REVIEW | doi:10.20944/preprints202106.0594.v1
Subject: Biology, Anatomy & Morphology Keywords: autophagy, glycogen, lysosome, glycophagy, Atg8, Stbd1, Gabarapl1
Online: 24 June 2021 (08:48:36 CEST)
Macro-autophagy is an essential cellular process involved in degradation of aberrant organelles and proteins. Initially proposed to be a ‘bulk’ degradation pathway, a more nuanced appreciation of selective autophagy pathways has emerged in recent years. The discovery of a glycogen-selective autophagy pathway (‘glycophagy’) has highlighted the importance of autophagy in regulating cellular metabolic homeostasis and identified a novel non-canonical major pathway of glycogen flux. The field of glycogen autophagy research is at an early evolutionary stage, but already it is clear that the implications of these discoveries are far-reaching and provide scope for multi-disciplinary investigations into the role of glycophagy in health and disease. With potential cognate protein partners identified, the opportunities for targeted intervention have become viable. Here we review the current evidence relating to specific protein mediators involved in glycophagy, and highlight areas of uncertainty that provide opportunity for further investigation.
ARTICLE | doi:10.20944/preprints201807.0411.v1
Online: 23 July 2018 (10:38:14 CEST)
We investigated whether post-exercise capsinoids (CSN) supplementation could enhance muscle glycogen resynthesis via GLUT4/Akt expressions in human skeletal muscle. Nine male college students (aged 21.4±0.2 years, BMI 21.9±1.3 kg/m2, VO2max 47.1±1.8 ml/kg/min) participated in this crossover designed study, and completed a 60-min cycling exercise at 70% VO2max. Immediately after exercise, participants consumed high-carbohydrate diet (2 g carb/kg bodyweight) with CSN (12 mg, single dosage) or placebo. Biopsied muscle samples (vastus lateralis) were obtained immediately (0h) and 3h after exercise. Blood and expired gas samples were collected before and after exercise. We found oral CSN supplementation immediately after exercise was unable to enhance glycogen resynthesis in exercised human skeletal muscle. Despite, CSN could alter the energy reliance on fat oxidation during post-exercise recovery, based on gaseous exchange measurement (NEFA and glycerol). We further identified no significant differences in postprandial glucose/insulin area under curve in both trials. Western blot data showed no significant response of p-Akt/Akt ratio with CSN during post-exercise recovery. Inconsistent with glycogen levels, muscle GLUT4 expression was significantly elevated at 3h in CSN trial. Our findings emphasize the necessity of further evidences to confirm the ergogenic properties of CSN in connection with glycogen recovery in exercised human skeletal muscle.
ARTICLE | doi:10.20944/preprints201903.0166.v1
Subject: Chemistry, Medicinal Chemistry Keywords: Structure-based design; glycogen phosphorylase inhibitor; glycogen metabolism; type 2 diabetes; X-ray crystallography; N-acyl-β-D-glucopyranosylamine
Online: 15 March 2019 (14:06:06 CET)
Structure-based design and synthesis of two biphenyl-N-acyl-β-D-glucopyranosylamine derivatives as well as their assessment as inhibitors of human liver glycogen phosphorylase (hlGPa, a pharmaceutical target for type 2 diabetes) is presented. X-ray crystallography revealed the importance of structural water molecules and that the inhibitory efficacy correlates with the degree of disturbance caused by the inhibitor binding to a loop crucial for the catalytic mechanism. The in silico derived models of the binding mode generated during the design process corresponded very well with the crystallographic data.
REVIEW | doi:10.20944/preprints202208.0142.v1
Subject: Biology, Physiology Keywords: glycogen; autophagy; lysosome; Stbd1; Gabarapl1; acid α-glucosidase (Gaa)
Online: 8 August 2022 (09:58:31 CEST)
Degradation of intracellular components through autophagy is a fundamental process to maintain cellular integrity and homeostasis. Recently a glycogen-selective autophagy pathway has been described, termed ‘glycophagy’. Glycogen is a primary storage depot and regulator of glucose availability, and glycophagy is emerging as a critical physiological process involved in energy metabolism. Glycophagy-mediated degradation of glycogen appears to operate in parallel with the well-described canonical pathway of glycogenolysis involving glycogen phosphorylase. Evidence suggests that starch-binding domain protein-1 (Stbd1) is a key glycogen-binding protein involved in tagging glycogen for glycophagy, and that Gabarapl1 is primarily involved as the Atg8 family protein recruiting the Stbd1-glycogen complex into the forming glycophagosome. The nuances of glycophagy protein machinery, regulation and lysosomal glucose release are yet to be fully elucidated. In this mini-review, we critically analyze the current evidence base for glycophagy as a selective-autophagy process of physiological importance and highlight areas where further investigation is warranted.
