhosis with liver failure. During the disease course, the proband presented rare intractable asymptomatic hypoglycemia. The liver pathology was in line with GSD IV. Both cases carried pathogenic compound heterozygous mutations in GBE1 mutations, i.e., a missense mutation (c.271T>A, p. W91R) in exon 2 and a deletion mutation in partial exons 3-7. Both mutations are first reported. The internationally pioneered split-liver transplantation was performed during progression to end-stage liver disease, and the patients had normal liver function and blood glucose after. This study broadens the mutation spectrum of the GBE1 gene and the phenotypic spectrum of GSD IV.

Keywords:  GBE1; GSD IV; asymptomatic hypoglycemia; case report; liver transplantation

DOI:  https://doi.org/10.3389/fgene.2022.1033944
Ital J Pediatr. 2022 Nov 21. 48(1): 187

Infantile Pompe disease with intrauterine onset: a case report and literature review.

Hongmin Xi, Xianghong Li, Lili Ma, Xiangyun Yin, Ping Yang, Lulu Zhang.

  BACKGROUND: Pompe disease is a rare autosomal recessive disease. Acid alpha-glucosidase (GAA) deficiency leads to glycogen storage in lysosomes, causing skeletal, cardiac, and smooth muscle lesions. Pompe disease is progressive, and its severity depends on the age of onset. Classic infantile Pompe disease, the most severe form, is characterized by an age of onset before 12 months. Pompe disease with intrauterine onset has rarely been reported.CASE PRESENTATION: The proband was born at a gestational age of 40 weeks and 3 days and admitted to our hospital because of intrauterine cardiac hypertrophy, shortness of breath, and cyanosis until 13 min postnatally. Physical examination at admission revealed poor responsiveness, pale skin, shortness of breath, reduced limb muscle tone, and bilateral pedal edema. The heart sounds were weak, and no heart murmur was heard. Echocardiography showed left (9 mm) and right (5 mm) ventricular hypertrophies. The patient was subjected to non-invasive ventilator-assisted respiration, fluid restriction, diuresis, and metoprolol treatment. Infantile Pompe disease was diagnosed on day 16 with a GAA enzymatic activity of 0.31 µmol/L/h and with the full-penetrance genetic test showing the homozygous gene mutation c.1844G>T(p.Gly615Val). Enzyme replacement therapy was refused by the patient's parents, and the patient died at seven months of age from cardiopulmonary failure.
CONCLUSION: Infants with intrauterine-onset Pompe disease usually have early manifestations of heart disease. Prompt GAA enzymatic activity determination and molecular genetic testing are helpful in aiding the parents' decision and planning the treatment.

Keywords:  Acid maltase deficiency; Glycogen storage disease type II; Intrauterine onset; Pompe disease

DOI:  https://doi.org/10.1186/s13052-022-01379-3
Int J Mol Sci. 2022 Nov 16. pii: 14133. [Epub ahead of print]23(22):

Glycogen Synthase Kinase 3β: A True Foe in Pancreatic Cancer.

Omer H M Elmadbouh, Stephen J Pandol, Mouad Edderkaoui.

  Glycogen synthase kinase 3 beta (GSK-3β) is a serine/threonine protein kinase involved in multiple normal and pathological cell functions, including cell signalling and metabolism. GSK-3β is highly expressed in the onset and progression of multiple cancers with strong involvement in the regulation of proliferation, apoptosis, and chemoresistance. Multiple studies showed pro- and anti-cancer roles of GSK-3β creating confusion about the benefit of targeting GSK-3β for treating cancer. In this mini-review, we focus on the role of GSK-3β in pancreatic cancer. We demonstrate that the proposed anti-cancer roles of GSK-3β are not relevant to pancreatic cancer, and we argue why GSK-3β is, indeed, a very promising therapeutic target in pancreatic cancer.

Keywords:  GSK-3β; pancreatic cancer

DOI:  https://doi.org/10.3390/ijms232214133
Mol Ther Methods Clin Dev. 2022 Dec 08. 27 464-487

Screening chimeric GAA variants in preclinicalstudy results in hematopoietic stem cell genetherapy candidate vectors for Pompe disease.

