bims-glecem 2022-09-04 papers

bims-glecem

Biomed News

on Glycogen metabolism in exercise, cancer and energy metabolism

Issue of 2022–09–04
eleven papers selected by
Dipsikha Biswas, Københavns Universitet

Fibre type and localisation-specific muscle glycogen utilisation during repeated high-intensity intermittent exercise.
Addition of Fructose to a Carbohydrate-Rich Breakfast Improves Cycling Endurance Capacity in Trained Cyclists.
STAT3 transcriptionally regulates the expression of genes related to glycogen metabolism in developing motor neurons.
Improvement in hypertrophic cardiomyopathy after using a high-fat, high-protein and low-carbohydrate diet in a non-adherent child with glycogen storage disease type IIIa.
Expanding the clinicopathological-genetic spectrum of glycogen storage disease type IXd by a Chinese neuromuscular center.
Repurposing of Empagliflozin as a Possible Treatment for Neutropenia and Inflammatory Bowel Disease in Glycogen Storage Disease Type Ib: A Case Report.
Glycogen Synthase Kinase-3 Isoform Variants and Their Inhibitory Phosphorylation in Human Testes and Spermatozoa.
Halophila beccarii extract ameliorate glucose uptake in 3T3-L1 adipocyte cells and improves glucose homeostasis in streptozotocin-induced diabetic rats.
A potent physiological method to magnify and sustain soleus oxidative metabolism improves glucose and lipid regulation.
Multiple endocrine factors regulate nutrient mobilization and storage in Aedes aegypti during a gonadotrophic cycle.
Carbohydrate Intake in Recovery from Aerobic Exercise Differentiates Skeletal Muscle microRNA Expression.

J Physiol. 2022 Aug 28.

Fibre type and localisation-specific muscle glycogen utilisation during repeated high-intensity intermittent exercise.

Jeppe F Vigh-Larsen, Niels Ørtenblad, Ole E Andersen, Hallur Thorsteinsson, Thea H Kristiansen, Stine Bilde, Mads S Mikkelsen, Joachim Nielsen, Magni Mohr, Kristian Overgaard.

   KEY POINTS: Muscle glycogen is the major fuel during high-intensity exercise and is stored in distinct subcellular areas of the muscle cell in the close vicinity of the main energy consumption sites. In the present study we used quantitative electron microscopy imaging to investigate the utilisation pattern of three distinct subcellular muscle glycogen fractions during repeated high-intensity intermittent exercise. We show that the utilisation differs dependent on fibre type, subcellular localisation and time-course of exercise and with large single-fibre heterogeneity. These findings expand on our understanding of subcellular muscle glycogen metabolism during exercise and may help us explain how muscle glycogen attenuates muscle function even at only moderately lowered whole-muscle glycogen concentrations.
ABSTRACT: Glycogen particles are situated in key areas of the muscle cell in the vicinity of the main energy-consumption sites and may be utilised heterogeneously dependent on the nature of the metabolic demands. The present study aimed to investigate the time-course of fibre type-specific utilisation of muscle glycogen in three distinct subcellular fractions (intermyofibrillar, IMF; intramyofibrillar, intra; and subsarcolemmal, SS) during repeated high-intensity intermittent exercise. Eighteen moderately to well-trained male participants performed three periods of 10×45-s cycling at ∼105% Wmax (EX1-EX3) coupled with 5×6-s maximal sprints at baseline and after each period. Muscle biopsies were sampled at baseline and after EX1 and EX3. A higher glycogen breakdown rate in type 2 compared to type 1 fibres was found during EX1 for the intra (-72 vs. -45%) and IMF (-59 vs. -35%) glycogen fractions (P<0.001) but with no differences for SS glycogen (-52 vs. -40%). In contrast, no fibre type differences were observed during EX2-EX3, where the utilisation of intra and IMF glycogen in type 2 fibres was reduced, resulting in depletion of all three subcellular fractions to very low levels post-exercise within both fibre types. Importantly, large heterogeneity in single-fibre glycogen utilisation was present with an early depletion of especially intra glycogen in individual type 2 fibres. In conclusion, there is a clear fibre type and localisation-specific glycogen utilisation during high-intensity intermittent exercise, which varies with time-course of exercise and is characterized by exacerbated pool-specific glycogen depletion at the single-fibre level. Abstract figure legend Subcellular muscle glycogen utilisation in three distinct fractions was investigated during repeated high-intensity intermittent exercise using transmission electron microscopy imaging of m. vastus lateralis muscle samples. Muscle fibres were imaged, fibre typed based on Z-disk width and subcellular glycogen volume fractions estimated based on point-counting and direct glycogen particle diameter measurements. Enhanced type 2 fibre-specific utilisation of intra and in part IMF glycogen was observed during an initial but not during a second series of high-intensity intermittent exercise, as the overall glycogen degradation rate was lowered and very low post-exercise levels reached. Notably, the early enhanced depletion mainly of intra glycogen was associated with pronounced depletion of a substantial proportion of single-fibres of this specific fraction already at moderately lowered whole-muscle levels. Jeppe F. Vigh-Larsen has recently completed his PhD in exercise biology at the Department of Public Health, Aarhus University and is about to start in a postdoc position at the Department of Sports Science and Clinical Biomechanics, University of Southern Denmark. His current research areas include muscle metabolism and fatigue during high-intensity intermittent exercise combining basic and translational approaches in relation to human performance and health using both in vivo and in vitro research experiments. This article is protected by copyright. All rights reserved.

