bims-glecem 2022-07-31 papers

bims-glecem

Biomed News

on Glycogen metabolism in exercise, cancer and energy metabolism

Issue of 2022–07–31
eleven papers selected by
Dipsikha Biswas, Københavns Universitet

McArdle disease in a patient with anorexia nervosa: a case report.
GSK-3β-mediated regulation of Nrf2/HO-1 signaling as a new therapeutic approach in the treatment of movement disorders.
Successful Treatment of Refractory Anemia in a Patient With Glycogen Storage Disease Type Ia Undergoing Hemodialysis.
A New Perspective on the Quality of Life of Children with Glycogen Storage Diseases.
Effect of Estradiol and IGF1 on Glycogen Synthesis in Bovine Uterine Epithelial Cells.
A Proteomic Platform Unveils the Brain Glycogen Phosphorylase as a Potential Therapeutic Target for Glioblastoma Multiforme.
The lack of Bmal1, a core clock gene, in the intestine decreases glucose absorption in mice.
[Late onset Pompe disease: an analysis of 19 patients from Mexico].
Three weeks of time-restricted eating improves glucose homeostasis in adults with type 2 diabetes but does not improve insulin sensitivity: a randomised crossover trial.
Modeling a Novel Variant of Glycogenosis IXa Using a Clonal Inducible Reprogramming System to Generate "Diseased" Hepatocytes for Accurate Diagnosis.
Rationed and satiated growth hormone transgenic Coho Salmon (Oncorhynchus kisutch) show tissue specific differences in energy stores.

Eat Weight Disord. 2022 Jul 24.

McArdle disease in a patient with anorexia nervosa: a case report.

Riccardo Dalle Grave, Enrico Patacca, Maddalena Conti, Fabio Soave, Laura Dametti, Anna Dalle Grave, Simona Calugi.

   BACKGROUND: McArdle disease is an autosomal recessive genetic disorder caused by a deficiency of the glycogen phosphorylase (myophosphorylase) enzyme, which muscles need to break down glycogen into glucose for energy. Symptoms include exercise intolerance, with fatigue, muscle pain, and cramps being manifested during the first few minutes of exercise, which may be accompanied by rhabdomyolysis.
CASE PRESENTATION: This case report describes for the first time the clinical features, diagnosis and management of a 20 year-old patient with anorexia nervosa and McArdle disease, documented by means of muscle biopsy.
CONCLUSION: Anorexia nervosa and McArdle disease interact in a detrimental bidirectional way. In addition, some laboratory parameter alterations (e.g., elevated values of creatine kinase) commonly attributed to the specific features of eating disorders (e.g., excessive exercising) may delay the diagnosis of metabolic muscle diseases. On the other hand, the coexistence of a chronic disease, such as McArdle disease, whose management requires the adoption of a healthy lifestyle, can help to engage patients in actively addressing their eating disorder.

Keywords:  Anorexia nervosa; Cognitive behavior therapy; Excessive exercise; Glycogen storage disease type V; McArdle disease; Treatment

DOI:  https://doi.org/10.1007/s40519-022-01451-1
Pharmacol Rep. 2022 Jul 26.

GSK-3β-mediated regulation of Nrf2/HO-1 signaling as a new therapeutic approach in the treatment of movement disorders.

Divya Soni, Puneet Kumar.