Yildirim Dogan, Cecilia N Barese, Jeffrey W Schindler, John K Yoon, Zeenath Unnisa, Swaroopa Guda, Mary E Jacobs, Christine Oborski, Tim Maiwald, Diana L Clarke, Axel Schambach, Richard Pfeifer, Claudia Harper, Chris Mason, Niek P van Til.

  Pompe disease is a rare genetic neuromuscular disorder caused by acid α-glucosidase (GAA) deficiency resulting in lysosomal glycogen accumulation and progressive myopathy. Enzyme replacement therapy, the current standard of care, penetrates poorly into the skeletal muscles and the peripheral and central nervous system (CNS), risks recombinant enzyme immunogenicity, and requires high doses and frequent infusions. Lentiviral vector-mediated hematopoietic stem and progenitor cell (HSPC) gene therapy was investigated in a Pompe mouse model using a clinically relevant promoter driving nine engineered GAA coding sequences incorporating distinct peptide tags and codon optimizations. Vectors solely including glycosylation-independent lysosomal targeting tags enhanced secretion and improved reduction of glycogen, myofiber, and CNS vacuolation in key tissues, although GAA enzyme activity and protein was consistently lower compared with native GAA. Genetically modified microglial cells in brains were detected at low levels but provided robust phenotypic correction. Furthermore, an amino acid substitution introduced in the tag reduced insulin receptor-mediated signaling with no evidence of an effect on blood glucose levels in Pompe mice. This study demonstrated the therapeutic potential of lentiviral HSPC gene therapy exploiting optimized GAA tagged coding sequences to reverse Pompe disease pathology in a preclinical mouse model, providing promising vector candidates for further investigation.

Keywords:  Pompe disease; glycosylation-independent lysosomal targeting; hematopoietic stem and progenitor cells; lentiviral vector; tag technology

DOI:  https://doi.org/10.1016/j.omtm.2022.10.017
Cell Signal. 2022 Nov 17. pii: S0898-6568(22)00288-1. [Epub ahead of print] 110526

GSK-3β phosphorylation of DHX33 leads to its ubiquitination mediated protein degradation.

Yandong Zhang, Shiyun Chen, Cheng Peng.

  DHX33 is a member of DEAD/H box protein family, and is involved in both RNA and DNA metabolism. It plays diverse roles in multiple cellular activities. DHX33 overexpression has been found to promote the development of many human cancers. However, the underlying mechanism to explain its high expression in cancer cells remains incompletely resolved. In this study, with both human cancer cell lines and normal fibroblasts, we found glycogen synthase kinase 3β (GSK-3β) regulates DHX33 protein stability. This is through its direct phosphorylation of DHX33 on T482, which triggers ubiquitination mediate protein degradation. We further identified one of the major ubiquitination sites of DHX33 to be on its N-terminal K94, a critical residue previously found to be important and highly conserved for ATP binding and helicase activity. Our study for the first time reveals an important upstream regulator, GSK-3β, as a critical kinase to phosphorylate DHX33 at the post-translational level leading to its degradation. Moreover, cancer cells have frequent GSK3β deactivation to disrupt this signaling cascade. Therefore, DHX33 is stabilized in many cancer cells as compared to normal cells. Our study unveils an important post-translational regulation of DHX33 in cells and further unveils a novel mechanism for DHX33 overexpression in cancer cells.

Keywords:  DHX33; GSK-3β; Protein degradation; RNA helicase; Ubiquitination

DOI:  https://doi.org/10.1016/j.cellsig.2022.110526
Am J Physiol Regul Integr Comp Physiol. 2022 Nov 21.

G-Protein-Coupled Lactate Receptor GPR81 Control of VMNvl Glucoregulatory Neurotransmitter and 5'-AMP-Activated Protein Kinase Expression.

Sagor Chandra Roy, Prabhat R Napit, Madhu Babu Pasula, Khaggeswar Bheemanapally, Karen P Briski.