Keywords:  carbohydrate; excitation-contraction coupling; fatigue; metabolism; performance; subcellular

DOI:  https://doi.org/10.1113/JP283225
Int J Sport Nutr Exerc Metab. 2022 Aug 30. 1-7

Addition of Fructose to a Carbohydrate-Rich Breakfast Improves Cycling Endurance Capacity in Trained Cyclists.

Tim Podlogar, Simon Cirnski, Špela Bokal, Nina Verdel, Javier T Gonzalez.

  It was previously demonstrated that postexercise ingestion of fructose-glucose mixtures can lead to superior liver and equal muscle glycogen synthesis as compared with glucose-based carbohydrates (CHOs) only. After an overnight fast, liver glycogen stores are reduced, and based on this we hypothesized that addition of fructose to a glucose-based breakfast would lead to improved subsequent endurance exercise capacity. In this double-blind cross-over randomized study (eight males, peak oxygen uptake: 62.2 ± 5.4 ml·kg-1·min-1), participants completed two experimental trials consisting of two exercise bouts. In the afternoon of Day 1, they completed a cycling interval training session to normalize glycogen stores after which a standardized high-CHO diet was provided for 4 hr. On Day 2, in the morning, participants received 2 g/kg of CHOs in the form of glucose and rice or fructose and rice, both in a CHO ratio of 1:2. Two hours later they commenced cycling exercise session at the intensity of the first ventilatory threshold until task failure. Exercise capacity was higher in fructose and rice (137.0 ± 22.7 min) as compared with glucose and rice (130.06 ± 19.87 min; p = .046). Blood glucose and blood lactate did not differ between the trials (p > .05) and neither did CHO and fat oxidation rates (p > .05). However, due to the duration of exercise, total CHO oxidation was higher in fructose and rice (326 ± 60 g vs. 298 ± 61 g, p = .009). Present data demonstrate that addition of fructose to a glucose-based CHO source at breakfast improves endurance exercise capacity. Further studies are required to determine the mechanisms and optimal dose and ratio.

Keywords:  carbohydrate metabolism; composite carbohydrates; exercise capacity; preexercise nutrition

DOI:  https://doi.org/10.1123/ijsnem.2022-0067
FEBS Lett. 2022 Sep 01.

STAT3 transcriptionally regulates the expression of genes related to glycogen metabolism in developing motor neurons.

Hitoshi Gotoh, Tatenda Alois Chimhanda, Tadashi Nomura, Katsuhiko Ono.

