bims-glecem 2022-04-10 papers

bims-glecem

Biomed News

on Glycogen metabolism in exercise, cancer and energy metabolism

Issue of 2022‒04‒10
sixteen papers selected by
Dipsikha Biswas, Københavns Universitet

Disrupting AMPK-Glycogen Binding in Mice Increases Carbohydrate Utilization and Reduces Exercise Capacity.
Peristomal cellulitis following percutaneous endoscopic gastrostomy tube placement in glycogen storage disease type 1b.
Brain glycogen content is increased in the acute and interictal chronic stages of the mouse pilocarpine model of epilepsy.
Case Report: Identification of Compound Heterozygous Mutations in a Patient With Late-Onset Glycogen Storage Disease Type II (Pompe Disease).
Glycogen as a Regulator of White Fat Browning.
Development of inhibitors targeting glycogen synthase kinase-3β for human diseases: Strategies to improve selectivity.
Evidence for investigating GSK-3 inhibitors as potential therapeutics for severe COVID-19.
Expression of glycogenic genes in the oviduct of Chinese brown frog (Rana dybowskii) during pre-brumation.
Aged green tea reduces high-fat diet-induced fat accumulation and inflammation via activating the AMP-activated protein kinase signaling pathway.
Exposure of zebrafish to a cold environment triggered cellular autophagy in zebrafish liver.
A Novel Formula Comprising Wolfberry, Figs, White Lentils, Raspberries, and Maca (WFWRM) Induced Antifatigue Effects in a Forced Exercise Mouse Model.
Metabolic Reservoir Cycles in Cancer.
Citrullination of glucokinase is linked to autoimmune diabetes.
Endocrine control of glycogen and triacylglycerol breakdown in the fly model.
Honokiol Inhibits Atrial Metabolic Remodeling in Atrial Fibrillation Through Sirt3 Pathway.
The Physiological Role of Irisin in the Regulation of Muscle Glucose Homeostasis.

Front Physiol. 2022 ;13 859246

Disrupting AMPK-Glycogen Binding in Mice Increases Carbohydrate Utilization and Reduces Exercise Capacity.

Natalie R Janzen, Jamie Whitfield, Lisa Murray-Segal, Bruce E Kemp, John A Hawley, Nolan J Hoffman.

  The AMP-activated protein kinase (AMPK) is a central regulator of cellular energy balance and metabolism and binds glycogen, the primary storage form of glucose in liver and skeletal muscle. The effects of disrupting whole-body AMPK-glycogen interactions on exercise capacity and substrate utilization during exercise in vivo remain unknown. We used male whole-body AMPK double knock-in (DKI) mice with chronic disruption of AMPK-glycogen binding to determine the effects of DKI mutation on exercise capacity, patterns of whole-body substrate utilization, and tissue metabolism during exercise. Maximal treadmill running speed and whole-body energy utilization during submaximal running were determined in wild type (WT) and DKI mice. Liver and skeletal muscle glycogen and skeletal muscle AMPK α and β2 subunit content and signaling were assessed in rested and maximally exercised WT and DKI mice. Despite a reduced maximal running speed and exercise time, DKI mice utilized similar absolute amounts of liver and skeletal muscle glycogen compared to WT. DKI skeletal muscle displayed reduced AMPK α and β2 content versus WT, but intact relative AMPK phosphorylation and downstream signaling at rest and following exercise. During submaximal running, DKI mice displayed an increased respiratory exchange ratio, indicative of greater reliance on carbohydrate-based fuels. In summary, whole-body disruption of AMPK-glycogen interactions reduces maximal running capacity and skeletal muscle AMPK α and β2 content and is associated with increased skeletal muscle glycogen utilization. These findings highlight potential unappreciated roles for AMPK in regulating tissue glycogen dynamics and expand AMPK's known roles in exercise and metabolism.