  Movement disorders are neurological conditions characterized by involuntary motor movements, such as dystonia, ataxia, chorea myoclonus, tremors, Huntington's disease (HD), and Parkinson's disease (PD). It is classified into two categories: hypokinetic and hyperkinetic movements. Globally, movement disorders are a major cause of death. The pathophysiological process is initiated by excessive ROS generation, mitochondrial dysfunction, neuroinflammation, and neurotransmitters imbalance that lead to motor dysfunction in PD and HD patients. Several endogenous targets including Nrf2 maintain oxidative balance in the body. Activation of Nrf2 signaling is regulated by the enzyme glycogen synthase kinase (GSK-3β). In the cytoplasm, inhibition of GSK-3β regulates cellular proliferation, homeostasis, and apoptotic process by stimulating the nuclear factor erythroid 2 (Nrf2) pathway which is involved in the elevation of the cellular antioxidant enzymes which controls the ROS generation. The activation of Nrf2 increases the expression of antioxidant response elements (ARE), such as (Hemeoxygenase-1) HO-1, which decreases excessive cellular stress, mitochondrial dysfunction, apoptosis, and neuronal degeneration, which is the major cause of motor dysfunction. The present review explores the GSK-3β-mediated neuroprotection in various movement disorders through the Nrf2/HO-1 antioxidant pathway. This review provides a link between GSK-3β and the Nrf2/HO-1 signaling pathway in the treatment of PD and HD. In addition to that it highlights various GSK-3β inhibitors and the Nrf2/HO-1 activators, which exert robust neuroprotection against motor disorders. Therefore, the present review will help in the discovery of new therapy for PD and HD patients.

Keywords:  GSK-3β; Huntington’s disease; Movement disorders; Neuroprotection; Nrf2/HO-1; Parkinson’s disease

DOI:  https://doi.org/10.1007/s43440-022-00390-z
Cureus. 2022 Jun;14(6): e26213

Successful Treatment of Refractory Anemia in a Patient With Glycogen Storage Disease Type Ia Undergoing Hemodialysis.

Hirotaka Sato, Kentaro Takase, Seikon Kin.

  Glycogen storage disease type Ⅰa (GSDIa), also known as von Gierke disease, is a rare inherited metabolic disorder caused by defective glucose 6-phosphatase (G6Pase) activity. Although anemia, renal failure, and hepatic adenoma are the major clinical manifestations of GSDIa, there has been no report of refractory anemia in GSDIa patients on maintenance hemodialysis (HD) concomitant with multiple liver adenomas. Herein, we present a case of refractory anemia in a patient with GSDIa undergoing HD with multiple hepatic adenomas, successfully managed through aggressive treatment for renal anemia and intravenous iron therapy (IIT). A 26-year-old man with GSDIa who had been on HD for a year suffered from refractory anemia. He had experienced hypoglycemia and hyperlactic acidemia repeatedly and unusual hypertriglyceridemia had been observed for a long time. In addition, multiple hepatic adenomas developed and his renal function gradually declined, eventually progressing to end-stage kidney disease, and HD was started. Despite 120 µg/week of darbepoetin alfa (DA), 200 mg/day of oral sodium ferrous citrate, and 600 mg/week of roxadustat, the anemia persisted and iron deficiency gradually progressed. We considered that renal anemia, blood loss by each HD session, and decreased intestinal iron absorption due to inappropriately increased hepcidin from hepatic adenomas were the main etiology of the anemia; hence, we changed oral sodium ferrous citrate to intravenous saccharated ferric oxide along with continuous aggressive treatment of renal anemia, and the anemia resolved quickly within three months. We believe that refractory anemia was mainly induced by renal anemia and chronic iron deficiency due to blood loss during HD and inappropriately elevated hepcidin levels in hepatic adenomas. Aggressive treatment of renal anemia, along with IIT, may be a promising treatment option. Strict monitoring of iron overload is essential for safe treatment.

Keywords:  anemia of chronic disease (acd); glycogen storage disease type 1a; hepatic adenoma; hepcidin; iron deficiency anemia (ida); maintenance hemodialysis

DOI:  https://doi.org/10.7759/cureus.26213
Pediatr Gastroenterol Hepatol Nutr. 2022 Jul;25(4): 321-331

A New Perspective on the Quality of Life of Children with Glycogen Storage Diseases.

Gihan Ahmed Sobhy, Mortada El-Shabrawi, Heba Safar.