  Motor neurons in the spinal cord are essential for movement. During the embryonic period, developing motor neurons store glycogen to protect against hypoglycemic and hypoxic stress. However, the mechanisms by which glycogen metabolism is regulated in motor neurons remain unclear. We herein investigated the transcriptional regulation of genes related to glycogen metabolism in the developing spinal cord. We focused on the regulatory mechanism of glycogen synthase (Gys1) and glycogen phosphorylase brain isoform (PygB), which play central roles in glycogen metabolism, and found that the transcription factor STAT3 regulated the expression of Gys1 and PygB via cis-regulatory promoter sequences in the developing spinal cord. These results suggest that STAT3 is important for the regulation of glycogen metabolism during motor neuron development.

Keywords:  Development; Glycogen; Metabolism; Motor neuron; STAT3; Transcription factors

DOI:  https://doi.org/10.1002/1873-3468.14489
Mol Genet Metab Rep. 2022 Sep;32 100904

Improvement in hypertrophic cardiomyopathy after using a high-fat, high-protein and low-carbohydrate diet in a non-adherent child with glycogen storage disease type IIIa.

Burcu Kumru Akin, Burcu Ozturk Hismi, Anne Daly.

   Background: Glycogen storage diseases type IIIa and b (GSDIII) are rare inherited metabolic disorders that are caused by deficiencies of the glycogen debranching enzyme, resulting in the accumulation of abnormal glycogen ('limit dextrin') in the muscles. The cardiac storage of limit dextrin causes a form of cardiomyopathy similar to primary hypertrophic cardiomyopathy. Treatment with a high fat diet is controversial but we report a positive outcome in a child with cardiomyopathy.
Case presentation: A 9-year-old boy with GSDIIIa developed left ventricular hypertrophy at 4.3 years of age. A high-fat (50%), high protein (20%), low-carbohydrates (30%) diet was introduced. After 18 months, echocardiogram, biochemical and clinical parameters improved (Creatine Kinase (CK), 1628➔1125 U/L; left ventricular outflow tract (LVOT), 35➔20 mmHg; interventricular septum (IVS), 21➔10 mm). The diet was abandoned for 2 years resulting in reversal of symptoms, but recommencement showed improvement after 6 months.
Conclusion: A high fat, high protein and low carbohydrate diet was successful in reversing cardiomyopathy. This form of treatment should be considered in children with GSD IIIa with cardiomyopathy.

Keywords:  Diet therapy; Glycogen storage disease type III; Hypertrophic cardiomyopathy

DOI:  https://doi.org/10.1016/j.ymgmr.2022.100904
Front Neurol. 2022 ;13 945280

Expanding the clinicopathological-genetic spectrum of glycogen storage disease type IXd by a Chinese neuromuscular center.

Kun Huang, Hui-Qian Duan, Qiu-Xiang Li, Yue-Bei Luo, Fang-Fang Bi, Huan Yang.

   Background: Glycogen storage disease (GSDs) is characterized by abnormally inherited glycogen metabolism. GSD IXd, which is caused by mutations in the PHKA1 gene, is an X-linked rare disease with mild myopathic symptoms. To date, only 13 patients with GSD IXd have been reported. In this study, we aimed to expand the clinicopathological-genetic spectrum of GSD IXd at a neuromuscular center in China.
Methods: Data on patients diagnosed with GSD IXd at our neuromuscular center were collected retrospectively. Clinical features, electrophysiology, muscle pathology, and genetic information were analyzed.
Results: Between 2015 and 2021, three patients were diagnosed with GSD IXd based on clinical manifestations, pathological findings, and genetic testing. One patient presented with mitochondrial myopathy. All patients exhibited muscle weakness and elevated levels of creatine kinase. Electromyography-detected myopathic changes were found in two patients, whereas one patient refused to undergo this examination. Pathological examinations in all patients revealed subsarcolemmal accumulation of glycogen under PAS staining. All patients had mutations in the PHKA1 gene and the patient with mitochondrial myopathy also had a mutation in the MT-TL1 gene.
Conclusion: Our study expands the clinicogenotype and phenotype of GSD IXd in a Chinese population. Our study also expands the known mutation spectrum for GSD IXd, contributing to a better characterization and understanding of this ultrarare neuromuscular disorder.

