bims-glecem 2024-01-21 papers

bims-glecem

Biomed News

on Glycogen metabolism in exercise, cancer and energy metabolism

Issue of 2024–01–21
nine papers selected by
Dipsikha Biswas, Københavns Universitet

Small-molecule inhibition of glycogen synthase 1 for the treatment of Pompe disease and other glycogen storage disorders.
Structural abnormality of hepatic glycogen in rat liver with diethylnitrosamine-induced carcinogenic injury.
The Synergistic Effect of GH13 and GH57 GBEs of Petrotoga mobilis Results in α-Glucan Molecules with a Higher Branch Density.
Epac2 activation mediates glucagon-induced glucogenesis in primary rat hepatocytes.
Four-week experimental plus 1-week taper period using live high train low does not alter muscle glycogen content.
Peak Week Carbohydrate Manipulation Practices in Physique Athletes: A Narrative Review.
Prenatal EGCG consumption impacts hepatic glycogen synthesis and lipid metabolism in adult mice.
The impact of bed rest on human skeletal muscle metabolism.
The effects of carbohydrate availability on cycling endurance at the maximal lactate steady state.

Sci Transl Med. 2024 Jan 17. 16(730): eadf1691

Small-molecule inhibition of glycogen synthase 1 for the treatment of Pompe disease and other glycogen storage disorders.

Julie C Ullman, Kevin T Mellem, Yannan Xi, Vyas Ramanan, Hanne Merritt, Rebeca Choy, Tarunmeet Gujral, Lyndsay E A Young, Kerrigan Blake, Samnang Tep, Julian R Homburger, Adam O'Regan, Sandya Ganesh, Perryn Wong, Terrence F Satterfield, Baiwei Lin, Eva Situ, Cecile Yu, Bryan Espanol, Richa Sarwaikar, Nathan Fastman, Christos Tzitzilonis, Patrick Lee, Daniel Reiton, Vivian Morton, Pam Santiago, Walter Won, Hannah Powers, Beryl B Cummings, Maarten Hoek, Robert R Graham, Sanjay J Chandriani, Russell Bainer, Anna A DePaoli-Roach, Peter J Roach, Thomas D Hurley, Ramon C Sun, Matthew S Gentry, Christopher Sinz, Ryan A Dick, Sarah B Noonberg, David T Beattie, David J Morgans, Eric M Green.

Glycogen synthase 1 (GYS1), the rate-limiting enzyme in muscle glycogen synthesis, plays a central role in energy homeostasis and has been proposed as a therapeutic target in multiple glycogen storage diseases. Despite decades of investigation, there are no known potent, selective small-molecule inhibitors of this enzyme. Here, we report the preclinical characterization of MZ-101, a small molecule that potently inhibits GYS1 in vitro and in vivo without inhibiting GYS2, a related isoform essential for synthesizing liver glycogen. Chronic treatment with MZ-101 depleted muscle glycogen and was well tolerated in mice. Pompe disease, a glycogen storage disease caused by mutations in acid α glucosidase (GAA), results in pathological accumulation of glycogen and consequent autophagolysosomal abnormalities, metabolic dysregulation, and muscle atrophy. Enzyme replacement therapy (ERT) with recombinant GAA is the only approved treatment for Pompe disease, but it requires frequent infusions, and efficacy is limited by suboptimal skeletal muscle distribution. In a mouse model of Pompe disease, chronic oral administration of MZ-101 alone reduced glycogen buildup in skeletal muscle with comparable efficacy to ERT. In addition, treatment with MZ-101 in combination with ERT had an additive effect and could normalize muscle glycogen concentrations. Biochemical, metabolomic, and transcriptomic analyses of muscle tissue demonstrated that lowering of glycogen concentrations with MZ-101, alone or in combination with ERT, corrected the cellular pathology in this mouse model. These data suggest that substrate reduction therapy with GYS1 inhibition may be a promising therapeutic approach for Pompe disease and other glycogen storage diseases.