  Astrocytes store glycogen as energy and promote neuro-metabolic stability through supply of oxidizable L-lactate. Whether lactate regulates ventromedial hypothalamic nucleus (VMN) glucostatic function as a metabolic volume transmitter is unknown. Current research investigated whether G-protein-coupled lactate receptor GPR81 controls astrocyte glycogen metabolism and glucose-regulatory neurotransmission in the ventrolateral VMN (VMNvl), where glucose-regulatory neurons reside. Female rats were pretreated by intra-VMN GPR81 or scramble siRNA infusion before insulin or vehicle injection. VMNvl cell or tissue samples were acquired by laser-catapult- or micropunch microdissection for Western blot protein or uHPLC-electrospray ionization-mass spectrometric glycogen analyses. Data show that GPR81 regulates eu- and/or hypoglycemic patterns of VMNvl astrocyte glycogen metabolic enzyme and 5'-AMP-activated protein kinase (AMPK) protein expression according to VMNvl segment. GPR81 inhibits baseline rostral and caudal VMNvl glycogen accumulation, but mediates glycogen breakdown in the former site during hypoglycemia. During euglycemia, GPR81 suppresses the transmitter marker neuronal nitric oxide synthase (nNOS) in rostral and caudal VMNvl nitrergic neurons, but stimulates (rostral VMNvl) or inhibits (caudal VMNvl) GABAergic neuron glutamate decarboxylase65/67 (GAD)protein. During hypoglycemia, GPR81 regulates AMPK activation in nitrergic and GABAergic neurons located in the rostral, but not caudal. VMNvl. VMN GPR81 knockdown amplified hypoglycemic hypercorticosteronemia, but not hyperglucagonemia. Results provide novel proof that VMNvl astrocyte and glucose-regulatory neurons express GPR81 protein. Data identify neuroanatomical subpopulations of VMNvl astrocytes and glucose-regulatory neurons that exhibit differential reactivity to GPR81 input. Heterogeneous GPR81 effects during eu- versus hypoglycemia infer that energy state may affect cellular sensitivity to or post-receptor processing of lactate transmitter signaling.

Keywords:  AMPK; GPR81; glycogen; neuronal nitric oxide synthase; ventrolateral ventromedial hypothalamic nucleus

DOI:  https://doi.org/10.1152/ajpregu.00100.2022
Clin Transplant. 2022 Nov 26. e14867

Outcome of liver transplantation in hepatic glycogen storage disease: A systematic review and meta-analysis.

Zahra Beyzaei, Zahra Bagheri, Sara Karimzadeh, Bita Geramizadeh.

  Liver transplantation (LT) is the choice of therapeutic option for end-stage hepatic GSD patients; however, reports about the long-term outcome of LT in these patients have remained controversial. We performed a systematic review and meta-analysis of observational studies to investigate the long-term outcome of LT in hepatic GSD patients. A total of 14 studies with 210 patients were included in our analysis. As the results showed, the pooled proportion of GSD patients with complications after liver transplant (e.g., hemorrhagic shock, biliary complications, tacrolimus encephalopathy, chronic hepatitis, hepatic artery thrombosis, hepatic adenoma, sepsis, liver dysfunction, chronic rejection, acute cellular rejection, and CMV infection) was 27.7% (95%CI: 20.42-35.67) without heterogeneity (I2 = 24.04%), as calculated by the random-effect model. The pooled proportion of GSD patients with complications related to GSD after LT, including HCC (Hepatocellular carcinoma), renal complication, muscle problems, delayed menarche, persistent neutropenia, pneumonitis, renal failure, and hepatic adenoma was 22.2% (95%CI: 7.97-40.01) with a high heterogeneity (I2 = 82.47%). Subgroup analysis including the age of patients (adult/pediatric), duration of follow-up, and type of donor was conducted to investigate the resources of heterogeneity. According to our investigation and review analysis, most GSD patients showed significant outcome improvement after liver transplantation. Overall, our findings showed an excellent outcome of liver transplantation in GSD patients; however, it needs further investigations to be confirmed. This article is protected by copyright. All rights reserved.

Keywords:  allograft; glycogen storage disease; graft rejection; liver transplantation; outcome

DOI:  https://doi.org/10.1111/ctr.14867
Metabolites. 2022 Nov 19. pii: 1142. [Epub ahead of print]12(11):

Integration of Liver Glycogen and Triglyceride NMR Isotopomer Analyses Provides a Comprehensive Coverage of Hepatic Glucose and Fructose Metabolism.