Keywords:  PHKA1; glycogen storage disease; glycogen storage disease type IXd; myopathy; neuromuscular disorder

DOI:  https://doi.org/10.3389/fneur.2022.945280
Cureus. 2022 Jul;14(7): e27264

Repurposing of Empagliflozin as a Possible Treatment for Neutropenia and Inflammatory Bowel Disease in Glycogen Storage Disease Type Ib: A Case Report.

Konstantinos Makrilakis, Aikaterini Barmpagianni, Maria Veiga-da-Cunha.

  Glycogen storage disease type Ib (GSD-Ib) is an autosomal-recessive inborn error of carbohydrate metabolism, where severe fasting hypoglycemia is associated (among other manifestations) with neutropenia and neutrophil dysfunction (predisposing to recurrent, potentially life-threatening infections) and inflammatory bowel disease (IBD). Granulocyte colony-stimulating factors (G-CSFs) are commonly used for its treatment. Although they have improved the prognosis of the disease, these medicines have also led to concerns about complications associated with their use (namely splenomegaly and hematopoietic malignancies), not to mention their increased cost. Recently, a novel new treatment for neutropenia associated with this disease was discovered. It was found that sodium-glucose cotransporter type 2 (SGLT-2) inhibitors, usually used for the treatment of diabetes mellitus, can ameliorate both neutropenia and IBD-related symptoms and improve the quality of life in patients suffering from these diseases. They do it by inhibiting the renal reabsorption of 1,5-anhydroglucitol, a dietary analog of glucose, whose accumulation due to the specific enzyme deficiency leads to toxic effects on granulocytes. Herein we report the treatment of an adult patient suffering from GSD-Ib with empagliflozin, an SGLT-2 inhibitor.

Keywords:  empagliflozin; glycogen storage disease type ib; inflammatory bowel disease; neutropenia; sglt-2 inhibitor

DOI:  https://doi.org/10.7759/cureus.27264
World J Mens Health. 2022 Aug 16.

Glycogen Synthase Kinase-3 Isoform Variants and Their Inhibitory Phosphorylation in Human Testes and Spermatozoa.

Seung Hyun Park, Yang Xu, Yong-Seog Park, Ju Tae Seo, Myung Chan Gye.

   PURPOSE: To clarify (phospho-) glycogen synthase kinase-3 (GSK3) isoform variants in the germline and soma of human testes and spermatozoa.
MATERIALS AND METHODS: GSK3 isoform variants in normospermatogenic and Sertoli cell-only (SCO) testicular biopsies and spermatozoa were examined.
RESULTS: In normospermatogenic testes, GSK3α and GSK3β variants 1 and 2 different in low complexity region (LCR) were expressed and their levels were decreased in SCO testes. GSK3β variant 3 was only expressed in SCO testes. GSK3β as well as GSK3α, the dominant isoforms in testes were decreased in SCO testes. In normospermatogenic testes, GSK3β were found in spermatogonia and markedly decreased in meiotic germ cells in which GSK3α was dominant. p-GSK3α/β were marginal in spermatogonia and early spermatocytes. In SCO testes, GSK3α/β immunoreactivity in seminiferous epithelia was weaker than those of normospermatogenic testes whereas p-GSK3α/β(Ser) immunoreactivity was visibly increased in Sertoli cells. GSK3α was dominant in ejaculated spermatozoa in which GSK3α and p-GSK3α(Ser) were found in the head, midpiece, and tail. In acrosome-reacted spermatozoa, GSK3α was found in the equatorial region of head, midpiece, and tail, and p-GSK3α(Ser) was only found in midpiece. During sperm capacitation, p-GSK3α(Ser) was significantly increased together with phosphotyrosine proteins and motility.
CONCLUSIONS: In human male germ cells, GSK3 isoforms different in LCRs switch from GSK3β to GSK3α during meiotic entry, suggesting the isoform-specific roles of GSK3α and GSK3β in meiosis and stemness or proliferation of spermatogonia, respectively. In dormant Sertoli cells of SCO testes kinase activity of GSK3 might be downregulated via inhibitory phosphorylation. In spermatozoa, inhibitory phosphorylation of GSK3α might be coupled with activation of motility during capacitation.