DOI: https://doi.org/10.1126/scitranslmed.adf1691
Int J Biol Macromol. 2024 Jan 14. pii: S0141-8130(24)00235-6. [Epub ahead of print]260(Pt 1): 129432

Structural abnormality of hepatic glycogen in rat liver with diethylnitrosamine-induced carcinogenic injury.

Jing-Yi Mou, Zhang-Wen Ma, Meng-Ying Zhang, Quan Yuan, Zi-Yi Wang, Qing-Hua Liu, Fen Li, Zhao Liu, Liang Wang.

  Growing evidence confirms associations between glycogen metabolic re-wiring and the development of liver cancer. Previous studies showed that glycogen structure changes abnormally in liver diseases such as cystic fibrosis, diabetes, etc. However, few studies focus on glycogen molecular structural characteristics during liver cancer development, which is worthy of further exploration. In this study, a rat model with carcinogenic liver injury induced by diethylnitrosamine (DEN) was successfully constructed, and hepatic glycogen structure was characterized. Compared with glycogen structure in the healthy rat liver, glycogen chain length distribution (CLD) shifts towards a short region. In contrast, glycogen particles were mainly present in small-sized β particles in DEN-damaged carcinogenic rat liver. Comparative transcriptomic analysis revealed significant expression changes of genes and pathways involved in carcinogenic liver injury. A combination of transcriptomic analysis, RT-qPCR, and western blot showed that the two genes, Gsy1 encoding glycogen synthase and Gbe1 encoding glycogen branching enzyme, were significantly altered and might be responsible for the structural abnormality of hepatic glycogen in carcinogenic liver injury. Taken together, this study confirmed that carcinogenic liver injury led to structural abnormality of hepatic glycogen, which provided clues to the future development of novel drug targets for potential therapeutics of carcinogenic liver injury.

Keywords:  Carcinogenic livery injury; Diethylnitrosamine; Glycogen structure

DOI:  https://doi.org/10.1016/j.ijbiomac.2024.129432
Polymers (Basel). 2023 Dec 02. pii: 4603. [Epub ahead of print]15(23):

The Synergistic Effect of GH13 and GH57 GBEs of Petrotoga mobilis Results in α-Glucan Molecules with a Higher Branch Density.

Hilda Hubertha Maria Bax, Aline Lucie Gaenssle, Marc Jos Elise Cornelis van der Maarel, Edita Jurak.

  Glycogen is a biopolymer consisting of glycosyl units, with a linear backbone connected by α-1,4-linkages and branches attached via α-1,6-linkages. In microorganisms, glycogen synthesis involves multiple enzymes, with glycogen branching enzymes (GBEs) being vital for creating α-1,6-linkages. GBEs exist in two families: glycoside hydrolase (GH) 13 and GH57. Some organisms possess either a single GH13 or GH57 GBE, while others, such as Petrotoga mobilis, have both types of GBEs. In this study, the simultaneous use of a GH13 and GH57 GBE each from Petrotoga mobilis for α-glucan modification was investigated using a linear maltodextrin substrate with a degree of polymerization of 18 (DP18). The products from modifications by one or both GBEs in various combinations were analyzed and demonstrated a synergistic effect when both enzymes were combined, leading to a higher branch density in the glycogen structure. In this cooperative process, PmGBE13 was responsible for creating longer branches, whereas PmGBE57 hydrolyzed these branches, resulting in shorter lengths. The combined action of the two enzymes significantly increased the number of branched chains compared to when they acted individually. The results of this study therefore give insight into the role of PmGBE13 and PmGBE57 in glycogen synthesis, and show the potential use of both enzymes in a two-step modification to create an α-glucan structure with short branches at a high branch density.

Keywords:  alpha-1,4-transglycosylation; branching activity; glycogen branching enzyme

DOI:  https://doi.org/10.3390/polym15234603
J Diabetes Investig. 2024 Jan 19.

Epac2 activation mediates glucagon-induced glucogenesis in primary rat hepatocytes.

Yusuke Shiozaki-Takagi, Nobuaki Ozaki, Yukiyasu Toyoda.

