bims-glecem 2023-08-13 papers

bims-glecem

Biomed News

on Glycogen metabolism in exercise, cancer and energy metabolism

Issue of 2023–08–13
nine papers selected by
Dipsikha Biswas, Københavns Universitet

The multifaceted roles of the brain glycogen.
Bacterial amylases enable glycogen degradation by the vaginal microbiome.
From Acid Alpha-Glucosidase Deficiency to Autophagy: Understanding the Bases of POMPE Disease.
Novel synergistic treatment for depression: involvement of GSK3β-regulated AMPA receptors in the prefrontal cortex of mice.
PP2A-Mediated GSK3β Dephosphorylation Is Required for Protocadherin-7-Dependent Regulation of Small GTPase RhoA in Osteoclasts.
Glycogen synthase kinase 3 controls T-cell exhaustion by regulating NFAT activation.
Regulation of plasma glucose levels by central dopamine D2 receptors is impaired in type 1 but not type 2 diabetic mouse models.
Clinical manifestations and MRI features of Danon disease: a case series.
Interruption of bile acid enterohepatic circulation inhibits glycogen synthesis and promotes hepatocellular carcinoma progression.

J Neurochem. 2023 Aug 09.

The multifaceted roles of the brain glycogen.

Kia H Markussen, Manuela Corti, Barry J Byrne, Craig W Vander Kooi, Ramon C Sun, Matthew S Gentry.

  Glycogen is a biologically essential macromolecule that is directly involved in multiple human diseases. While its primary role in carbohydrate storage and energy metabolism in the liver and muscle is well characterized, recent research has highlighted critical metabolic and non-metabolic roles for glycogen in the brain. In this review, the emerging roles of glycogen homeostasis in the healthy and diseased brain are discussed with a focus on advancing our understanding of the role of glycogen in the brain. Innovative technologies that have led to novel insights into glycogen functions are detailed. Key insights into how cellular localization impacts neuronal and glial function are discussed. Perturbed glycogen functions are observed in multiple disorders of the brain, including where it serves as a disease driver in the emerging category of neurological glycogen storage diseases (n-GSDs). n-GSDs include Lafora disease (LD), adult polyglucosan body disease (APBD), Cori disease, Glucose transporter type 1 deficiency syndrome (G1D), GSD0b, and late-onset Pompe disease (PD). They are neurogenetic disorders characterized by aberrant glycogen which results in devastating neurological and systemic symptoms. In the most severe cases, rapid neurodegeneration coupled with dementia results in death soon after diagnosis. Finally, we discuss current treatment strategies that are currently being developed and have the potential to be of great benefit to patients with n-GSD. Taken together, novel technologies and biological insights have resulted in a renaissance in brain glycogen that dramatically advanced our understanding of both biology and disease. Future studies are needed to expand our understanding and the multifaceted roles of glycogen and effectively apply these insights to human disease.

Keywords:  N-linked glycosylation; brain metabolism; congenital disorders of glycosylation; epilepsy; glycogen; glycogen storage disease

DOI:  https://doi.org/10.1111/jnc.15926
Nat Microbiol. 2023 Aug 10.

Bacterial amylases enable glycogen degradation by the vaginal microbiome.

Dominick J Jenkins, Benjamin M Woolston, M Indriati Hood-Pishchany, Paula Pelayo, Alyssa N Konopaski, M Quinn Peters, Michael T France, Jacques Ravel, Caroline M Mitchell, Seth Rakoff-Nahoum, Christopher Whidbey, Emily P Balskus.

The human vaginal microbiota is frequently dominated by lactobacilli and transition to a more diverse community of anaerobic microbes is associated with health risks. Glycogen released by lysed epithelial cells is believed to be an important nutrient source in the vagina. However, the mechanism by which vaginal bacteria metabolize glycogen is unclear, with evidence implicating both bacterial and human enzymes. Here we biochemically characterize six glycogen-degrading enzymes (GDEs), all of which are pullanases (PulA homologues), from vaginal bacteria that support the growth of amylase-deficient Lactobacillus crispatus on glycogen. We reveal variations in their pH tolerance, substrate preferences, breakdown products and susceptibility to inhibition. Analysis of vaginal microbiome datasets shows that these enzymes are expressed in all community state types. Finally, we confirm the presence and activity of bacterial and human GDEs in cervicovaginal fluid. This work establishes that bacterial GDEs can participate in the breakdown of glycogen, providing insight into metabolism that may shape the vaginal microbiota.