Keywords:  Glycogen synthase kinase 3; Human; Sertoli cell-only; Spermatozoa; Testis

DOI:  https://doi.org/10.5534/wjmh.220108
Heliyon. 2022 Aug;8(8): e10252

Halophila beccarii extract ameliorate glucose uptake in 3T3-L1 adipocyte cells and improves glucose homeostasis in streptozotocin-induced diabetic rats.

Vani Mathakala, Muni Kesavulu Muppuru, Uma Maheswari Devi Palempalli.

  The regulation of carbohydrate metabolizing enzymes is an effective way of reducing blood glucose levels and improving glycogen synthesis during the management of type 2 diabetes. The present investigation was conducted to explain the detailed mechanism with which a Seagrass, Halophila beccarii extract (HBE) enhances the glucose uptake in the 3T3-L1 adipocyte cell culture system in invitro. HBE stimulates the glucose uptake by the translocation of glucose transporter 4 (GLUT4) on to plasma cell membrane through induction of insulin receptor substrate 1 (IRS-1)/protein kinase B (Akt) signaling pathways. To assess the effect of HBE on T2DM, we used invivo experimental diabetes rat models induced with streptozotocin (STZ) to perform oral GTT and ITT. Furthermore, we assessed the enzymatic profile of Glycolysis, Pentose phosphate pathway, and gluconeogenesis from liver tissue homogenate. After long-term exposure with HBE, our results confirmed, that HBE improves the glucose uptake in 3T3-L1 cell lines by up-regulation of glucose transporter type 4 (GLUT4) through uptake of glucose by the adipocytes. The resulting data indicated that HBE had a great potentiality in preventing diabetes and maintaining glucose homeostasis through improving glucose uptake. The present data also showed that HBE with its insulin mimetic activity activates glycogen synthesis and enhances glucose utilization by regulating the carbohydrate metabolic enzymes. The similarity between HBE and insulin indicates that the HBE follows the mechanisms same as the insulin signaling pathway to show the antidiabetic activity.

Keywords:  GLUT4; Glucose uptake activity; HBE; Metabolic enzymes; Molecular docking; T2DM

DOI:  https://doi.org/10.1016/j.heliyon.2022.e10252
iScience. 2022 Sep 16. 25(9): 104869

A potent physiological method to magnify and sustain soleus oxidative metabolism improves glucose and lipid regulation.

Marc T Hamilton, Deborah G Hamilton, Theodore W Zderic.

  Slow oxidative muscle, most notably the soleus, is inherently well equipped with the molecular machinery for regulating blood-borne substrates. However, the entire human musculature accounts for only ∼15% of the body's oxidative metabolism of glucose at the resting energy expenditure, despite being the body's largest lean tissue mass. We found the human soleus muscle could raise local oxidative metabolism to high levels for hours without fatigue, during a type of soleus-dominant activity while sitting, even in unfit volunteers. Muscle biopsies revealed there was minimal glycogen use. Magnifying the otherwise negligible local energy expenditure with isolated contractions improved systemic VLDL-triglyceride and glucose homeostasis by a large magnitude, e.g., 52% less postprandial glucose excursion (∼50 mg/dL less between ∼1 and 2 h) with 60% less hyperinsulinemia. Targeting a small oxidative muscle mass (∼1% body mass) with local contractile activity is a potent method for improving systemic metabolic regulation while prolonging the benefits of oxidative metabolism.

Keywords:  Health sciences; Human metabolism; Physiology

DOI:  https://doi.org/10.1016/j.isci.2022.104869
Insect Sci. 2022 Sep 02.

Multiple endocrine factors regulate nutrient mobilization and storage in Aedes aegypti during a gonadotrophic cycle.

Xiaoyi Dou, Kangkang Chen, Mark R Brown, Michael R Strand.