   AIMS/INTRODUCTION: Glucagon plays an essential role in hepatic glucogenesis by enhancing glycogen breakdown, inducing gluconeogenesis, and suppressing glycogenesis. Moreover, glucagon increases cyclic adenosine monophosphate (cAMP) levels, thereby activating protein kinase A (PKA) and cAMP guanine nucleotide exchange factor (also known as Epac). Although the function of PKA in the liver has been studied extensively, the function of hepatic Epac is poorly understood. The aim of this study was to elucidate the role of Epac in mediating the action of glucagon on the hepatocytes.
MATERIALS AND METHODS: Epac mRNA and protein expression, localization, and activity in the hepatocytes were analyzed by reverse transcription polymerase chain reaction, western blotting, immunofluorescence staining, and Rap1 activity assay, respectively. Additionally, we investigated the effects of an Epac-specific activator, 8-CPT, and an Epac-specific inhibitor, ESI-05, on glycogen metabolism in isolated rat hepatocytes. Further mechanisms of glycogen metabolism were evaluated by examining glucokinase (GK) translocation and mRNA expression of gluconeogenic enzymes.
RESULTS: Epac2, but not Epac1, was predominantly expressed in the liver. Moreover, 8-CPT inhibited glycogen accumulation and GK translocation and enhanced the mRNA expression of gluconeogenic enzymes. ESI-05 failed to reverse glucagon-induced suppression of glycogen storage and partially inhibited glucagon-induced GK translocation and the mRNA expression of gluconeogenic enzymes.
CONCLUSIONS: Epac signaling plays a role in mediating the glucogenic action of glucagon in the hepatocytes.

Keywords:  EPAC; Glucagon; Glucogenic action

DOI:  https://doi.org/10.1111/jdi.14142
Eur J Appl Physiol. 2024 Jan 17.

Four-week experimental plus 1-week taper period using live high train low does not alter muscle glycogen content.

Danilo R Bertucci, Carlos Dellavechia de Carvalho, Pedro P M Scariot, Carlos A Kalva-Filho, Gabriel Luches-Pereira, Tarine B Arruda, Isabela S Alves, Camila B Gardim, Marcelo Castiglia, Marcelo Riberto, Claudio Alexandre Gobatto, Marcelo Papoti.

  This study aimed to investigate the effects of a 4-week live high train low (LHTL; FiO2 ~ 13.5%), intervention, followed by a tapering phase, on muscle glycogen concentration. Fourteen physically active males (28 ± 6 years, 81.6 ± 15.4 kg, 179 ± 5.2 cm) were divided into a control group (CON; n = 5), and the group that performed the LHTL, which was exposed to hypoxia (LHTL; n = 9). The subjects trained using a one-legged knee extension exercise, which enabled four experimental conditions: leg training in hypoxia (TLHYP); leg control in hypoxia (CLHYP, n = 9); leg trained in normoxia (TLNOR, n = 5), and leg control in normoxia (CLNOR, n = 5). All participants performed 18 training sessions lasting between 20 and 45 min [80-200% of intensity corresponding to the time to exhaustion (TTE) reached in the graded exercise test]. Additionally, participants spent approximately 10 h day-1 in either a normobaric hypoxic environment (14.5% FiO2; ~ 3000 m) or a control condition (i.e., staying in similar tents on ~ 530 m). Thereafter, participants underwent a taper protocol consisting of six additional training sessions with a reduced training load. SpO2 was lower, and the hypoxic dose was higher in LHTL compared to CON (p < 0.001). After 4 weeks, glycogen had increased significantly only in the TLNOR and TLHYP groups and remained elevated after the taper (p < 0.016). Time to exhaustion in the LHTL increased after both the 4-week training period and the taper compared to the baseline (p < 0.001). Although the 4-week training promoted substantial increases in muscle glycogen content, TTE increased in LHTL condition.

Keywords:  High-intensity performance; Hypoxia; Muscle metabolism; Normobaric hypoxia; One-leg exercise

DOI:  https://doi.org/10.1007/s00421-023-05404-z
Sports Med Open. 2024 Jan 13. 10(1): 8

Peak Week Carbohydrate Manipulation Practices in Physique Athletes: A Narrative Review.

