bims-glecem Biomed News
on Glycogen metabolism in exercise, cancer and energy metabolism
Issue of 2024–02–11
seven papers selected by
Dipsikha Biswas, Københavns Universitet
  1. Acute ketone supplementation in the absence of muscle glycogen utilization: Insights from McArdle disease.
  2. Defect in degradation of glycogenin-exposed residual glycogen in lysosomes is the fundamental pathomechanism of Pompe disease.
  3. Brain-Type Glycogen Phosphorylase (PYGB) in the Pathologies of Diseases: A Systematic Review.
  4. Integrative analysis of pathogenic variants in glucose-6-phosphatase based on an AlphaFold2 model.
  5. Glycogen synthase kinase 3β: the nexus of chemoresistance, invasive capacity, and cancer stemness in pancreatic cancer.
  6. Artemether regulates liver glycogen and lipid utilization through mitochondrial pyruvate oxidation in db/db mice.
  7. Chemerin affects blood lipid of high-fat diet male mice at sedentary and exercise states and its mechanisms.
  1. Clin Nutr. 2024 Jan 26. pii: S0261-5614(24)00036-0. [Epub ahead of print]43(3): 692-700
    Acute ketone supplementation in the absence of muscle glycogen utilization: Insights from McArdle disease.
    Pedro L Valenzuela, Alfredo Santalla, Lidia B Alejo, Asunción Bustos, Laureano M Ozcoidi, Laura Castellote-Bellés, Roser Ferrer-Costa, Mónica Villarreal-Salazar, María Morán, David Barranco-Gil, Tomàs Pinós, Alejandro Lucia.
       BACKGROUND & AIMS: Ketone supplementation is gaining popularity. Yet, its effects on exercise performance when muscle glycogen cannot be used remain to be determined. McArdle disease can provide insight into this question, as these patients are unable to obtain energy from muscle glycogen, presenting a severely impaired physical capacity. We therefore aimed to assess the effects of acute ketone supplementation in the absence of muscle glycogen utilization (McArdle disease).
    METHODS: In a randomized cross-over design, patients with an inherited block in muscle glycogen breakdown (i.e., McArdle disease, n = 8) and healthy controls (n = 7) underwent a submaximal (constant-load) test that was followed by a maximal ramp test, after the ingestion of a placebo or an exogenous ketone ester supplement (30 g of D-beta hydroxybutyrate/D 1,3 butanediol monoester). Patients were also assessed after carbohydrate (75 g) ingestion, which is currently considered best clinical practice in McArdle disease.
    RESULTS: Ketone supplementation induced ketosis in all participants (blood [ketones] = 3.7 ± 0.9 mM) and modified some gas-exchange responses (notably increasing respiratory exchange ratio, especially in patients). Patients showed an impaired exercise capacity (-65 % peak power output (PPO) compared to controls, p < 0.001) and ketone supplementation resulted in a further impairment (-11.6 % vs. placebo, p = 0.001), with no effects in controls (p = 0.268). In patients, carbohydrate supplementation resulted in a higher PPO compared to ketones (+21.5 %, p = 0.001) and a similar response was observed vs. placebo (+12.6 %, p = 0.057).
    CONCLUSIONS: In individuals who cannot utilize muscle glycogen but have a preserved ability to oxidize blood-borne glucose and fat (McArdle disease), acute ketone supplementation impairs exercise capacity, whereas carbohydrate ingestion exerts the opposite, beneficial effect.
    Keywords:  Carbohydrates; Glycogenosis; Ketone bodies; Metabolism; Performance
    DOI:  https://doi.org/10.1016/j.clnu.2024.01.026
  2. J Pathol. 2024 Feb 09.
    Defect in degradation of glycogenin-exposed residual glycogen in lysosomes is the fundamental pathomechanism of Pompe disease.
    Na Zhang, Fuchen Liu, Yuying Zhao, Xiaohan Sun, Bing Wen, Jian-Qiang Lu, Chuanzhu Yan, Duoling Li.
      Pompe disease is a lysosomal storage disorder that preferentially affects muscles, and it is caused by GAA mutation coding acid alpha-glucosidase in lysosome and glycophagy deficiency. While the initial pathology of Pompe disease is glycogen accumulation in lysosomes, the special role of the lysosomal pathway in glycogen degradation is not fully understood. Hence, we investigated the characteristics of accumulated glycogen and the mechanism underlying glycophagy disturbance in Pompe disease. Skeletal muscle specimens were obtained from the affected sites of patients and mouse models with Pompe disease. Histological analysis, immunoblot analysis, immunofluorescence assay, and lysosome isolation were utilized to analyze the characteristics of accumulated glycogen. Cell culture, lentiviral infection, and the CRISPR/Cas9 approach were utilized to investigate the regulation of glycophagy accumulation. We demonstrated residual glycogen, which was distinguishable from mature glycogen by exposed glycogenin and more α-amylase resistance, accumulated in the skeletal muscle of Pompe disease. Lysosome isolation revealed glycogen-free glycogenin in wild type mouse lysosomes and variously sized glycogenin in Gaa-/- mouse lysosomes. Our study identified that a defect in the degradation of glycogenin-exposed residual glycogen in lysosomes was the fundamental pathological mechanism of Pompe disease. Meanwhile, glycogenin-exposed residual glycogen was absent in other glycogen storage diseases caused by cytoplasmic glycogenolysis deficiencies. In vitro, the generation of residual glycogen resulted from cytoplasmic glycogenolysis. Notably, the inhibition of glycogen phosphorylase led to a reduction in glycogenin-exposed residual glycogen and glycophagy accumulations in cellular models of Pompe disease. Therefore, the lysosomal hydrolysis pathway played a crucial role in the degradation of residual glycogen into glycogenin, which took place in tandem with cytoplasmic glycogenolysis. These findings may offer a novel substrate reduction therapeutic strategy for Pompe disease. © 2024 The Pathological Society of Great Britain and Ireland.
