bims-glecem 2023-10-15 papers

bims-glecem

Biomed News

on Glycogen metabolism in exercise, cancer and energy metabolism

Issue of 2023‒10‒15
seven papers selected by
Dipsikha Biswas, Københavns Universitet

Inhibition of mitochondrial fission activates glycogen synthesis to support cell survival in colon cancer.
Depletion of IQ motif-containing GTPase activating protein 2 (IQGAP2) reduces hepatic glycogen and impairs insulin signaling.
Activation-induced shift in nutrient preference and function-specific nutrient dependence in human neutrophils.
A Case Report of McArdle Disease Diagnosed Following Statin-Induced Myositis.
Metabolic switch from glycogen to lipid in the liver maintains glucose homeostasis in neonatal mice.
Kinin B1 receptor modulates glucose homeostasis and physical exercise capacity by altering adrenal catecholamine synthesis and secretion.
Long-term benefits of physical activity in adult patients with late onset Pompe disease: a retrospective cohort study with 10 years of follow-up.

Cell Death Dis. 2023 Oct 10. 14(10): 664

Inhibition of mitochondrial fission activates glycogen synthesis to support cell survival in colon cancer.

Sumati Hasani, Lyndsay E A Young, Warren Van Nort, Moumita Banerjee, Dylan R Rivas, Jinhwan Kim, Xiaopeng Xiong, Ramon C Sun, Matthew S Gentry, Hiromi Sesaki, Tianyan Gao.

Metabolic reprogramming has been recognized as one of the major mechanisms that fuel tumor initiation and progression. Our previous studies demonstrate that activation of Drp1 promotes fatty acid oxidation and downstream Wnt signaling. Here we investigate the role of Drp1 in regulating glycogen metabolism in colon cancer. Knockdown of Drp1 decreases mitochondrial respiration without increasing glycolysis. Analysis of cellular metabolites reveals that the levels of glucose-6-phosphate, a precursor for glycogenesis, are significantly elevated whereas pyruvate and other TCA cycle metabolites remain unchanged in Drp1 knockdown cells. Additionally, silencing Drp1 activates AMPK to stimulate the expression glycogen synthase 1 (GYS1) mRNA and promote glycogen storage. Using 3D organoids from Apcf/f/Villin-CreERT2 models, we show that glycogen levels are elevated in tumor organoids upon genetic deletion of Drp1. Similarly, increased GYS1 expression and glycogen accumulation are detected in xenograft tumors derived from Drp1 knockdown colon cancer cells. Functionally, increased glycogen storage provides survival advantage to Drp1 knockdown cells. Co-targeting glycogen phosphorylase-mediated glycogenolysis sensitizes Drp1 knockdown cells to chemotherapy drug treatment. Taken together, our results suggest that Drp1-loss activates glucose uptake and glycogenesis as compensative metabolic pathways to promote cell survival. Combined inhibition of glycogen metabolism may enhance the efficacy of chemotherapeutic agents for colon cancer treatment.

DOI: https://doi.org/10.1038/s41419-023-06202-3
J Biol Chem. 2023 Oct 05. pii: S0021-9258(23)02350-5. [Epub ahead of print] 105322

Depletion of IQ motif-containing GTPase activating protein 2 (IQGAP2) reduces hepatic glycogen and impairs insulin signaling.

Anushna Sen, Sara Youssef, Karen Wendt, Sayeepriyadarshini Anakk.

  The liver is critical in maintaining metabolic homeostasis, regulating both anabolic and catabolic processes. Scaffold protein IQGAP2 is highly expressed in the liver and implicated in fatty acid uptake. However, its role in coordinating either fed or fasted responses is not well understood. Here we report that IQGAP2 is widely expressed in the liver that is pronounced in the pericentral region. Although control and IQGAP2 knockout (Iqgap2-/-) mouse model showed comparable hepatic gene expression in the fasted state, we found significant defects in fed state responses. Glycogen levels were reduced in the periportal region when IQGAP2 was deleted. Consistently, we observed a decrease in phosphorylated glycogen synthase kinase 3α (GSK3α) and total glycogen synthase (GYS2) protein in the fed Iqgap2-/- mice which suggest inadequate glycogen synthesis. Moreover, immunoprecipitation of IQGAP2 revealed its interaction with GSK3 and GYS. Furthermore, our study demonstrated that knocking down IQGAP2 in vitro significantly decreased the phosphorylation of AKT and FOXO3 proteins downstream of insulin signaling. These findings suggest that IQGAP2 contributes to liver fed-state metabolism by interacting with glycogen synthesis regulators and affecting the phosphorylation of insulin pathway components. Our results suggest that IQGAP2 plays a role in regulating fed-state metabolism.