CONCEPT PAPER | doi:10.20944/preprints201911.0225.v1
Subject: Biology, Physiology Keywords: astrocyte; ATP; brain; exercise; glucose; glycogen; McArdle's disease; muscle, neuron; phosphocreatine; seizure
Online: 19 November 2019 (04:09:47 CET)
Key features of glycogen metabolism in excitable tissues are not well-explained by current concepts. Glycogen stores in brain and skeletal muscle are generally considered to function as local glucose reserves, to be utilized during transient mismatches between glucose supply and demand; however, quantitative measures show that blood glucose supply is likely never rate-limiting for energy metabolism in either brain or muscle under physiological conditions. These tissues nevertheless do normally utilize glycogen during intervals of increased energy demand, despite the availability of free glucose, and despite the ATP cost of cycling glucose through glycogen polymer. This seemingly wasteful shunt can be explained by considering the effect of glycogenolysis on the amount of energy derived from ATP (ΔG’ATP). ΔG’ATP is diminished by elevations in Pi, such as occur at sites of rapid ATP hydrolysis and net phosphocreatine consumption. Glycogen utilization counters this effect by sequestering Pi in glycolytic metabolites (glycogenn + Pi → glycogenn-1 + glucose-1-phosphate → phosphorylated glycolytic intermediates), and thereby maintains the amount of energy obtained from ATP at sites of rapid ATP consumption. This thermodynamic effect may be particularly important in the narrow, spatially constricted astrocyte processes that ensheath neuronal synapses. This effect can also explain the co-localization of glycogen and cytosolic phosphocreatine in brain astrocytes, glycolytic super-compensation in brain when glycogen is not available, and aspects of exercise physiology in muscle glycogen phosphorylase deficiency (McArdle’s disease).
REVIEW | doi:10.20944/preprints201912.0165.v2
Subject: Medicine & Pharmacology, Nutrition Keywords: glucose; pentose phosphate pathway; NADPH; redox balance; glycogen; glycolysis; stress resistance; insulin resistance
Online: 30 January 2020 (12:49:19 CET)
A human organism depends on stable glucose blood levels in order to maintain the metabolic needs. Glucose is considered as the most important energy source and glycolysis is postulated as a backbone pathway. However, when glucose supply is limited, ketone bodies and amino acids can be used to produce enough ATP. In contrast, for the functioning of pentose phosphate pathway (PPP) glucose is essential and cannot be substituted by other metabolites. PPP generates and maintains levels of NADPH needed for reduction of oxidized glutathione and protein thiols, synthesis of lipids and DNA as well as for xenobiotic detoxification, regulatory redox signaling and counteracting infections. Flux of glucose into a PPP, particularly under extreme oxidative and toxic challenges is critical for survival, whereas the glycolytic pathway is primarily activated when glucose is abundant, and there is lack of NADP+ that is required for activation of glucose-6 phosphate dehydrogenase. An important role of glycogen stores in resistance to oxidative challenges is discussed. Current evidences explain disruptive metabolic effects and detrimental health consequences of chronic nutritional carbohydrate overload and provides new insights into positive metabolic effects of intermittent fasting, caloric restriction, exercise, and ketogenic diet through modulation of redox homeostasis.
ARTICLE | doi:10.20944/preprints202007.0611.v1
Subject: Medicine & Pharmacology, Obstetrics & Gynaecology Keywords: Lysosomal Disorders; Glycogen storage disease Type II; Pompe disease; LOPD; Pregnancy; Enzyme Replacement Therapy
Online: 25 July 2020 (15:48:01 CEST)
There is limited data on pregnancy outcomes in Pompe Disease (PD) resulting from deficiency of the lysosomal enzyme acid alpha-glucosidase. Late-onset PD is characterized by progressive proximal muscle weakness and decline of respiratory function secondary to the involvement of the respiratory muscles. In a cohort of twenty-five females, the effects of both PD on the course of pregnancy and the effects of pregnancy on PD were investigated. Reproductive history, course of pregnancy, use of Enzyme replacement therapy (ERT), PD symptoms, and outcomes of each pregnancy were obtained through a questionnaire. Among 20 subjects that reported one or more pregnancies, one subject conceived while on ERT and continued therapy through two normal pregnancies with worsening of weakness during pregnancy and improvement postpartum. While fertility was not affected, pregnancy may worsen symptoms, or cause initial symptoms to arise. Complications with pregnancy or birth were not higher, except for an increase in the rate of stillbirths (3.8% compared to the national average of 0.2-0.7%). Given small sample size and possible bias of respondents being only women who have been pregnant, further data may be needed to better analyze the effects of pregnancy on PD, and the effects of ERT on pregnancy outcomes.