Ivan Viegas, Giada Di Nunzio, Getachew D Belew, Alejandra N Torres, João G Silva, Luis Perpétuo, Cristina Barosa, Ludgero C Tavares, John G Jones.

  Dietary glucose and fructose are both efficiently assimilated by the liver but a comprehensive measurement of this process starting from their conversion to sugar phosphates, involvement of the pentose phosphate pathway (PPP), and conversion to glycogen and lipid storage products, remains incomplete. Mice were fed a chow diet supplemented with 35 g/100 mL drinking water of a 55/45 fructose/glucose mixture for 18 weeks. On the final night, the sugar mixture was enriched with either [U-13C]glucose or [U-13C]fructose, and deuterated water (2H2O) was also administered. 13C-isotopomers representing newly synthesized hepatic glucose-6-phosphate (glucose-6-P), glycerol-3-phosphate, and lipogenic acetyl-CoA were quantified by 2H and 13C NMR analysis of post-mortem liver glycogen and triglyceride. These data were applied to a metabolic model covering glucose-6-P, PPP, triose-P, and de novo lipogenesis (DNL) fluxes. The glucose supplement was converted to glucose-6-P via the direct pathway, while the fructose supplement was metabolized by the liver to gluconeogenic triose-P via fructokinase-aldolase-triokinase. Glucose-6-P from all carbohydrate sources accounted for 40-60% of lipogenic acetyl-CoA and 10-12% was oxidized by the pentose phosphate pathway (PPP). The yield of NADPH from PPP flux accounted for a minority (~30%) of the total DNL requirement. In conclusion, this approach integrates measurements of glucose-6-P, PPP, and DNL fluxes to provide a holistic and informative assessment of hepatic glucose and fructose metabolism.

Keywords:  13C NMR; acetyl-CoA; lipogenesis; pentose phosphate pathway; triose phosphates

DOI:  https://doi.org/10.3390/metabo12111142
Int J Mol Sci. 2022 Nov 12. pii: 13964. [Epub ahead of print]23(22):

Generation of the First Human In Vitro Model for McArdle Disease Based on iPSC Technology.

María Del Carmen Ortuño-Costela, Victoria Cerrada, Ana Moreno-Izquierdo, Inés García-Consuegra, Camille Laberthonnière, Mégane Delourme, Rafael Garesse, Joaquín Arenas, Carla Fuster García, Gema García García, José María Millán, Frédérique Magdinier, María Esther Gallardo.

  McArdle disease is a rare autosomal recessive disorder caused by mutations in the PYGM gene. This gene encodes for the skeletal muscle isoform of glycogen phosphorylase (myophosphorylase), the first enzyme in glycogenolysis. Patients with this disorder are unable to obtain energy from their glycogen stored in skeletal muscle, prompting an exercise intolerance. Currently, there is no treatment for this disease, and the lack of suitable in vitro human models has prevented the search for therapies against it. In this article, we have established the first human iPSC-based model for McArdle disease. For the generation of this model, induced pluripotent stem cells (iPSCs) from a patient with McArdle disease (harbouring the homozygous mutation c.148C>T; p.R50* in the PYGM gene) were differentiated into myogenic cells able to contract spontaneously in the presence of motor neurons and generate calcium transients, a proof of their maturity and functionality. Additionally, an isogenic skeletal muscle model of McArdle disease was created. As a proof-of-concept, we have tested in this model the rescue of PYGM expression by two different read-through compounds (PTC124 and RTC13). The developed model will be very useful as a platform for testing drugs or compounds with potential pharmacological activity.

Keywords:  CRISPR/Cas9; McArdle disease; PYGM; disease modelling; gene editing; iPSCs; isogenic control; read-through drugs; skeletal muscle differentiation

DOI:  https://doi.org/10.3390/ijms232213964
Br J Nutr. 2022 Nov 21. 1-37

The dysfunction of hormone-sensitive lipase induces lipid deposition and reprogramming of nutrient metabolism.

Jin-Gang Wang, Si-Han Zhao, Yu-Cheng Qian, Yi-Fan Qian, Yi-Chan Liu, Fang Qiao, Yuan Luo, Mei-Ling Zhang, Zhen-Yu Du.