Keywords:  and insulin signaling; carbohydrate; glycogen synthase (GYS2); glycogen synthase kinase 3 (GSK‐3); liver; protein kinase B (PKB/AKT); scaffold protein

DOI:  https://doi.org/10.1016/j.jbc.2023.105322
bioRxiv. 2023 Sep 26. pii: 2023.09.25.559385. [Epub ahead of print]

Activation-induced shift in nutrient preference and function-specific nutrient dependence in human neutrophils.

Emily C Britt, Xin Qing, James A Votava, Jorgo Lika, Andrew Wagner, Simone Shen, Nicholas L Arp, Hamidullah Khan, Stefan M Schieke, Christopher D Fletcher, Anna Huttenlocher, Jing Fan.

Neutrophils are the first responders in innate immunity. Neutrophils can perform a variety of effector functions which are associated with specific metabolic demand. The utilization of various metabolic sources, including extracellular glucose, intracellular glycogen, and other alternative substrates, have been found critical for neutrophil fitness and functions in recent studies. However, the quantitative contribution of these nutrients under specific conditions and the relative dependence of various cell functions on specific nutrients remain unclear. Here using ex vivo and in vivo isotopic tracing, we revealed that under resting condition, human peripheral blood neutrophils, in contrast to in vitro cultured human neutrophil-like cell lines, rely on glycogen as a major direct source of glycolysis and pentose phosphate pathway. Extracellular glucose contributes slightly less than half, and other sources have minor contributions. Upon activation with a diversity of stimuli (including zymosan A, TNFα, PMA, LPS, or Pseudomonas aeruginosa ), neutrophils undergo a significant nutrient preference shift, with glucose becoming the dominant metabolic source. The shift to glucose utilization is often rapid and driven by multi-fold increases in glucose uptake, which is mechanistically mediated by the phosphorylation and translocation of GLUT1. At the same time, cycling between gross glycogenesis and glycogenolysis is also substantially increased, while the net flux favors sustained or increased glycogen storage. Different effector functions of activated neutrophils have specific nutrient dependence. The oxidative burst is most dependent on extracellular glucose, while the release of neutrophil extracellular traps can be flexibly supported by either glucose or glycogen utilization. Shifting neutrophil away from glycogen utilization increases migration and fungal control. Together, these results quantitatively characterize fundamental features of neutrophil metabolism and elucidate how metabolic remodeling supports and shapes neutrophil functions upon activation.

DOI: https://doi.org/10.1101/2023.09.25.559385
Cureus. 2023 Sep;15(9): e44701

A Case Report of McArdle Disease Diagnosed Following Statin-Induced Myositis.

João S Teles, Catarina T Ramos, Beatriz M Almeida, Anabela V Sousa.

  McArdle disease is a rare condition, characterized by a deficiency of phosphorylase muscle isoform, an enzyme responsible for the breaking down of glycogen, necessary for obtaining energy. Patients typically present with exercise intolerance, myalgias, fatigue, cramps, muscle stiffness, and/or weakness induced by physical activity. The diagnosis is generally established late, with a median delay of about 29 years. We present the case of a female patient with a long history of myalgias, muscle weakness, and exercise intolerance, diagnosed with McArdle disease by the age of 74, after statin-induced myopathy. We aim to review the diagnosis and treatment of this disease, as a way to raise awareness among the medical community.

Keywords:  exercise intolerance; mcardle disease; myalgias; myophosphorylase; statins

DOI:  https://doi.org/10.7759/cureus.44701
J Lipid Res. 2023 Oct 10. pii: S0022-2275(23)00113-X. [Epub ahead of print]64(10): 100440

Metabolic switch from glycogen to lipid in the liver maintains glucose homeostasis in neonatal mice.

Liangkui Li, Haoyu Zhou, Jinhui Wang, Jiaxin Li, Xuchao Lyu, Wenshan Wang, Chengting Luo, He Huang, Dawang Zhou, Xiaowei Chen, Li Xu, Peng Li.