Subject: Chemistry, Organic Chemistry Keywords: Type 2 diabetes; glycogen phosphorylase; anomeric spironucleosides; 1,6-dioxa-4-azaspiro[4.5]decane; [1,5]-radical translocation
Online: 18 June 2019 (10:26:30 CEST)
In the case of type 2 diabetes, inhibitors of glycogen phosphorylase (GP) might prevent unwanted glycogenolysis under high glucose conditions and thus aim at the reduction of excessive glucose production by the liver. Anomeric spironucleosides, such as hydantocidin, present a rich synthetic chemistry and important biological function, e.g., inhibition of GP. Herein, the Suárez radical methodology is successfully applied to synthesize the first example of a 1,6-dioxa-4-azaspiro[4.5]decane system, not been previously constructed via a radical pathway, starting from 6-hydroxymethyl-b-D-glucopyranosyluracil. It is shown that in the rigid pyranosyl conformation the required [1,5]-radical translocation is a minor process. The stereochemistry of the spirocycles obtained was unequivocally determined based on the chemical shifts of key sugar protons in the 1H NMR spectra. The two spirocycles were found to be modest inhibitors of RMGPb.
CONCEPT PAPER | doi:10.20944/preprints202009.0723.v1
Subject: Life Sciences, Biochemistry Keywords: Glycogen Storage Disease Type 1a, Glucose-6-phosphatase Catalytic Subunit (G6PC), Glucose-6-phosphatase (G6Pase), prime editing, mRNA delivery, CRISPR
Online: 30 September 2020 (08:05:17 CEST)
One of the rare diseases throughout the world is Glycogen Storage Disease, which appears due to problems in glycogen metabolism. Among various subtypes of GSD, GSD Type 1a is the most abundant one of GSD Type 1, seen in approximately 80% and caused by different kinds of mutations in the Glucose-6-Phosphatase Catalytic Subunit (G6PC) gene in human chromosome 17q21. G6PC gene encodes for glucose-6-phosphatase (G6Pase) protein, which cleaves glucose-6-phosphate into glucose and inorganic phosphate (Pi), and GSD Type 1a patients fail to breakdown glucose-6-phosphate due to several mutations in the G6PC gene. In our study, we aim to create new therapeutic approaches for GSD 1a. We collected mutation data of 57 GSD Type 1a patients from Turkey. According to the data, 16 types of mutations were observed in the G6PC gene. Allele frequencies of these mutations are calculated as 59% for R83C/H, 11% for W160*, 7% for G270V, and 28% for others which have less frequency. Up to now, the tertiary protein structure of G6Pase has not been structured yet. To understand the possible impacts of these mutations, we statistically obtained possible tertiary structure predictions of G6Pase by running 5 different tools. At the end of the study, we suggest two effective and promising gene therapy methods for GSD Type 1a, Prime Editing for R83C/H mutations, and mRNA delivery for other mutations, in addition to a promising, commercially available drug suggestion for patients with W160*, W86*, and S15* mutations, although the drug belongs to another disease.
Subject: Life Sciences, Biochemistry Keywords: glucose; glycogen; gluconeogenesis; early life adversity; acute stress; chronic stress; psychosocial stress; hypothalamus-pituitary-adrenal axis; ageing; immuno-senescence; inflamm-ageing; Developmental origins of health and disease
Online: 23 March 2021 (09:04:41 CET)
The physiological response to a psychological stressor broadly impacts energy metabolism. In-versely, changes in energy availability affect the physiological response to the stressor in terms of hypothalamus, pituitary adrenal axis (HPA) and sympathetic nervous system activation. Glu-cocorticoids, the endpoint of the HPA axis, are critical checkpoints in endocrine control of ener-gy homeostasis and have been linked to metabolic diseases including obesity, insulin resistance and type 2 diabetes. Glucocorticoids, through the glucocorticoid receptor, activate transcription of genes associated with glucose and lipid regulatory pathways and thereby control both physi-ological and pathophysiological systemic energy homeostasis. Here, we summarize the current knowledge of glucocorticoid functions in energy metabolism and systemic metabolic dysfunc-tion, particularly focusing on glucose and lipid metabolism. There are elements in the external environment that induce lifelong changes in the HPA axis stress response and glucocorticoid levels, the most prominent are early-life adversity, or exposure to traumatic stress. We hypothe-sise that when the HPA axis is so disturbed after early-life adversity, it will fundamentally alter hepatic gluconeogenesis, inducing hyperglycaemia, and hence crystalise the significant lifelong risk of developing either the metabolic syndrome, or type 2 diabetes. This gives a “Jekyll and Hyde” role to gluconeogenesis, providing the necessary energy in situations of acute stress, but driving towards pathophysiological consequences when the HPA axis has been altered.