Keywords:  AMP-activated protein kinase; carbohydrate binding module; energy utilization; exercise; glycogen; metabolism; skeletal muscle

DOI:  https://doi.org/10.3389/fphys.2022.859246
Pediatr Neonatol. 2022 Mar 15. pii: S1875-9572(22)00050-X. [Epub ahead of print]

Peristomal cellulitis following percutaneous endoscopic gastrostomy tube placement in glycogen storage disease type 1b.

Ryo Kobayashi, Kei Matayoshi, Morihiro Katsura, Toshifumi Yodoshi.

DOI: https://doi.org/10.1016/j.pedneo.2022.03.001
Epilepsia Open. 2022 Apr 04.

Brain glycogen content is increased in the acute and interictal chronic stages of the mouse pilocarpine model of epilepsy.

Gi Young Seo, Elliott S Neal, Felicity Han, Diana Vidovic, Fathima Nooru-Mohamed, Gerald A Dienel, Mitchell A Sullivan, Karin Borges.

  Glucose is the main brain fuel in fed conditions, while astrocytic glycogen is used as supplemental fuel when the brain is stimulated. Brain glycogen levels are decreased after induced seizures in rodents, but little is known about how glycogen levels are affected interictally in chronic models of epilepsy. Reduced glutamine synthetase activity has been suggested to lead to increased brain glycogen levels in humans with chronic epilepsy. Here, we used the mouse pilocarpine model of epilepsy to investigate if brain glycogen levels are altered, both acutely and in the chronic stage of the model. One day after pilocarpine-induced convulsive status epilepticus (CSE), glycogen levels were higher in the hippocampal formation, cerebral cortex and cerebellum. Opposite to expected, this was accompanied by elevated glutamine synthetase activity in the hippocampus but not cortex. Increased interictal glycogen amounts were seen in the hippocampal formation and cerebral cortex in the chronic stage of the model (21 days post-CSE), suggesting long-lasting alterations in glycogen metabolism. Glycogen solubility in the cerebral cortex was unaltered in this epilepsy mouse model. Glycogen synthase kinase 3 beta (Gsk3b) mRNA levels were reduced in the hippocampal formations of mice in the chronic stage, which may underlie the elevated brain glycogen content in this model. This is the first report of elevated interictal glycogen levels in a chronic epilepsy model. Increased glycogen amounts in the brain may influence seizure susceptibility in this model and this warrants further investigation.

Keywords:  Gsk3b; glutamine synthetase; status epilepticus; temporal lobe epilepsy

DOI:  https://doi.org/10.1002/epi4.12599
Front Neurol. 2022 ;13 839263

Case Report: Identification of Compound Heterozygous Mutations in a Patient With Late-Onset Glycogen Storage Disease Type II (Pompe Disease).

Huiting Zhang, Jun Chen, Yuchang Zhu, Xiaotang Ma, Wangtao Zhong.

  Pompe disease is an autosomal recessive hereditary lysosomal disorder and correlated with acid α-glucosidase enzyme (GAA) deficiencies, which lead to accumulation of glycogen in all tissues, most notably in skeletal muscles. Adult late-onset Pompe disease (LOPD) is a slowly progressive disease of proximal myopathy with later involvement of the respiratory muscles, resulting in respiratory failure. In this study, we reported a 22-year-old Chinese woman with inability to withstand heavy physical activity since childhood, who presented with respiratory and ambulation weakness in 2 months. On admission, her bilateral upper limbs strength was 4/5 and lower limbs strength was 3/5 according to Medical Research Council (MRC) score. The patient had compound heterozygotes containing a newly identified 4 nt deletion of coding sequence (deletion nt 1411_1414) in one of the acid α-glucosidase alleles and a c.2238G>C (p.Trp746Cys) missense mutation. This deletion has been reported in infant-onset Pompe disease (IOPD) but not LOPD. Intriguingly, this deletion mutation was not found in the patient's family and was considered as pathogenic. Muscle biopsy showed scattered vacuoles with basophilic granules inside the subsarcolemmal area, which were strongly stained by periodic acid-Schiff (PAS). Laboratory tests revealed a significant increase of creatine kinase MB isoenzyme (CK-MB) and lactate dehydrogenase (LDH). GAA level was 9.77 nmol/1 h/mg and was not sufficient for the diagnosis of GAA activity deficiency (0-3.78 nmol/1 h/mg). In summary, mutational analysis of GAA and muscle biopsy are crucial in the diagnosis of Pompe disease.