    Keywords:  Pompe disease; glycogenin; glycophagy; lysosomal pathway; lysosomal storage disease; residual glycogen
    DOI:  https://doi.org/10.1002/path.6255
  3. Cells. 2024 Feb 05. pii: 289. [Epub ahead of print]13(3):
    Brain-Type Glycogen Phosphorylase (PYGB) in the Pathologies of Diseases: A Systematic Review.
    Caiting Yang, Haojun Wang, Miaomiao Shao, Fengyu Chu, Yuyu He, Xiaoli Chen, Jiahui Fan, Jingwen Chen, Qianqian Cai, Changxin Wu.
      Glycogen metabolism is a form of crucial metabolic reprogramming in cells. PYGB, the brain-type glycogen phosphorylase (GP), serves as the rate-limiting enzyme of glycogen catabolism. Evidence is mounting for the association of PYGB with diverse human diseases. This review covers the advancements in PYGB research across a range of diseases, including cancer, cardiovascular diseases, metabolic diseases, nervous system diseases, and other diseases, providing a succinct overview of how PYGB functions as a critical factor in both physiological and pathological processes. We present the latest progress in PYGB in the diagnosis and treatment of various diseases and discuss the current limitations and future prospects of this novel and promising target.
    Keywords:  brain-type glycogen phosphorylase (PYGB); glycogen metabolism; glycogen phosphorylase; pathology of diseases
    DOI:  https://doi.org/10.3390/cells13030289
  4. PNAS Nexus. 2024 Feb;3(2): pgae036
    Integrative analysis of pathogenic variants in glucose-6-phosphatase based on an AlphaFold2 model.
    Matt Sinclair, Richard A Stein, Jonathan H Sheehan, Emily M Hawes, Richard M O'Brien, Emad Tajkhorshid, Derek P Claxton.
      Mediating the terminal reaction of gluconeogenesis and glycogenolysis, the integral membrane protein glucose-6-phosphate catalytic subunit 1 (G6PC1) regulates hepatic glucose production by catalyzing hydrolysis of glucose-6-phosphate (G6P) within the lumen of the endoplasmic reticulum. Consistent with its vital contribution to glucose homeostasis, inactivating mutations in G6PC1 causes glycogen storage disease (GSD) type 1a characterized by hepatomegaly and severe hypoglycemia. Despite its physiological importance, the structural basis of G6P binding to G6PC1 and the molecular disruptions induced by missense mutations within the active site that give rise to GSD type 1a are unknown. In this study, we determine the atomic interactions governing G6P binding as well as explore the perturbations imposed by disease-linked missense variants by subjecting an AlphaFold2 G6PC1 structural model to molecular dynamics simulations and in silico predictions of thermodynamic stability validated with robust in vitro and in situ biochemical assays. We identify a collection of side chains, including conserved residues from the signature phosphatidic acid phosphatase motif, that contribute to a hydrogen bonding and van der Waals network stabilizing G6P in the active site. The introduction of GSD type 1a mutations modified the thermodynamic landscape, altered side chain packing and substrate-binding interactions, and induced trapping of catalytic intermediates. Our results, which corroborate the high quality of the AF2 model as a guide for experimental design and to interpret outcomes, not only confirm the active-site structural organization but also identify previously unobserved mechanistic contributions of catalytic and noncatalytic side chains.
    Keywords:  AlphaFold2; G6Pase; Rosetta; glycogen storage disease; molecular dynamics
    DOI:  https://doi.org/10.1093/pnasnexus/pgae036
  5. Cancer Drug Resist. 2024 ;7 4
    Glycogen synthase kinase 3β: the nexus of chemoresistance, invasive capacity, and cancer stemness in pancreatic cancer.
    Masahiro Uehara, Takahiro Domoto, Satoshi Takenaka, Osamu Takeuchi, Takeo Shimasaki, Tomoharu Miyashita, Toshinari Minamoto.