DOI: https://doi.org/10.1038/s41564-023-01447-2
Int J Mol Sci. 2023 Aug 05. pii: 12481. [Epub ahead of print]24(15):

From Acid Alpha-Glucosidase Deficiency to Autophagy: Understanding the Bases of POMPE Disease.

Valentina Sánchez-Porras, Johana Maria Guevara-Morales, Olga Yaneth Echeverri-Peña.

  Pompe disease (PD) is caused by mutations in the GAA gene, which encodes the lysosomal enzyme acid alpha-glucosidase, causing lysosomal glycogen accumulation, mainly in muscular tissue. Autophagic buildup is considered the main factor affecting skeletal muscle, although other processes are also involved. Uncovering how these mechanisms are interconnected could be an approximation to address long-lasting concerns, like the differential skeletal and cardiac involvement in each clinical phenotype. In this sense, a network reconstruction based on a comprehensive literature review of evidence found in PD enriched with the STRING database and other scientific articles is presented. The role of autophagic lysosome reformation, PGC-1α, MCOLN1, calcineurin, and Keap1 as intermediates between the events involved in the pathologic cascade is discussed and contextualized within their relationship with mTORC1/AMPK. The intermediates and mechanisms found open the possibility of new hypotheses and questions that can be addressed in future experimental studies of PD.

Keywords:  Pompe disease; acid alpha-glucosidase; autophagy; glycogen storage disease type II; interaction network

DOI:  https://doi.org/10.3390/ijms241512481
Cereb Cortex. 2023 Aug 11. pii: bhad299. [Epub ahead of print]

Novel synergistic treatment for depression: involvement of GSK3β-regulated AMPA receptors in the prefrontal cortex of mice.

Lei Guo, Shuzhuo Wang, Haihua Tian, Mengyuan Shang, Jia Xu, Chuang Wang.

  Previous evidence has suggested a vital role of glycogen synthase kinase 3β-mediated α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid receptors trafficking in depression. Considering the antidepressant effect of α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid receptors activation in the prefrontal cortex, we hypothesized that glycogen synthase kinase 3β-induced alterations in α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid receptors function in the prefrontal cortex participate in depression. Herein, we confirmed that the levels of phosphorylated glycogen synthase kinase 3β and GluA1, the latter being a subunit of α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid receptors, were decreased in the prefrontal cortex of the chronic social defeat stress model mice presenting with depressive-like behaviors. We then found that a glycogen synthase kinase 3β (p.S9A) point mutation downregulated GluA1 and induced depressive-like behaviors in mice, whereas an agonist of α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid receptors, PF-4778574 (2 mg/kg) did not reversed the molecular changes. On the other hand, the antidepressant effect of PF-4778574 was dose dependent, and the single administration of PF-4778574 at a lower dose (0.5 mg/kg) or of the glycogen synthase kinase 3β inhibitor SB216763 (5 and 10 mg/kg) did not evoke an antidepressant effect. In contrast, co-treatment with PF-4778574 (0.5 mg/kg) and SB216763 (10 mg/kg) led to antidepressant effects similar to those of PF-4778574 (2 mg/kg). Our results suggest that glycogen synthase kinase 3β-induced α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid receptors dysfunction in the prefrontal cortex is one of the key mechanisms of depression, and the combination of a lower dose of PF-4778574 with SB216763 shows potential as a novel synergistic treatment for depression.

Keywords:  GSK3β; major depressive disorder (MDD); α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid receptor (AMPARs)

DOI:  https://doi.org/10.1093/cercor/bhad299
Cells. 2023 Jul 29. pii: 1967. [Epub ahead of print]12(15):

PP2A-Mediated GSK3β Dephosphorylation Is Required for Protocadherin-7-Dependent Regulation of Small GTPase RhoA in Osteoclasts.

