bims-glecem 2023-05-07 papers

bims-glecem

Biomed News

on Glycogen metabolism in exercise, cancer and energy metabolism

Issue of 2023–05–07
nine papers selected by
Dipsikha Biswas, Københavns Universitet

Comparison of three type of muscle glycogen loading interventions using a very-high-carbohydrate diet in an elite male racewalker: a case report.
miR-22-enriched breast cancer cells display repressed glycolytic metabolism, increased glycogen synthesis, and reduced survival in low glucose conditions.
Identifying Potential Ligand Binding Sites on Glycogen Synthase Kinase 3 Using Atomistic Cosolvent Simulations.
Harnessing metabolomics to better understand exercise-mediated substrate metabolism.
REDD1 deletion and treadmill running increase liver hepcidin and gluconeogenic enzymes in male mice.
Hepatic glycogenolysis and hypometabolism induced by chemogenetic stimulation of C1 neurons.
Hypoglycemic mechanisms of Polygonatum sibiricum polysaccharide in db/db mice via regulation of glycolysis/gluconeogenesis pathway and alteration of gut microbiota.
High-intensity interval training induces renal injury and fibrosis in type 2 diabetic mice.
Inhibition of GSK3B phosphorylation improves glucose and lipid metabolism disorder.

Phys Act Nutr. 2023 Mar;27(1): 47-54

Comparison of three type of muscle glycogen loading interventions using a very-high-carbohydrate diet in an elite male racewalker: a case report.

Emi Kondo, Eri Takai, Hiroyuki Sagayama, Hideyuki Takahashi.

   PURPOSE: Muscle glycogen storage before a race is necessary for endurance athletes to achieve the best performance. Generally, the recommended carbohydrate intake for preparation over 90 min of the race is 10-12 g·kg--1·day--1. However, it remains unclear whether an elite athlete with an already high-carbohydrate diet can further increase muscle glycogen through a very-high-carbohydrate intake. Therefore, we compared the effects of three types of glycogen loading in a 28-year-old male athlete who belongs to the top 50 racewalkers in the world, consuming a daily energy intake of 4507 kcal and a carbohydrate intake of 12.7 g·kg--1·day--1.
METHODS: The racewalker consumed very-high-carbohydrate diets three times for 2 days each, 13.7 g·kg--1·day--1 for trial 1, 13.9 g·kg--1·day--1 for trial 2, and 15.9 g·kg--1·day-1 for trial 3. Muscle glycogen concentrations in the anterior (vastus lateralis and vastus intermedius) and posterior thighs (semimembranosus, semitendinosus, and biceps femoris) were measured using carbon-13 magnetic resonance spectroscopy.
RESULTS: Muscle glycogen concentrations in both the anterior and posterior thighs increased in all trials, particularly in trial 3. Body mass also increased by 1.5 kg in trials 1 and 2 and by 1.8 kg in trial 3 before and after the trials. The participant felt satiated throughout the day and experienced stomach discomfort during trial 3.
CONCLUSION: We found that a 2-day very-high-carbohydrate diet and tapering of training could further increase the muscle glycogen concentration in athletes. However, we speculated that 15.9 g·kg--1·day--1 carbohy.

Keywords:  carbohydrate loading; elite athlete; endurance training; gastrointestinal symptom; glycogen synthesis; track and field

DOI:  https://doi.org/10.20463/pan.2023.0006
Mol Biol Rep. 2023 Apr 29.

miR-22-enriched breast cancer cells display repressed glycolytic metabolism, increased glycogen synthesis, and reduced survival in low glucose conditions.

Costas Koufaris, Margarita E Papandreou, James K Ellis, Vicky Nicolaidou, Hector C Keun.

   BACKGROUND: Breast cancer (BC) is the second leading cause of cancer-related mortality among women. Beyond the established tumourigenic role of genetic mutations, metabolic reprogramming is another key cancer hallmark. Glucose metabolism in particular is known to be prominently altered in tumours, in order to support biomass accumulation and cancer cell survival. The tumor suppressor microRNA (miRNA) miR-22 has been previously associated with a plethora of BC phenotypes such as growth, invasion-metastasis, and regulation of metabolic phenotypes such as lipid and folate metabolism. In this study, we aimed to investigate the role of miR-22 in the regulation of glucose metabolism in BC cells.
METHODS AND RESULTS: Here we examined how miR-22 affects glucose metabolism in the MCF-7 BC cells. We found that over-expression of miR-22 caused a reduced glycolytic rate in these cells. Moreover, the miRNA also rendered MCF-7 cells more sensitive to lower glucose levels. We next unbiasedly screened the transcript levels of 84 genes relevant to glucose metabolism using the Human Glucose RT2 Profiler PCR Array. Interestingly, the strongest effect identified by this screen was the upregulation of genes involved in glycogen synthesis and the repression of gene involved in glycogen catabolism. Examination of publicly available transcriptomic datasets confirmed the correlations between expression of miR-22 and these glycogen metabolism genes in BC cells.
CONCLUSION: This study has generated evidence for a regulatory role of miR-22 in glucose and glycogen metabolism, expanding the involvement of this miRNA in BC metabolic reprogramming.