   Purpose: This study aimed to assess the quality of life (QoL) of children with glycogen storage disease (GSD) and their parents and to determine the impact of myopathies.
Methods: A prospective case-control study was conducted at the Cairo University Children's Hospital and National Liver Institute, Menoufia University. A promising new style of questionnaire called the Stark Quality of Life Questionnaire was used to assess the quality of life.
Results: Fifty-two children diagnosed with GSD (cases) and 55 age- and sex-matched healthy children (controls) were included. A statistically significant difference was found between cases and controls regarding food intake; mental behavior parameters such as mood, energy, and social contact; and physical behavior parameters such as running and tying shoelaces. Children with myopathies had significantly lower QoL scores in most of the parameters.
Conclusion: GSDs alter children and their parents' mental and physical abilities. Lower QoL scores were detected in children with both skeletal myopathy and cardiomyopathy, but the difference was not statistically significant when compared with the children without myopathies.

Keywords:  Glycogen storage diseases; Muscular diseases; Quality of life

DOI:  https://doi.org/10.5223/pghn.2022.25.4.321
Reproduction. 2022 Jul 01. pii: REP-22-0040. [Epub ahead of print]

Effect of Estradiol and IGF1 on Glycogen Synthesis in Bovine Uterine Epithelial Cells.

Alexis Gonzalez, Malia Berg, Bruce Southey, Matthew Dean.

Glycogen storage in the uterine epithelium peaks near estrus and is a potential source of glucose for the endometrium and embryos. However, the hormonal regulation of glycogen synthesis in the uterine epithelium is poorly understood. Our objective was to evaluate the effect of estradiol (E2) and insulin-like growth factor 1 (IGF1) on glycogenesis in immortalized bovine uterine epithelial (BUTE) cells. Treatment of BUTE cells with E2 (0.1-10 nM) did not increase glycogen levels. However, treatment of BUTE cells with IGF1 (50 or 100 ng/ml) resulted in a >2-fold increase in glycogen. To determine if the uterine stroma produced IGF1 in response to E2, bovine uterine fibroblasts (BFIBs) were treated with E2, which increased IGF1 levels. Immunohistochemistry showed higher levels of IGF1 in the stroma on day 1 than day 11, which coincides with higher glycogen levels in the uterine epithelium. Western blots revealed that IGF1 treatment increased levels of phospho-AKT, phospho-GSKβ, hexokinase 1, and glycogen synthase in BUTE cells. Metabolomic (GC-MS) analysis showed that IGF1 increased 3-phosphoglycerate and lactate, potentially indicative of increased flux through glycolysis. We also found higher levels of N-acetyl-glucosamine and protein glycosylation after IGF1 treatment, indicating increased hexosamine biosynthetic pathway activity. In conclusion, IGF1 is produced by uterine fibroblasts due to E2, and IGF1 increases glucose metabolism and glycogenesis in uterine epithelial cells. Glycogen stored in the uterine epithelium due to E2/IGF1 signaling at estrus could provide glucose to the endometrium or be secreted into the uterine lumen as a component of histotroph.

DOI: https://doi.org/10.1530/REP-22-0040
Int J Mol Sci. 2022 Jul 25. pii: 8200. [Epub ahead of print]23(15):

A Proteomic Platform Unveils the Brain Glycogen Phosphorylase as a Potential Therapeutic Target for Glioblastoma Multiforme.

Giusy Ferraro, Matteo Mozzicafreddo, Roberta Ettari, Lorenzo Corsi, Maria Chiara Monti.

  In the last few years, several efforts have been made to identify original strategies against glioblastoma multiforme (GBM): this requires a more detailed investigation of the molecular mechanism of GBM so that novel targets can be identified for new possible therapeutic agents. Here, using a combined biochemical and proteomic approach, we evaluated the ability of a blood-brain barrier-permeable 2,3-benzodiazepin-4-one, called 1g, to interfere with the activity and the expression of brain glycogen phosphorylase (PYGB) on U87MG cell line in parallel with the capability of this compound to inhibit the cell growth and cycle. Thus, our results highlighted PYGB as a potential therapeutic target in GBM prompting 1g as a capable anticancer drug thanks to its ability to negatively modulate the uptake and metabolism of glucose, the so-called "Warburg effect", whose increase is considered a common feature of cancer cells in respect of their normal counterparts.

Keywords:  2,3-benzodiazepin-4-one; glioblastoma multiforme; glycogen phosphorylase; proteomics; target identification

DOI:  https://doi.org/10.3390/ijms23158200
Endocrinology. 2022 Jul 29. pii: bqac119. [Epub ahead of print]

The lack of Bmal1, a core clock gene, in the intestine decreases glucose absorption in mice.