Hyunsoo Kim, Noriko Takegahara, Yongwon Choi.

  Protocadherin-7 (Pcdh7) is a member of the non-clustered protocadherin δ1 subgroup of the cadherin superfamily. Pcdh7 has been revealed to control osteoclast differentiation by regulating Rho-family small GTPases, RhoA and Rac1, through its intracellular SET binding domain. However, the mechanisms by which small GTPases are regulated downstream of Pcdh7 remain unclear. Here, we demonstrate that protein phosphatase 2A (PP2A)-mediated dephosphorylation of Glycogen synthase kinase-3β (GSK3β) is required for Pcdh7-dependent activation of RhoA during osteoclast differentiation. Pcdh7-deficient (Pcdh7-/-) cells showed impaired PP2A activity, despite their normal expression of PP2A. GSK3β, whose activity is regulated by its inhibitory phosphorylation at Ser9, was dephosphorylated during osteoclast differentiation in a Pcdh7-dependent manner. Inhibition of protein phosphatase by okadaic acid reduced dephosphorylation of GSK3β in Pcdh7+/+ cells, while activation of PP2A by DT-061 rescued impaired dephosphorylation of GSK3β in Pcdh7-/- cells. Inhibition of GSK3β by AR-A014418 inhibited RANKL-induced RhoA activation and osteoclast differentiation in Pcdh7+/+ cells. On the other hand, DT-061 treatment rescued impaired RhoA activation and RANKL-induced osteoclast differentiation in Pcdh7-/- cells. Taken together, these results demonstrate that PP2A dephosphorylates GSK3β and thereby activates it in a Pcdh7-dependent manner, which is required for activation of small GTPase RhoA and proper osteoclast differentiation.

Keywords:  GSK3β; PP2A; Pcdh7; RhoA; differentiation; osteoclasts

DOI:  https://doi.org/10.3390/cells12151967
Cell Mol Immunol. 2023 Aug 09.

Glycogen synthase kinase 3 controls T-cell exhaustion by regulating NFAT activation.

Yubing Fu, Jinjia Wang, Chenfeng Liu, Kunyu Liao, Xianjun Gao, Ronghan Tang, Binbin Fan, Yazhen Hong, Nengming Xiao, Changchun Xiao, Wen-Hsien Liu.

  Cellular immunity mediated by CD8+ T cells plays an indispensable role in bacterial and viral clearance and cancers. However, persistent antigen stimulation of CD8+ T cells leads to an exhausted or dysfunctional cellular state characterized by the loss of effector function and high expression of inhibitory receptors during chronic viral infection and in tumors. Numerous studies have shown that glycogen synthase kinase 3 (GSK3) controls the function and development of immune cells, but whether GSK3 affects CD8+ T cells is not clearly elucidated. Here, we demonstrate that mice with deletion of Gsk3α and Gsk3β in activated CD8+ T cells (DKO) exhibited decreased CTL differentiation and effector function during acute and chronic viral infection. In addition, DKO mice failed to control tumor growth due to the upregulated expression of inhibitory receptors and augmented T-cell exhaustion in tumor-infiltrating CD8+ T cells. Strikingly, anti-PD-1 immunotherapy substantially restored tumor rejection in DKO mice. Mechanistically, GSK3 regulates T-cell exhaustion by suppressing TCR-induced nuclear import of NFAT, thereby in turn dampening NFAT-mediated exhaustion-related gene expression, including TOX/TOX2 and PD-1. Thus, we uncovered the molecular mechanisms underlying GSK3 regulation of CTL differentiation and T-cell exhaustion in anti-tumor immune responses.

Keywords:  Anti-tumor immunity; GSK3; Inhibitory receptors; T-cell exhaustion; Viral infection

DOI:  https://doi.org/10.1038/s41423-023-01075-0
Eur J Pharmacol. 2023 Aug 09. pii: S0014-2999(23)00496-X. [Epub ahead of print] 175984

Regulation of plasma glucose levels by central dopamine D2 receptors is impaired in type 1 but not type 2 diabetic mouse models.