  Anautogenous mosquitoes must blood feed on a vertebrate host to produce eggs. Each gonadotrophic cycle is subdivided into a sugar-feeding previtellogenic phase that produces primary follicles and a blood meal-activated vitellogenic phase in which large numbers of eggs synchronously mature and are laid. Multiple endocrine factors including juvenile hormone (JH), insulin-like peptides (ILPs), ovary ecdysteroidogenic hormone (OEH) and 20-hydroxyecdysone (20E) coordinate each gonadotrophic cycle. Egg formation also requires nutrients from feeding that are stored in the fat body. Regulation of egg formation is best understood in Aedes aegypti but the role different endocrine factors play in regulating nutrient mobilization and storage remains unclear. In this study, we report that adult female Ae. aegypti maintained triacylglycerol (TAG) stores during the previtellogenic phase of the first gonadotrophic cycle while glycogen stores declined. In contrast, TAG and glycogen stores were rapidly mobilized during the vitellogenic phase and then replenishment. Several genes encoding enzymes with functions in TAG and glycogen metabolism were differentially expressed in the fat body, which suggested regulation was mediated in part at the transcriptional level. Gain of function assays indicated that stored nutrients were primarily mobilized by adipokinetic hormone (AKH) while juvenoids and OEH regulated replenishment. ILP3 further showed evidence of negatively regulating certain lipolytic enzymes. Loss of function assays further indicated AKH depends on the AKH receptor (AKHR) for function. Altogether, our results indicate that the opposing activities of different hormones regulate nutrient stores during a gonadotrophic cycle in Ae. aegypti. This article is protected by copyright. All rights reserved.

Keywords:  adipokinetic hormone; ecdysone; endocrine; glycogen; insulin-like peptide; juvenile hormone; mosquito; nutrient; ovary ecdysteroidogenic hormone; triacylglycerol

DOI:  https://doi.org/10.1111/1744-7917.13110
Am J Physiol Endocrinol Metab. 2022 Aug 31.

Carbohydrate Intake in Recovery from Aerobic Exercise Differentiates Skeletal Muscle microRNA Expression.

Lee M Margolis, Christopher T Carrigan, Nancy E Murphy, Marissa N Dibella, Marques A Wilson, Claire C Whitney, Emily E Howard, Stefan M Pasiakos, Donato A Rivas.

  Post-transcriptional regulation by microRNA (miRNA) facilitates exercise and diet-induced skeletal muscle adaptations. However, the impact of diet on miRNA expression during post-exercise recovery remains unclear. The objective of this study was to examine the effects of consuming carbohydrate or a nutrient free control on skeletal muscle miRNA expression during 3 hours of recovery from aerobic exercise. Using a randomized, crossover design, 7 men (mean±SD, age: 21±3 y; body mass: 83±13 kg; V̇O2peak: 43±2 mL/kg/min) completed 2 cycle ergometry glycogen depletion trials followed by 3 hours of recovery while consuming either carbohydrate (CHO: 1 g/kg/hr) or control (CON: nutrient free). Muscle biopsy samples were obtained under resting fasted conditions at baseline and at the end of the 3 hour recovery (REC) period. miRNA expression was determined using unbiased RT-qPCR microarray analysis. Trials were separated by 7 days. Twenty-five miRNA were different (P<0.05) between CHO and CON at REC, with Let7i-5p and miR-195-5p being the most predictive of treatment. In vitro overexpression of Let7i-5p and miR-195-p5 in C2C12 skeletal muscle cells decreased (P<0.05) the expression of protein breakdown (Foxo1,Trim63, Casp3 and Atf4) genes, ubiquitylation, and protease enzyme activity compared to control. Energy sensing (Prkaa1 and Prkab1) and glycolysis (Gsy1 and Gsk3b) genes were lower (P<0.05) with Let7i-5p overexpression compared to miR-195-5p and control. Fat metabolism (Cpt1a, Scd1, and Hadha) genes were lower (P<0.05) in miR-195-5p compared to control. These data indicate that consuming CHO after aerobic exercise alters miRNA profiles compared to CON, and these difference may govern mechanisms facilitating muscle recovery.

Keywords:  Endurance Exercise; Glycogen; Let7; miR-195

DOI:  https://doi.org/10.1152/ajpendo.00110.2022