Shinsuke Onuma, Saori Kinoshita, Shigeki Shimba, Keiichi Ozono, Toshimi Michigami, Masanobu Kawai.

  The circadian clock network is an evolutionarily conserved system that regulates systemic metabolism, such as glucose homeostasis. Intestinal tissue is a pivotal organ for the regulation of glucose metabolism mainly via glucose absorption into the circulation; however, the significance of the intestinal circadian clock network for glucose metabolism remains largely unclear. We herein utilized a mouse model in which Bmal1, a core clock gene, was deleted in an intestine-specific manner (Bmal1Int-/- mice) and demonstrated a rhythmic expression of Sglt1 with its peak at zeitgeber time (ZT) 10.7±2.8 in control mice, whereas this was lost in Bmal1Int-/- mice. Mechanistically, a chromatin-immunoprecipitation analysis revealed a rhythmic binding of CLOCK to the E-box elements in the Sglt1 gene in control mice; however, this was absent in Bmal1Int-/- mice. Accordingly, SGLT1 protein levels were decreased during the dark phase in Bmal1Int-/- mice and this was associated with impaired glucose absorption, leading to a decline in hepatic glycogen levels at ZT4, which was restored by an ingestion of a high-sucrose water. Additionally, when mice were starved from ZT0, a greater expression of lipolysis-related gene, Pnpla2, was observed in adipose tissue of Bmal1Int-/- mice, and this was not noted when glycogen storage was restored by a high-sucrose water prior to fasting, suggesting that a higher Pnpla2 expression in Bmal1Int-/- mice was likely caused by lower glycogen storage. These results indicate that the disruption of the intestinal circadian clock system impairs glucose absorption in the intestine and affects systemic glucose homeostasis.

Keywords:  BMAL1; Circadian Rhythm; Glucose Absorption; Glycogen; SGLT1

DOI:  https://doi.org/10.1210/endocr/bqac119
Rev Neurol. 2022 Sep 01. 75(5): 103-108

[Late onset Pompe disease: an analysis of 19 patients from Mexico].

L M Sánchez-Sánchez, V Martinez-Montoya, R Sandoval-Pacheco, B Torres-Octavo, D M Anaya-Castro, O Padilla-de la Torre, C A Arellano-Valdez, C A Ávila-Rejón, P A Aguilar-Juárez, M Espino-Pluma, A González-Santillanes Cruz, E Kazakova, R I Martinez-Segovia, D Olmos-Morfin, P F Radillo-Díaz, I Solís-Sánchez, M Vázquez Del Mercado-Espinosa, C E Villarroel-Cortés, J S Velarde-Félix.

INTRODUCTION: Pompe disease (PD) is a rare metabolic myopathy with an ample and heterogeneous clinical spectrum, particularly late onset PD (LOPD), which is characterized by appearance at older age and slower disease progression, leading to diagnostic confirmation difficulty and delay.
AIM: To describe the genotype and clinical characteristics of Mexican patients with LOPD.
MATERIAL AND METHODS: Clinical information from 19 Mexican patients with LOPD confirmed with enzyme activity and GAA gene analysis was reviewed. Genetic information of our population was crossed with international genetic databases.
RESULTS: Median age between onset of symptoms and diagnosis was 19 years (range 2-43) and diagnostic confirmation 36 years (range 9-52). Most frequently referred symptoms were proximal axial weakness (n = 17; 89.5%), waddling gait (n = 17; 89.5%) and hyperlordosis (n = 7; 36.8%). Sixteen patients (84.2%) were evaluated with electromyography; a myopathic pattern was reported in 11 (57.8%), but only in 5 patients (26%) paraspinal muscle evaluation was included. The most pathogenic mutations in our group were c.-32-13T>G, c.1799G>A and c.1082C>T.
CONCLUSIONS: Similar to other international publications, LOPD in Mexico is clinically heterogeneous; patients may delay years before diagnosis is established. Axial and proximal weakness is the most frequent clinical feature; thus, electromyography with paraspinal muscle evaluation is essential. Except for one, the mutations found in our patients have been previously reported in PD genetic databases.