Keywords:  acid α-glucosidase enzyme; c.1411_1414del; glycogen storage disease type II; late-onset Pompe disease; metabolic myopathy

DOI:  https://doi.org/10.3389/fneur.2022.839263
Mol Cells. 2022 Apr 30. 45(4): 177-179

Glycogen as a Regulator of White Fat Browning.

Seri Choi.

DOI: https://doi.org/10.14348/molcells.2022.2050
Eur J Med Chem. 2022 Mar 31. pii: S0223-5234(22)00203-3. [Epub ahead of print]236 114301

Development of inhibitors targeting glycogen synthase kinase-3β for human diseases: Strategies to improve selectivity.

Junxia Wei, Jiaxing Wang, Jifa Zhang, Jinliang Yang, Guan Wang, Yuxi Wang.

  Glycogen synthase kinase-3β (GSK-3β) is a conserved serine/threonine kinase that participates in the transmission of multiple signaling pathways and plays an important role in the occurrence and development of human diseases, such as metabolic diseases, neurological diseases and cancer, making it to be a potential and promising drug target. To date, copious GSK-3β inhibitors have been synthesized, but only few have entered clinical trials. Most of them exerts poor selectivity, concomitant off-target effects and side effects. This review summarizes the structural characteristics, biological functions and relationship with diseases of GSK-3β, as well as the selectivity profile and therapeutic potential of different categories of GSK-3β inhibitors. Strategies for increasing selectivity and reducing adverse effects are proposed for the future design of GSK-3β inhibitors.

Keywords:  Cancer treatment; GSK-3β; Inhibitors; Selectivity

DOI:  https://doi.org/10.1016/j.ejmech.2022.114301
Biochem Biophys Res Commun. 2022 Mar 16. pii: S0006-291X(22)00360-6. [Epub ahead of print]605 171-176

Evidence for investigating GSK-3 inhibitors as potential therapeutics for severe COVID-19.

Davoud Ghazanfari, Maria Cecilia Courreges, Lydia Belinski, Stephen C Bergmeier, Kelly D McCall, Douglas J Goetz.

  A key component of severe COVID-19 is a "cytokine storm" i.e., the excessive expression of unneeded cytokines. Previous studies suggest that SARS-CoV-2 proteins can induce macrophages to secrete pro-inflammatory cytokines; a process that may involve Toll-like receptors (TLRs). Glycogen synthase kinase-3 (GSK-3) has been implicated in TLR signal transduction and a selective GSK-3 inhibitor, termed COB-187, dramatically attenuates cytokine expression induced by the TLR ligand lipopolysaccharide (LPS). In the present study, we provide evidence that the SARS-CoV-2 spike protein (S) and the S2 subunit (S2) induce production of CXCL10 (a chemokine elevated in severe COVID-19) by a human macrophage cell line. Further, we report that two clinically relevant GSK-3 inhibitors and COB-187 attenuate S and S2 protein-induced CXCL10 production. Combined, our observations provide impetus for investigating GSK-3 inhibitors as potential therapeutics for severe COVID-19.

Keywords:  COVID-19; CXCL10; Cytokine storm; Glycogen synthase kinase-3; Spike protein

DOI:  https://doi.org/10.1016/j.bbrc.2022.03.035
Theriogenology. 2022 Mar 18. pii: S0093-691X(22)00095-4. [Epub ahead of print]185 78-87

Expression of glycogenic genes in the oviduct of Chinese brown frog (Rana dybowskii) during pre-brumation.

Chang Fan, Yuning Liu, Yawei Wang, Ao Zhang, Wenqian Xie, Haolin Zhang, Qiang Weng, Meiyu Xu.