Kai A Homer, Matt R Cross, Eric R Helms.

   BACKGROUND: Physique athletes are ranked by a panel of judges against the judging criteria of the corresponding division. To enhance on-stage presentation and performance, competitors in certain categories (i.e. bodybuilding and classic physique) achieve extreme muscle size and definition aided by implementing acute "peaking protocols" in the days before competition. Such practices can involve manipulating nutrition and training variables to increase intramuscular glycogen and water while minimising the thickness of the subcutaneous layer. Carbohydrate manipulation is a prevalent strategy utilised to plausibly induce muscle glycogen supercompensation and subsequently increase muscle size. The relationship between carbohydrate intake and muscle glycogen saturation was first examined in endurance event performance and similar strategies have been adopted by physique athletes despite the distinct physiological dissimilarities and aims between the sports.
OBJECTIVES: The aim of this narrative review is to (1) critically examine and appraise the existing scientific literature relating to carbohydrate manipulation practices in physique athletes prior to competition; (2) identify research gaps and provide direction for future studies; and (3) provide broad practical applications based on the findings and physiological reasoning for coaches and competitors.
FINDINGS: The findings of this review indicate that carbohydrate manipulation practices are prevalent amongst physique athletes despite a paucity of experimental evidence demonstrating the efficacy of such strategies on physique performance. Competitors have also been observed to manipulate water and electrolytes in conjunction with carbohydrate predicated on speculative physiological mechanisms which may be detrimental for performance.
CONCLUSIONS: Further experimental evidence which closely replicates the nutritional and training practices of physique athletes during peak week is required to make conclusions on the efficacy of carbohydrate manipulation strategies. Quasi-experimental designs may be a feasible alternative to randomised controlled trials to examine such strategies due to the difficulty in recruiting the population of interest. Finally, we recommend that coaches and competitors manipulate as few variables as possible, and experiment with different magnitudes of carbohydrate loads in advance of competition if implementing a peaking strategy.

Keywords:  Bodybuilding; Carbohydrate; Contest preparation; Muscle glycogen; Peak week; Physique sport

DOI:  https://doi.org/10.1186/s40798-024-00674-z
Int J Biol Macromol. 2024 Jan 14. pii: S0141-8130(24)00294-0. [Epub ahead of print]260(Pt 1): 129491

Prenatal EGCG consumption impacts hepatic glycogen synthesis and lipid metabolism in adult mice.

Kunlin Ou, Quan Zhang, Feifei Xi, Huizhen Ni, Jiebo Lu, Xuejing Lyu, Chonggang Wang, Qiyuan Li, Qin Wang.

  In this study, the impact of prenatal exposure to Epigallocatechin gallate (EGCG) on the liver of adult offspring mice was investigated. While EGCG is known for its health benefits, its effects of prenatal exposure on the liver remain unclear. Pregnant C57BL/6 J mice were exposed to 1 mg/kg of EGCG for 16 days to assess hepatotoxicity effects of adult offspring. Transcriptomics and metabolomics were employed to elucidate the hepatotoxicity mechanisms. The findings revealed that prenatal EGCG exposure led to a decrease in liver somatic index, enhanced inflammatory responses and disrupted liver function through increased glycogen accumulation in adult mice. The integrated omics analysis revealed significant alterations in key pathways involved in liver glucose lipid metabolism, such as gluconeogenesis, dysregulation of insulin signaling, and induction of liver inflammation. Furthermore, the study found a negative correlation between the promoter methylation levels of Ppara and their mRNA levels, suggesting that EGCG could reduce hepatic lipid content through epigenetic modifications. The findings suggest that prenatal EGCG exposure can have detrimental impacts on the liver among adult individuals and emphasize the need for a comprehensive evaluation of the potential risks associated with EGCG consumption during pregnancy.