Keywords:  Breast cancer; Glucose; Glycogen; MCF-7; miR-22; microRNA

DOI:  https://doi.org/10.1007/s11033-023-08458-6
ACS Appl Bio Mater. 2023 May 04.

Identifying Potential Ligand Binding Sites on Glycogen Synthase Kinase 3 Using Atomistic Cosolvent Simulations.

Debarati DasGupta, Ramin Mehrani, Heather A Carlson, Sumit Sharma.

  Glycogen synthase kinase 3 β (GSK3β) is a serine/threonine kinase that phosphorylates several protein substrates in crucial cell signaling pathways. Owing to its therapeutic importance, there is a need to develop GSK3β inhibitors with high specificity and potency. One approach is to find small molecules that can allosterically bind to the GSK3β protein surface. We have employed fully atomistic mixed-solvent molecular dynamics (MixMD) simulations to identify three plausible allosteric sites on GSK3β that can facilitate the search for allosteric inhibitors. Our MixMD simulations narrow down the allosteric sites to precise regions on the GSK3β surface, thereby improving upon the previous predictions of the locations of these sites.

Keywords:  GSK3 allosteric site mapping; MixMD; cosolvent simulations; structure-based drug design

DOI:  https://doi.org/10.1021/acsabm.2c01079
Exp Physiol. 2023 May 01.

Harnessing metabolomics to better understand exercise-mediated substrate metabolism.

Colleen S Deane, Jonathan R Swann.



Keywords:  amino acids; bioinformatics; exercise; glycogen; heat stress; metabolomics; protein

DOI:  https://doi.org/10.1113/EP091127
J Nutr Sci. 2023 ;12 e49

REDD1 deletion and treadmill running increase liver hepcidin and gluconeogenic enzymes in male mice.

David E Barney, Bradley S Gordon, Stephen R Hennigar.

  The iron-regulatory hormone hepcidin is transcriptionally up-regulated by gluconeogenic signals. Recent evidence suggeststhat increases in circulating hepcidin may decrease dietary iron absorption following prolonged exercise, however evidence is limited on whether gluconeogenic signals contribute to post-exercise increases in hepcidin. Mice with genetic knockout of regulated in development and DNA response-1 (REDD1) display greater glycogen depletion following exercise, possibly indicating greater gluconeogenesis. The objective of the present study was to determine liver hepcidin, markers of gluconeogenesis and iron metabolism in REDD1 knockout and wild-type mice following prolonged exercise. Twelve-week-old male REDD1 knockout and wild-type mice were randomised to rest or 60 min treadmill running with 1, 3 or 6 h recovery (n = 5-8/genotype/group). Liver gene expression of hepcidin (Hamp) and gluconeogenic enzymes (Ppargc1a, Creb3l3, Pck1, Pygl) were determined by qRT-PCR. Effects of genotype, exercise and their interaction were assessed by two-way ANOVAs with Tukey's post-hoc tests, and Pearson correlations were used to assess the relationships between Hamp and study outcomes. Liver Hamp increased 1- and 4-fold at 3 and 6 h post-exercise, compared to rest (P-adjusted < 0⋅009 for all), and was 50% greater in REDD1 knockout compared to wild-type mice (P = 0⋅0015). Liver Ppargc1a, Creb3l3 and Pck1 increased with treadmill running (P < 0⋅0001 for all), and liver Ppargc1a, Pck1 and Pygl were greater with REDD1 deletion (P < 0⋅02 for all). Liver Hamp was positively correlated with liver Creb3l3 (R = 0⋅62, P < 0⋅0001) and Pck1 (R = 0⋅44, P = 0⋅0014). In conclusion, REDD1 deletion and prolonged treadmill running increased liver Hamp and gluconeogenic regulators of Hamp, suggesting gluconeogenic signalling of hepcidin with prolonged exercise.

Keywords:  CREB3L3, hepatic-specific cAMP response element binding protein-3-like-3; CRP, C-reactive protein; Exercise; Gluconeogenesis; Hepcidin; IL, interleukin; Iron deficiency; KO, knockout; PGC1α, peroxisome proliferator-activated receptor-γ coactivator-1α; REDD1; REDD1, regulated in development and DNA damage response-1; WT, wild-type; qRT-PCR, quantitative real-time polymerase chain reaction

DOI:  https://doi.org/10.1017/jns.2023.37
J Physiol. 2023 May 01.