      The treatment of pancreatic cancer remains a significant clinical challenge due to the limited number of patients eligible for curative (R0) surgery, failures in the clinical development of targeted and immune therapies, and the pervasive acquisition of chemotherapeutic resistance. Refractory pancreatic cancer is typified by high invasiveness and resistance to therapy, with both attributes related to tumor cell stemness. These malignant characteristics mutually enhance each other, leading to rapid cancer progression. Over the past two decades, numerous studies have produced evidence of the pivotal role of glycogen synthase kinase (GSK)3β in the progression of over 25 different cancer types, including pancreatic cancer. In this review, we synthesize the current knowledge on the pathological roles of aberrant GSK3β in supporting tumor cell proliferation and invasion, as well as its contribution to gemcitabine resistance in pancreatic cancer. Importantly, we discuss the central role of GSK3β as a molecular hub that mechanistically connects chemoresistance, tumor cell invasion, and stemness in pancreatic cancer. We also discuss the involvement of GSK3β in the formation of desmoplastic tumor stroma and in promoting anti-cancer immune evasion, both of which constitute major obstacles to successful cancer treatment. Overall, GSK3β has characteristics of a promising therapeutic target to overcome chemoresistance in pancreatic cancer.
    Keywords:  Pancreatic cancer; cancer stemness; chemoresistance; glycogen synthase kinase 3β; tumor invasion
    DOI:  https://doi.org/10.20517/cdr.2023.84
  6. Am J Transl Res. 2024 ;16(1): 27-38
    Artemether regulates liver glycogen and lipid utilization through mitochondrial pyruvate oxidation in db/db mice.
    Wenci Weng, Lingling Shen, Xuewen Yu, Rui Yuan, Mumin Shao, Pengxun Han, Huili Sun.
       OBJECTIVES: Diabetes is an important global health problem. The occurrence and development of type 2 diabetes (T2D) involves multiple organs, among which the liver is an important organ. Artemether is a methyl ether derivative of artemisinin and has displayed significant antidiabetic effects. However, its regulation of glucose metabolism is not clearly elucidated. This study explored the effect of artemether on liver mitochondrial pyruvate metabolism.
    METHODS: T2D db/db mice were used and grouped into db/db and db/db+Art groups. Lean wild type mice served as control. After artemether intervention for 12 weeks, the respiratory exchange ratio (RER), redox state, relevant serum lipid content, liver glycogen and lipid content, liver insulin and insulin-like growth factor 1 (IGF-1) signal transduction, mitochondrial pyruvate oxidation pathway, fatty acid and glycogen metabolic pathways were evaluated.
    RESULTS: This experiment demonstrated that artemether raised RER and enhanced liver mitochondrial pyruvate metabolism in db/db mice. Artemether also reduced serum and urinary lipid peroxidation products and regulated the redox status in liver. The accumulation of liver glycogen in diabetic mice was attenuated, the proportion of lipid content in serum and liver was changed by artemether. The signal pathway associated with liver glycogen metabolism was also regulated by artemether. In addition, artemether increased serum insulin and regulated insulin/IGF-1 signal pathway in liver.
    CONCLUSIONS: The present study confirmed that artemether can regulate liver glycogen and lipid utilization in T2D mice, its biological mechanisms were associated with mitochondrial pyruvate oxidation in the liver.
    Keywords:  Artemether; glycogen; lipid; liver; pyruvate
  7. Endocr Connect. 2024 Feb 01. pii: EC-23-0484. [Epub ahead of print]
    Chemerin affects blood lipid of high-fat diet male mice at sedentary and exercise states and its mechanisms.
    Yi Jia, Yanan Yang, Jing Qu, Lijun Yin, Xiaohui Wang.
      Adipokine chemerin plays important roles in disorders of glucose and lipid metabolism of obesity and obesity-related diseases, and exercise-induced improvement of glucose and lipid metabolism is closely related to the decrease of chemerin, but the mechanisms by which chemerin regulates glucose and lipid metabolism remain unclarified. Hypotestosterone induces male obesity and disorders of glucose and lipid metabolism through androgen receptor (AR) and its target genes: glucose and lipid metabolism related molecules (including FOXO1, PEPCK, PGC-1α and SCD1). Recently, the link between them has been reported that chemerin modulated the secretion of androgen. In this study, global chemerin knockout [chemerin(-/-)] mice were established to demonstrate the roles of chemerin in regulating blood glucose and blood lipid of mice under diet (high-fat and normal diet) and exercise interventions, then to explore its mechanisms (AR- glucose and lipid metabolism enzymes). We found that the blood lipid and adipocyte size were lowed accompanied with the improvements of the levels of serum testosterone, gastrocnemius AR, and gastrocnemius FOXO1, SCD1 and PGC-1α in HFD chemerin(-/-) mice, but exercise-induced improvements of the above indicators in HFD WT mice were attenuated or abolished in HFD chemerin(-/-) mice. In conclusion, the decrease of chemerin improved blood lipid of HFD male mice at sedentary and exercise states, mediated partly by the increases of testosterone and AR to regulate glucose and lipid metabolism enzymes. To our knowledge, it is the first report about chemerin's regulation on glucose and lipid metabolism might be mediated by testosterone and AR in vivo.
    DOI:  https://doi.org/10.1530/EC-23-0484
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