DOI: https://doi.org/10.33588/rn.7505.2022227
Diabetologia. 2022 Jul 25.

Three weeks of time-restricted eating improves glucose homeostasis in adults with type 2 diabetes but does not improve insulin sensitivity: a randomised crossover trial.

Charlotte Andriessen, Ciarán E Fealy, Anna Veelen, Sten M M van Beek, Kay H M Roumans, Niels J Connell, Julian Mevenkamp, Esther Moonen-Kornips, Bas Havekes, Vera B Schrauwen-Hinderling, Joris Hoeks, Patrick Schrauwen.

   AIMS/HYPOTHESIS: Time-restricted eating (TRE) is suggested to improve metabolic health by limiting food intake to a defined time window, thereby prolonging the overnight fast. This prolonged fast is expected to lead to a more pronounced depletion of hepatic glycogen stores overnight and might improve insulin sensitivity due to an increased need to replenish nutrient storage. Previous studies showed beneficial metabolic effects of 6-8 h TRE regimens in healthy, overweight adults under controlled conditions. However, the effects of TRE on glucose homeostasis in individuals with type 2 diabetes are unclear. Here, we extensively investigated the effects of TRE on hepatic glycogen levels and insulin sensitivity in individuals with type 2 diabetes.
METHODS: Fourteen adults with type 2 diabetes (BMI 30.5±4.2 kg/m2, HbA1c 46.1±7.2 mmol/mol [6.4±0.7%]) participated in a 3 week TRE (daily food intake within 10 h) vs control (spreading food intake over ≥14 h) regimen in a randomised, crossover trial design. The study was performed at Maastricht University, the Netherlands. Eligibility criteria included diagnosis of type 2 diabetes, intermediate chronotype and absence of medical conditions that could interfere with the study execution and/or outcome. Randomisation was performed by a study-independent investigator, ensuring that an equal amount of participants started with TRE and CON. Due to the nature of the study, neither volunteers nor investigators were blinded to the study interventions. The quality of the data was checked without knowledge on intervention allocation. Hepatic glycogen levels were assessed with 13C-MRS and insulin sensitivity was assessed using a hyperinsulinaemic-euglycaemic two-step clamp. Furthermore, glucose homeostasis was assessed with 24 h continuous glucose monitoring devices. Secondary outcomes included 24 h energy expenditure and substrate oxidation, hepatic lipid content and skeletal muscle mitochondrial capacity.
RESULTS: Results are depicted as mean ± SEM. Hepatic glycogen content was similar between TRE and control condition (0.15±0.01 vs 0.15±0.01 AU, p=0.88). M value was not significantly affected by TRE (19.6±1.8 vs 17.7±1.8 μmol kg-1 min-1 in TRE vs control, respectively, p=0.10). Hepatic and peripheral insulin sensitivity also remained unaffected by TRE (p=0.67 and p=0.25, respectively). Yet, insulin-induced non-oxidative glucose disposal was increased with TRE (non-oxidative glucose disposal 4.3±1.1 vs 1.5±1.7 μmol kg-1 min-1, p=0.04). TRE increased the time spent in the normoglycaemic range (15.1±0.8 vs 12.2±1.1 h per day, p=0.01), and decreased fasting glucose (7.6±0.4 vs 8.6±0.4 mmol/l, p=0.03) and 24 h glucose levels (6.8±0.2 vs 7.6±0.3 mmol/l, p<0.01). Energy expenditure over 24 h was unaffected; nevertheless, TRE decreased 24 h glucose oxidation (260.2±7.6 vs 277.8±10.7 g/day, p=0.04). No adverse events were reported that were related to the interventions.
CONCLUSIONS/INTERPRETATION: We show that a 10 h TRE regimen is a feasible, safe and effective means to improve 24 h glucose homeostasis in free-living adults with type 2 diabetes. However, these changes were not accompanied by changes in insulin sensitivity or hepatic glycogen.
TRIAL REGISTRATION: ClinicalTrials.gov NCT03992248 FUNDING: ZonMW, 459001013.