  The oviduct of Chinese brown frog (Rana dybowskii) displays seasonal morphological and functional changes, which expands specifically during pre-brumation. To uncover the molecular mechanism underlying this phenomenon, we firstly confirmed the increased weight and enlarged diameter of the oviduct in pre-brumation by morphological observation. Interestingly, the glycogen content in the oviduct increased significantly during pre-brumation, indicating Rana dybowskii stores energy in the oviduct before brumation. Transcriptome analysis further identified the differentially expressed genes in the synthesis and metabolism pathways of carbohydrates in the oviduct during pre-brumation. Based on that evidence, we focused on the mRNA and protein expression of glycogenic genes in the oviduct of Rana dybowskii. qPCR confirmed that the expression of glycolysis and glycogenesis-related genes were up-regulated while gluconeogenesis-related genes were down-regulated during pre-brumation. Western blot data showed that glucose transporter GLUT1 and glycogen synthesis-regulation proteins including GYS, and p-GSK-3β were highly expressed in the oviduct during pre-brumation. Moreover, immunohistochemical data showed that GLUT1, GYS, p-GYS, GSK-3β and p-GSK-3β were expressed regionally in the oviduct of Rana dybowskii. The data suggests that glycogen synthesis may be involved in the oviductal expansion of Rana dybowskii during the pre-brumation.

Keywords:  Glycogen synthesis; Oviduct; Pre-brumation; Rana dybowskii

DOI:  https://doi.org/10.1016/j.theriogenology.2022.03.006
Food Nutr Res. 2022 ;66

Aged green tea reduces high-fat diet-induced fat accumulation and inflammation via activating the AMP-activated protein kinase signaling pathway.

Ruohong Chen, Xingfei Lai, Limin Xiang, Qiuhua Li, Lingli Sun, Zhaoxiang Lai, Zhigang Li, Wenji Zhang, Shuai Wen, Junxi Cao, Shili Sun.

  Background: Obesity is a global public health concern and increases the risk of metabolic syndrome and other diseases. The anti-obesity effects of various plant-derived bioactive compounds, such as tea extracts, are well-established. The mechanisms underlying the anti-obesity activity of Jinxuan green tea (JXGT) from different storage years are still unclear.Objective: The aim of this study was to evaluate the effects of JXGTs from three different years on the high fat diet (HFD)-fed mouse model.
Design: The mice were divided into six groups, the control group received normal diet and the obese model group received HFD. We analyzed the effects of JXGTs from 2005, 2008, and 2016 on HFD-fed obese mice over a period of 7 weeks.
Results: The JXGTs reduced the body weight of the obese mice, and also alleviated fat accumulation and hepatic steatosis. Mechanistically, JXGTs increased the phosphorylation of AMP-activated protein kinase (p-AMPK)/AMP-activated protein kinase (AMPK) ratio, up-regulated carnitine acyl transferase 1A (CPT-1A), and down-regulated fatty acid synthase (FAS), Glycogen synthase kinase-3beta (GSK-3β), Peroxisome proliferator-activated receptor-gamma co-activator-1alpha (PGC-1α), Interleukin 6 (IL-6), and Tumour necrosis factor alpha (TNFα). Thus, JXGTs can alleviate HFD-induced obesity by inhibiting lipid biosynthesis and inflammation, thereby promoting fatty acid oxidation via the AMPK pathway.
Discussion: The anti-obesity effect of three aged JXGTs were similar. However, JXGT2016 exhibited a more potent activation of AMPK, and JXGT2005 and JXGT2008 exhibited a more potent inhibiting glycogen synthase and inflammation effect. Furthermore, the polyphenol (-)-epicatechin (EC) showed the strongest positive correlation with the anti-obesity effect of JXGT.
Conclusions: These findings demonstrate that JXGT treatment has a potential protection on HFD-induced obesity mice via activating the AMPK/CPT-1A and down-regulating FAS/GSK-3β/PGC-1α and IL-6/TNFα. Our study results also revealed that different storage time would not affect the anti-obesity and anti-inflammation effect of JXGT.
Graphical abstract:

Keywords:  AMPK; aged green tea; anti-inflammation; anti-obesity; metabolism

DOI:  https://doi.org/10.29219/fnr.v66.7923
J Fish Dis. 2022 Apr 08.