Hepatic glycogenolysis and hypometabolism induced by chemogenetic stimulation of C1 neurons.

Chikara Abe, Chikako Katayama, Murat Bazek, Kento Ohbayashi, Kazuhiro Horii, Mamoru Tanida, Fumiaki Nin, Yusaku Iwasaki.

  The precise regulation of blood glucose levels is indispensable for maintaining physiological functions. C1 neurons determine the outflow of the autonomic nervous and endocrine systems to maintain blood glucose levels in the body. In contrast, activation of C1 neurons induces a decrease in activity, suggesting that hypoactivity also participates in maintaining blood glucose levels. To examine this, we evaluated both glycogenolysis and hypometabolism induced by the selective activation of C1 neurons. We used DbhCre/0 mice expressing receptors for chemogenetic tools in C1 neurons, owing to microinjection of the viral vector. C1 neurons were activated by intraperitoneal injection of clozapine N-oxide (CNO). The chemogenetic activation of C1 neurons significantly decreased body temperature, oxygen consumption, and carbon dioxide production. On the other hand, the blood glucose level was increased by the activation of C1 neurons 2 h after CNO administration, even in the fasting state. In this situation, an increase in glucagon and corticosterone levels was observed, while hepatic glycogen content decreased significantly. Plasma insulin level was not changed by the activation of C1 neurons despite the blood glucose level increased. Furthermore, adrenal sympathetic nerve activity was significantly increased by the activation of C1 neurons, and plasma catecholamine levels increased significantly. In conclusion, the selective activation of C1 neurons using chemogenetic tools induced an increase in blood glucose level, probably because of hepatic glycogenolysis and hypometabolism. KEY POINTS: Chemogenetic activation of C1 neurons in medulla oblongata decreased body temperature. Oxygen consumption and carbon dioxide production were decreased by chemogenetic activation of C1 neurons in medulla oblongata. Blood glucose level was increased by chemogenetic activation of C1 neurons in medulla oblongata. Chemogenetic activation of C1 neurons in medulla oblongata increased glucagon, corticosterone, and catecholamine levels in plasma. Increase in blood glucose level by activation of C1 neurons occurred due to combined effect of hepatic glycogenolysis and hypometabolism. Abstract figure legend We investigated the effects of selectively activating C1 neurons using chemogenetic tools on blood glucose levels. The activation of C1 neurons resulted in an increase in blood glucose levels. This increase is due to the activation of hepatic glycogenolysis through the release of humoral factors, including adrenaline, glucagon, and corticosterone. Additionally, the decrease in energy expenditure, as evidenced by a reduction in body temperature, oxygen consumption, and carbon dioxide production, suggests that activation of C1 neurons may induce hypometabolism, which could also contribute to an increase in blood glucose levels. These responses indicate that C1 neurons may serve as a switch for energy conservation to maintain blood glucose levels, presumably by being activated in a stressful situation. This article is protected by copyright. All rights reserved.

Keywords:  adrenaline; carbon dioxide production; corticosterone; glucagon; oxygen consumption

DOI:  https://doi.org/10.1113/JP284319
Heliyon. 2023 Apr;9(4): e15484

Hypoglycemic mechanisms of Polygonatum sibiricum polysaccharide in db/db mice via regulation of glycolysis/gluconeogenesis pathway and alteration of gut microbiota.

Xuan Chen, Ye-Ling Tong, Ze-Ming Ren, Si-Si Chen, Xi-Yu Mei, Qing-Yun Zhou, Guan-Hai Dai.

  Polygonatum rhizoma polysaccharide (PP) is a main ingredient of Polygonatum rhizoma , which is both food and traditional herbal medicine. In this study, we aimed to investigate the hypoglycemic effect of PP and the underlying mechanisms in db/db mice. Our finding showed that PP significantly ameliorates diabetic symptoms by reducing glucose levels in blood and urine and increasing insulin and leptin abundance in the serum. Histopathological examination revealed that PP improved the pathological state and increased hepatic glycogen storage in liver. Additionally, RT-qPCR results indicated that PP significantly down-regulated the expression of phosphoenolpyruvate carboxykinase 1. Furthermore, 16s rRNA sequencing results demonstrated that PP intervention resulted in an increase in beneficial bacteria genus and a reduction in harmful genus. Redundancy analysis revealed the correlation between intestinal flora and clinical factors. Taken together, these results suggest that PP has a significant hypoglycemic effect on type 2 diabetes (T2D) through up-regulating serum insulin and leptin, as well as hepatic glycogen storage, and down-regulating hepatic phosphoenolpyruvate carboxykinase 1 expression, as well as modulating gut microbiota composition. In conclusion, this study investigated the mechanisms of PP in the treatment of diabetes in db/db mice. To the best of our knowledge, this is the first study to explore the positive and negative correlations between gut microbiota and clinical factors, such as oxidative stress injury in liver and glucose related indicators in the blood.