Keywords:  Circadian rhythm; Glucose homeostasis; Hepatic fat; Hepatic glycogen; Insulin sensitivity; Intermittent fasting; Lifestyle intervention; Mitochondrial oxidative capacity; TRE; Type 2 diabetes

DOI:  https://doi.org/10.1007/s00125-022-05752-z
J Pers Med. 2022 Jul 07. pii: 1111. [Epub ahead of print]12(7):

Modeling a Novel Variant of Glycogenosis IXa Using a Clonal Inducible Reprogramming System to Generate "Diseased" Hepatocytes for Accurate Diagnosis.

Guillem Garcia-Llorens, Sergi Lopez-Navarro, Teresa Jaijo, Jose V Castell, Roque Bort.

  The diagnosis of inherited metabolic disorders is a long and tedious process. The matching of clinical data with a genomic variant in a specific metabolic pathway is an essential step, but the link between a genome and the clinical data is normally difficult, primarily for new missense variants or alterations in intron sequences. Notwithstanding, elucidation of the pathogenicity of a specific variant might be critical for an accurate diagnosis. In this study, we described a novel intronic variant c.2597 + 5G > T in the donor splice sequence of the PHKA2 gene. To investigate PHKA2 mRNA splicing, as well as the functional consequences on glycogen metabolism, we generated hepatocyte-like cells from a proband's fibroblasts by direct reprogramming. We demonstrated an aberrant splicing of PHKA2, resulting in the incorporation of a 27 bp upstream of intron 23 into exon 23, which leads to an immediate premature STOP codon. The truncated protein was unable to phosphorylate the PYGL protein, causing a 4-fold increase in the accumulation of glycogen in hepatocyte-like cells. Collectively, the generation of personalized hepatocyte-like cells enabled an unequivocal molecular diagnosis and qualified the sister's proband, a carrier of the same mutation, as a candidate for a preimplantation genetic diagnosis. Additionally, our direct reprogramming strategy allows for an unlimited source of "diseased" hepatocyte-like cells compatible with high-throughput platforms.

Keywords:  GSD type IX; direct reprogramming; glycogen; hepatocyte-like cells; high throughput

DOI:  https://doi.org/10.3390/jpm12071111
Comp Biochem Physiol B Biochem Mol Biol. 2022 Jul 25. pii: S1096-4959(22)00069-0. [Epub ahead of print] 110781

Rationed and satiated growth hormone transgenic Coho Salmon (Oncorhynchus kisutch) show tissue specific differences in energy stores.

W A Thompson, G Y Lau, J G Richards, R H Devlin.

  Growth hormone transgenic coho salmon experience increased growth rates, driven primarily through elevated feed intake and feed conversion. However, neuropeptides that signal appetite stimulation have been shown to exhibit variable responses across fed states, suggesting a more complex system mediating growth in these fish. Studies have proposed that growth hormone may have a modulatory role on the energy reserves of fish, possibly through AMP-activated protein kinase (AMPK) activation. AMPK, an energy sensor in cells, has previously been shown to be upregulated in growth hormone transgenic salmon when compared to wild type, however, whether this effect is seen across fed states is unknown. Here, we tested the hypothesis that growth hormone induces an energetic deficit in metabolic tissues, leading to constitutive AMPK activation in growth hormone transgenic salmon. This study compared AMPK activity, ATP, and glycogen, of the liver, heart, and muscle of wild-type, and growth hormone transgenic salmon either fed to satiation or a wild-type ration. The results suggest that white muscle ATP levels in growth hormone salmon are elevated in satiation and rationed conditions. In the liver, growth hormone transgenic salmon fed a rationed wild-type diet experience reductions in ATP level and glycogen. In none of the tissues examined, did AMPK activity change. Taken together, these results indicate that growth hormone transgenic salmon experience metabolic duress when not fed to satiation.

Keywords:  AMPK; ATP; Aquaculture; Glycogen; Growth hormone; Salmon

DOI:  https://doi.org/10.1016/j.cbpb.2022.110781