Exposure of zebrafish to a cold environment triggered cellular autophagy in zebrafish liver.

Hong Chen, Fange Zhao, Kexing Chen, Yihan Guo, Yue Liang, Huiying Zhao, Shulin Chen.

  Water temperature is the major ecophysiological factor for fish survival in nature and aquaculture. Compared with many homeotherms, fish can survive prolonged periods under the condition of low temperature. However, the metabolic strategies of the liver under a cold environment are still unknown in this species. In our present study, adult zebrafish were exposed to a cold or cold plus starvation environment to analyse the morphological characteristics of hepatocytes by light microscopy and transmission electron microscopy (TEM). The fish livers were dissected and observed under a microscope, and the liver size and shape appeared normal in all groups. Periodic acid-Schiff and TEM analysis showed that hepatic glycogen was significantly lower in zebrafish exposed to cold acclimation (CF group) than that zebrafish at the control water temperature (CT group). Moreover, qPCR and IHC results indicated that the expression of PYGL (a key enzyme involved in glycogenolysis) markedly increased in the CF group. After cold plus starvation treatment (CS group), autophagy activity was significantly enhanced and numerous mitophagic vacuoles were present in the cytoplasm of hepatocytes. In conclusion, hepatic glycogen was first mobilizing to supply energy, and then autophagy, especially mitophagy, played vital roles during nutrient deprivation in fish species.

Keywords:  Zebrafish; aquaculture; autophagy; hepatic glycogen; temperature

DOI:  https://doi.org/10.1111/jfd.13620
Evid Based Complement Alternat Med. 2022 ;2022 3784580

A Novel Formula Comprising Wolfberry, Figs, White Lentils, Raspberries, and Maca (WFWRM) Induced Antifatigue Effects in a Forced Exercise Mouse Model.

Caixia Yang, Jingyan Yang, Li Tan, Pan Tang, Ting Pen, Tinghui Gao, Sijing Liu, Jinlin Guo.

Long-term body fatigue poses a threat to human health. To explore novel sources of antifatigue medicine and food, we developed a novel formula composed of wolfberry, figs, white lentils, raspberries, and maca (WFWRM) according to the theory of traditional Chinese medicine. In this study, we explored whether the administration of the WFWRM relieves fatigue. Thirty male Kunming mice were divided into three groups, which received either intragastric administration of saline, vitamin C (100 mg/kg), or WFWRM (1.00 g/kg) every day. After 30 days of treatment, all mice exhaustively performed weight-bearing swimming. Another ten mice that did not perform swimming were treated with saline for 30 days and used as sedentary control. The antifatigue effect and biochemical oxidation phenomena were assessed in the exercise-exhausted model and sedentary controls. The histopathological changes in the liver and kidney tissues of mice were observed by performing hematoxylin-eosin (HE) staining. After 30 days of oral administration, the liver and kidney tissues of mice were healthy and show no pathological changes. Compared to the fatigue model group, WFWRM significantly increased the rota-rod time of the mice. Also, the concentrations of lactic acid (LA), blood urea nitrogen (BUN), creatine kinase (CK), and lactate dehydrogenase (LDH) in the WFWRM group significantly reduced. On the contrary, the levels of hepatic glycogen (LG), muscle glycogen (MG), and serum glucose (GLU) increased in the WFWRM group. Besides, WFWRM markedly reduced the levels of malondialdehyde (MDA) but increased the levels of glutathione peroxidase (GSH-PX) and superoxide dismutase (SOD). Pearson correlation analysis indicated that the concentrations of the sources of energy (LG, MG, and GLU) significantly correlated with those of metabolites (BLA, BUN, CK, and LDH) and antioxidant levels (SOD, GSH-PX, and MDA). Overall, our results suggested that the supplementation of WFWRM could improve exercise capacity and relieve fatigue probably by normalizing energy metabolism and attenuating oxidation.