Keywords:  Db/db mouse; Gut microbiota; Pepck; Polygonatum rhizoma polysaccharide; Type 2 diabetes

DOI:  https://doi.org/10.1016/j.heliyon.2023.e15484
Life Sci. 2023 Apr 27. pii: S0024-3205(23)00374-0. [Epub ahead of print]324 121740

High-intensity interval training induces renal injury and fibrosis in type 2 diabetic mice.

Lifang Zheng, Ruiting Qin, Zhijian Rao, Weihua Xiao.

   AIMS: Previous studies showed that high-intensity interval training (HIIT) improved fasting blood glucose and insulin resistance in type 2 diabetes mellitus (T2DM) mice. However, the effect of HIIT on the kidneys of mice with T2DM has not been examined. This study aimed to investigate the impact of HIIT on the kidneys of T2DM mice.
MATERIALS AND METHODS: T2DM mice were induced with a high-fat diet (HFD) and one-time 100 mg/kg streptozotocin intraperitoneal injection, and then T2DM mice were treated with 8 weeks of HIIT. Renal function and glycogen deposition were observed by serum creatinine levels and PAS staining, respectively. Sirius red staining, hematoxylin-eosin staining, and Oil red O staining were used to detect fibrosis and lipid deposition. Western blotting was performed to detect the protein levels.
KEY FINDINGS: HIIT significantly ameliorated the body composition, fasting blood glucose, and serum insulin of the T2DM mice. HIIT also improved glucose tolerance, insulin tolerance, and renal lipid deposition of T2DM mice. However, we found that HIIT increased serum creatinine and glycogen accumulation in the kidneys of T2DM mice. Western blot analysis showed that the PI3K/AKT/mTOR signaling pathway was activated after HIIT. The expression of fibrosis-related proteins (TGF-β1, CTGF, collagen-III, α-SMA) increased, while the expression of klotho (sklotho) and MMP13 decreased in the kidneys of HIIT mice.
SIGNIFICANCE: This study concluded that HIIT induced renal injury and fibrosis, although it also improved glucose homeostasis in T2DM mice. The current study reminds us that patients with T2DM should be cautious when participating in HIIT.

Keywords:  High-intensity interval training; Kidney fibrosis; Renal injury; Type 2 diabetes mellitus

DOI:  https://doi.org/10.1016/j.lfs.2023.121740
Biochim Biophys Acta Mol Basis Dis. 2023 May 03. pii: S0925-4439(23)00092-3. [Epub ahead of print] 166726

Inhibition of GSK3B phosphorylation improves glucose and lipid metabolism disorder.

Ze Yan, Xiaojuan Cao, Shouxiang Sun, Bing Sun, Jian Gao.

  Hepatic glycolipid metabolism disorder is considered as one of the key pathogenic factors for many chronic diseases. Revealing the molecular mechanism of metabolic disorder and exploring drug targets are crucial for the treatment of glucose and lipid metabolic diseases. Glyceraldehyde-3-phosphate dehydrogenase (GAPDH) has been reported to be associated with the pathogenesis of various metabolic diseases. Herein, GAPDH-knockdown ZFL cells and GAPDH-downregulation zebrafish exhibited significant lipid deposition increase and glycogen reduction, thus inducing glucose and lipid metabolism disorders. Using high-sensitivity mass spectrometry-based proteomic and phosphoproteomic analysis, we identified 6838 proteins and 3738 phosphorylated proteins in GAPDH-knockdown ZFL cells. The protein-protein interaction network and DEPPs analyses showed that gsk3baY216 were involved in lipid and glucose metabolism, which was verified by In vitro study. The enzyme activity analysis and cell staining results showed that HepG2 and NCTC-1469 cells transfected with GSK3BY216F plasmid had significantly lower glucose and insulin levels, the decreased lipid deposition, and the increased glycogen synthesis than those transfected with GSK3BY216E plasmid, suggesting that inhibition of GSK3B phosphorylation could significantly improve GSK3B hyperphosphorylation-induced glucose tolerance impairment and insulin sensitivity reduction. To our knowledge, this is the first multi-omic study of GAPDH-knockdown ZFL cells. This study provides insights into the molecular mechanism of glucose and lipid metabolic disorder, and provides potential targets (kinases) for the treatments of human glucose and lipid metabolic diseases.

Keywords:  GAPDH; GSK3B phosphorylation; Glucose and lipid metabolism; Phosphoproteomics; Proteomics

DOI:  https://doi.org/10.1016/j.bbadis.2023.166726