  Hormone-sensitive lipase is one of the rate-determining enzymes in the hydrolysis of triglyceride, playing a crucial role in lipid metabolism. However, the role of HSL-mediated lipolysis in systemic nutrient homeostasis has not been intensively understood. Therefore, we used CRISPR/Cas9 technique and Hsl inhibitor (HSL-IN-1) to establish hsla-deficient (hsla-/-) and Hsl-inhibited zebrafish models, respectively. As a result, the hsla-/- zebrafish showed retarded growth and reduced oxygen consumption rate, accompanied with higher mRNA expression of the genes related to inflammation and apoptosis in liver and muscle. Furthermore, hsla-/- and HSL-IN-1 treated zebrafish both exhibited severe fat deposition, whereas their expressions of the genes related to lipolysis and fatty acid oxidation were markedly reduced. The thin layer chromatography results also showed that the dysfunction of Hsl changed the whole body lipid profile, including increasing the content of TG and decreasing the proportion of PL. In addition, the systemic metabolic pattern was remodeled in hsla-/- and HSL-IN-1 treated zebrafish. The dysfunction of Hsl lowered the glycogen content in liver and muscle, enhanced the utilization of glucose plus the expressions of glucose transporter and glycolysis genes. Besides, the whole-body protein content had significantly decreased in the hsla-/- and HSL-IN-1 treated zebrafish, accompanied with the lower activation of the mTOR pathway and enhanced protein and amino acid catabolism. Taken together, Hsl plays an essential role in energy homeostasis, and its dysfunction would cause the disturbance of lipid catabolism but enhanced breakdown of glycogen and protein for energy compensation.

Keywords:  Energy homeostasis; Glycogen utilization; Hormone-sensitive lipase; Lipolysis; Protein metabolism; Zebrafish

DOI:  https://doi.org/10.1017/S0007114522003622
Arq Bras Cardiol. 2022 Nov 21. pii: S0066-782X2022005018201. [Epub ahead of print]

Right Ventricle Involvement by Glycogen Storage Cardiomyopathy (PRKAG2): Standard and Advanced Echocardiography Analyses.

José Luiz Barros Pena, Fabricio Junqueira de Melo, Wander Costa Santos, Isabel Cristina Gomes Moura, Gabriela Pansanato Nakashima, Natalia Costa Freitas, Eduardo Back Sternick.

BACKGROUND: PRKAG2 syndrome is a rare, early-onset autosomal dominant inherited disease. We aimed to describe the right ventricle (RV) echocardiographic findings using two and three-dimensional (2D and 3D) modalities including myocardial deformation indices in this cardiomyopathy. We also aimed to demonstrate whether this technique could identify changes in RV function that could distinguish any particular findings.METHODS: Thirty patients with genetically proven PRKAG2 (R302Q and H401Q), 16 (53.3%) males, mean age 39.1 ± 15.4 years, underwent complete echocardiography examination. RV-focused, 4-chamber view was acquired for 2D and 3D measurements. Student's t or Wilcoxon-Mann-Whitney tests were used to compare numerical variables between 2 groups, and p < 0.05 was considered significant.
RESULTS: Twelve patients (40%) had a pacemaker implanted for 12.4 ± 9.9 years. RV free wall mean diastolic thickness was 7.9 ± 2.9 mm. RV 4-chamber longitudinal strain (RV4LS), including the free wall and interventricular septum, was -17.3% ± 6.7%, and RV free wall longitudinal strain (RVFWLS) was -19.1% ± 8.5%. The RVFWLS apical ratio measured 0.63 ± 0.15. Mean RV 3D ejection fraction (EF) was 42.6% ± 10.9% and below normal limits in 56.7% of patients. Positive correlation occurred between RV 3DEF, RV4LS, and RVFWLS, especially for patients without a pacemaker (p = 0.006).
CONCLUSION: RV involvement in PRKAG2 syndrome is frequent, occurring in different degrees. Echocardiography is a valuable tool in detecting RV myocardial abnormalities in this condition. The use of 2D RV4LS, RVFWLS, and 3DEF offers reliable indicators of RV systolic dysfunction in this rare, challenging cardiomyopathy.

DOI: https://doi.org/10.36660/abc.20210801