  Neonates strive to acquire energy when the continuous transplacental nutrient supply ceases at birth, whereas milk consumption takes hours to start. Using murine models, we report the metabolic switches in the first days of life, with an unexpected discovery of glucose as the universal fuel essential for neonatal life. Blood glucose quickly drops as soon as birth, but immediately rebounds even before suckling and maintains stable afterward. Meanwhile, neonatal liver undergoes drastic metabolic changes, from extensive glycogenolysis before suckling to dramatically induced fatty acid oxidation (FAO) and gluconeogenesis after milk suckling. Unexpectedly, blocking hepatic glycogenolysis only caused a transient hypoglycemia before milk suckling without causing lethality. Limiting lipid supply in milk (low-fat milk, [LFM]) using Cidea-/- mice, however, led to a chronic and severe hypoglycemia and consequently claimed neonatal lives. While fat replenishment rescued LFM-caused neonatal lethality, the rescue effects were abolished by blocking FAO or gluconeogenesis, pointing to a funneling of lipids and downstream metabolites into glucose as the essential fuel. Finally, glucose administration also rescued LFM-caused neonatal lethality, independent on FAO or gluconeogenesis. Therefore, our results show that the liver works as an energy conversion center to maintain blood glucose homeostasis in neonates, providing theoretical basis for managing infant hypoglycemia.

Keywords:  Physiology; biological sciences; gluconeogenesis; glucose homeostasis; glycogen; lipids; neonates

DOI:  https://doi.org/10.1016/j.jlr.2023.100440
Mol Cell Endocrinol. 2023 Oct 10. pii: S0303-7207(23)00236-8. [Epub ahead of print] 112085

Kinin B1 receptor modulates glucose homeostasis and physical exercise capacity by altering adrenal catecholamine synthesis and secretion.

Marcos Fernandes Gregnani, Alexandre Budu, Rogério Oliveira Batista, Fábio Henrique Ornellas, Gabriel Rufino Estrela, Adriano Cleis Arruda, Leandro Ceotto Freitas Lima, Jean Lucas Kremer, Lys Angela Favaroni Mendes, Dulce Elena Casarini, Claudimara Ferini Pacicco Lotfi, Lila Missae Oyama, Michael Bader, Ronaldo Carvalho Araújo.

  Our group has shown in several papers that kinin B1 receptor (B1R) is involved in metabolic adaptations, mediating glucose homeostasis and interfering in leptin and insulin signaling. Since catecholamines are involved with metabolism management, we sought to evaluate B1R role in catecholamine synthesis/secretion. Using B1R global knockout mice, we observed increased basal epinephrine content, accompanied by decreased hepatic glycogen content and increased glucosuria. When these mice were challenged with maximal intensity exercise, they showed decreased epinephrine and norepinephrine response, accompanied by disturbed glycemic responses to effort and poor performance. This phenotype was related to alterations in adrenal catecholamine synthesis: increased basal epinephrine concentration and reduced norepinephrine content in response to exercise, as well decreased gene expression and protein content of tyrosine hydroxylase and decreased gene expression of dopamine beta hydroxylase and kinin B2 receptor. We conclude that the global absence of B1R impairs catecholamine synthesis, interfering with glucose metabolism at rest and during maximal exercise.

Keywords:  Catecholamines; Glucose homeostasis; Kinin receptors; Physical exercise

DOI:  https://doi.org/10.1016/j.mce.2023.112085
Orphanet J Rare Dis. 2023 Oct 11. 18(1): 319

Long-term benefits of physical activity in adult patients with late onset Pompe disease: a retrospective cohort study with 10 years of follow-up.

Gamida Ismailova, Margreet A E M Wagenmakers, Esther Brusse, Ans T van der Ploeg, Marein M Favejee, Nadine A M E van der Beek, Linda E M van den Berg.

  BACKGROUND: In 2011 a 12 weeks personalized exercise training program in 23 mildly affected adult late onset Pompe patients (age 19.6-70.5 years) improved endurance, muscle strength and function. Data on long-term effects of this program or of other physical activity in Pompe disease are absent. This retrospective cohort study aimed to explore effects of long-term healthy physical activity according to the WHO norm and the former exercise training program on the disease course.RESULTS: A total of 29 adult late onset Pompe patients were included: 19 former exercise training program participants and 10 comparable control patients. Patients, who based on interviews, met the 2010 WHO healthy physical activity norm (active, n = 16) performed better on endurance (maximal cardiopulmonary exercise test), muscle strength and function compared to patients not meeting this norm (inactive, n = 13) (p < 0.05). Majority of the outcomes, including endurance and manually tested muscle strength, tended to be higher in the active patients of the 2011 training cohort who continued the program compared to active control patients (p > 0.05).
CONCLUSION: In Pompe disease long-term healthy physical activity according to the 2010 WHO norm leads to physical benefits and a personalized exercise training program may have additional favorable effects and both should be recommended as standard of care.

Keywords:  Endurance; Exercise training program; Late onset Pompe disease; Muscle function; Muscle strength; WHO physical activity norm

DOI:  https://doi.org/10.1186/s13023-023-02924-x