Keywords:  EGCG; Glycogen synthesis and lipid metabolism; Prenatal exposure

DOI:  https://doi.org/10.1016/j.ijbiomac.2024.129491
Cell Rep Med. 2024 Jan 16. pii: S2666-3791(23)00601-8. [Epub ahead of print]5(1): 101372

The impact of bed rest on human skeletal muscle metabolism.

Moritz Eggelbusch, Braeden T Charlton, Alessandra Bosutti, Bergita Ganse, Ifigenia Giakoumaki, Anita E Grootemaat, Paul W Hendrickse, Yorrick Jaspers, Stephan Kemp, Tom J Kerkhoff, Wendy Noort, Michel van Weeghel, Nicole N van der Wel, Julia R Wesseling, Petra Frings-Meuthen, Jörn Rittweger, Edwin R Mulder, Richard T Jaspers, Hans Degens, Rob C I Wüst.

  Insulin sensitivity and metabolic flexibility decrease in response to bed rest, but the temporal and causal adaptations in human skeletal muscle metabolism are not fully defined. Here, we use an integrative approach to assess human skeletal muscle metabolism during bed rest and provide a multi-system analysis of how skeletal muscle and the circulatory system adapt to short- and long-term bed rest (German Clinical Trials: DRKS00015677). We uncover that intracellular glycogen accumulation after short-term bed rest accompanies a rapid reduction in systemic insulin sensitivity and less GLUT4 localization at the muscle cell membrane, preventing further intracellular glycogen deposition after long-term bed rest. We provide evidence of a temporal link between the accumulation of intracellular triglycerides, lipotoxic ceramides, and sphingomyelins and an altered skeletal muscle mitochondrial structure and function after long-term bed rest. An intracellular nutrient overload therefore represents a crucial determinant for rapid skeletal muscle insulin insensitivity and mitochondrial alterations after prolonged bed rest.

Keywords:  GLUT4; bed rest; insulin sensitivity; lipotoxicity; metabolism; mitochondria; nutrient overload; physical inactivity; skeletal muscle

DOI:  https://doi.org/10.1016/j.xcrm.2023.101372
Am J Physiol Regul Integr Comp Physiol. 2024 Jan 15.

The effects of carbohydrate availability on cycling endurance at the maximal lactate steady state.

Colton P Quinn, Rachel M McDougall, Saied Jalal Aboodarda, Juan M Murias, Martin J MacInnis.

  The impacts of carbohydrate (CHO) availability on time to task failure (TTF) and physiological responses to exercise at the maximal lactate steady state (MLSS) have not been studied. Ten participants (3 females, 7 males) completed this double blinded, placebo-controlled study that involved a ramp incremental test, MLSS determination, and four TTF trials at MLSS, all performed on a cycle ergometer. Using a combination of nutritional (CHO [7g/kg] and placebo [PLA; 0g/kg] drinks) and exercise interventions (no exercise [REST] and glycogen reducing exercise [EX]), the four conditions were expected to differ in pre-exercise CHO availability (RESTCHO > RESTPLA > EXCHO > EXPLA). TTF at MLSS was not improved by CHO loading, as RESTCHO (57.1 [16.6] min) and RESTPLA (57.1 [15.6] min) were not different (p=1.00); however, TTF was ~50% shorter in EX conditions compared to REST conditions on average (p < 0.05), with EXCHO (39.1 [9.2] min) ~90% longer than EXPLA (20.6 [6.9] min; p < 0.001). There were effects of condition for all perceptual and cardiometabolic variables when compared at isotime (p<0.05) and TF (p<0.05), except for ventilation, perceptual responses, and neuromuscular function measures, which were not different at TF (p>0.05). Blood lactate concentration was stable in all conditions for participants who completed 30 min of exercise. These findings indicate that TTF at MLSS is not enhanced by pre-exercise CHO supplementation, but recent intense exercise decreases TTF at MLSS even with CHO supplementation. Extreme fluctuations in diet and strenuous exercise that reduce CHO availability should be avoided before MLSS determination.

Keywords:  Blood lactate concentration; cycling; exercise metabolism; performance fatiguability; sports nutrition

DOI:  https://doi.org/10.1152/ajpregu.00178.2023