Hiroko Ikeda, Risa Mikami, Naomi Yonemochi, John L Waddington.

  Glucose metabolism is reported to be regulated by the central nervous system, but it is unclear whether this regulation is altered in diabetes. We investigated whether regulation of glucose metabolism by central dopamine D2 receptors is altered in type 1 and type 2 diabetic models. Intracerebroventricular injections of both the dopamine D2 receptor agonist quinpirole and the antagonist l-sulpiride induced hyperglycemia in control mice, but not in streptozotocin (STZ)-induced diabetic mice, a type 1 diabetic model. Hyperglycemia induced by quinpirole or l-sulpiride was diminished following fasting and these drugs did not affect hyperglycemia in the pyruvate tolerance test. Both quinpirole and l-sulpiride increased hepatic glucose-6-phosphatase (G6Pase) mRNA. In STZ-induced diabetic mice, dopamine and dopamine D2 receptor mRNA in the hypothalamus, which regulates glucose homeostasis, were decreased. Hepatic glycogen and G6Pase mRNA were decreased in STZ-induced diabetic mice. Neither quinpirole nor l-sulpiride increased hepatic G6Pase mRNA in STZ-induced diabetic mice. In diet-induced obesity mice, a type 2 diabetic model, both quinpirole and l-sulpiride induced hyperglycemia, and hypothalamic dopamine and dopamine D2 receptor mRNA were not altered. These results indicate that (i) stimulation or blockade of dopamine D2 receptors causes hyperglycemia by increasing hepatic glycogenolysis, and (ii) stimulation or blockade of dopamine D2 receptors does not affect glucose levels in type 1 but does so in type 2 diabetic models. Moreover, hypothalamic dopaminergic function and hepatic glycogenolysis are decreased in the type 1 diabetic model, which reduces hyperglycemia induced by stimulation or blockade of dopamine D2 receptors.

Keywords:  Central nervous system; Diabetes mellitus; Dopamine D(2) receptors; Hepatic glucose production; Hyperglycemia

DOI:  https://doi.org/10.1016/j.ejphar.2023.175984
BMC Cardiovasc Disord. 2023 Aug 11. 23(1): 397

Clinical manifestations and MRI features of Danon disease: a case series.

Yang Zhang, Ren Zhao, Yushan Yuan, Yongqiang Yu, Bin Liu, Xiaohu Li.

   BACKGROUND: Danon disease (DD) is an exceptionally uncommon X-linked dominant lysosomal glycogen storage disorder characterized by pronounced ventricular hypertrophy and cardiac insufficiency. The timely identification of cardiac impairment in individuals with DD holds significant clinical importance.
CASE PRESENTATION: We present a case of Danon Disease in a three-generation pedigree from Anhui Province, China. Clinical features and laboratory data were collected and analyzed for a 16-year-old male proband (III-1) and two affected female family members (II-2 and II-3). The proband exhibited Wolf-Parkinson-White syndrome, hypertrophic cardiomyopathy, abnormal cognitive function, and muscle weakness. Gene sequencing confirmed a mutation (c.963G > A) in the LAMP-2 gene.
CONCLUSION: Patients with DD may present both dilated and hypertrophic cardiomyopathy. Comprehensive myocardial tissue characterization by MRI plays a key role in the diagnosis of the disease.

Keywords:  Danon disease; Extracellular volume fraction; Magnetic resonance imaging; T1 mapping

DOI:  https://doi.org/10.1186/s12872-023-03356-y
Genes Dis. 2023 Nov;10(6): 2218-2221

Interruption of bile acid enterohepatic circulation inhibits glycogen synthesis and promotes hepatocellular carcinoma progression.

Jiyan Wang, Xintong Dai, Hongkai Chang, Qingle Gao, Jianshuang Guo, Juze Yang, Shuai Zhang, Changliang Shan.

DOI: https://doi.org/10.1016/j.gendis.2023.02.026