DOI: https://doi.org/10.1155/2022/3784580
Semin Cancer Biol. 2022 Apr 04. pii: S1044-579X(22)00079-7. [Epub ahead of print]

Metabolic Reservoir Cycles in Cancer.

Cissy Zhang, Addison Quinones, Anne Le.

  Cancer cells possess various biological processes to ensure survival and proliferation even under unfavorable conditions such as hypoxia, nutrient deprivation, and oxidative stress. One of the defining hallmarks of cancer cells is their ability to reprogram their metabolism to suit their needs. Building on over a decade of research in the field of cancer metabolism, numerous unique metabolic capabilities are still being discovered in the present day. One recent discovery in the field of cancer metabolism that was hitherto unexpected is the ability of cancer cells to store vital metabolites in forms that can be readily converted to glucose and glutamine for later use. We called these forms "metabolic reservoirs." While many studies have been conducted on storage molecules such as glycogen, triglyceride, and phosphocreatine (PCr), few have explored the concept of "metabolic reservoirs" for cancer as a whole. In this review, we will provide an overview of this concept, the previously known reservoirs including glycogen, triglyceride, and PCr, and the new discoveries made including the newly discovered reservoirs such as N-acetyl-aspartyl-glutamate (NAAG), lactate, and γ- aminobutyric acid (GABA). We will also discuss whether disrupting these reservoir cycles may be a new avenue for cancer treatment.

Keywords:  Metabolic reservoir; N-acetyl-aspartyl-glutamate (NAAG); cancer metabolism; gamma aminobutyric acid (GABA); lactate

DOI:  https://doi.org/10.1016/j.semcancer.2022.03.023
Nat Commun. 2022 Apr 06. 13(1): 1870

Citrullination of glucokinase is linked to autoimmune diabetes.

Mei-Ling Yang, Sheryl Horstman, Renelle Gee, Perrin Guyer, TuKiet T Lam, Jean Kanyo, Ana L Perdigoto, Cate Speake, Carla J Greenbaum, Aïsha Callebaut, Lut Overbergh, Richard G Kibbey, Kevan C Herold, Eddie A James, Mark J Mamula.

Inflammation, including reactive oxygen species and inflammatory cytokines in tissues amplify various post-translational modifications of self-proteins. A number of post-translational modifications have been identified as autoimmune biomarkers in the initiation and progression of Type 1 diabetes. Here we show the citrullination of pancreatic glucokinase as a result of inflammation, triggering autoimmunity and affecting glucokinase biological functions. Glucokinase is expressed in hepatocytes to regulate glycogen synthesis, and in pancreatic beta cells as a glucose sensor to initiate glycolysis and insulin signaling. We identify autoantibodies and autoreactive CD4+ T cells to glucokinase epitopes in the circulation of Type 1 diabetes patients and NOD mice. Finally, citrullination alters glucokinase biologic activity and suppresses glucose-stimulated insulin secretion. Our study define glucokinase as a Type 1 diabetes biomarker, providing new insights of how inflammation drives post-translational modifications to create both neoautoantigens and affect beta cell metabolism.

DOI: https://doi.org/10.1038/s41467-022-29512-0
Semin Cell Dev Biol. 2022 Apr 05. pii: S1084-9521(22)00116-1. [Epub ahead of print]

Endocrine control of glycogen and triacylglycerol breakdown in the fly model.

Martina Gáliková, Peter Klepsatel.

  Over the last decade, the combination of genetics, transcriptomic and proteomic approaches yielded substantial insights into the mechanisms behind the synthesis and breakdown of energy stores in the model organisms. The fruit fly Drosophila melanogaster has been particularly useful to unravel genetic regulations of energy metabolism. Despite the considerable evolutionary distance between humans and flies, the energy storage organs, main metabolic pathways, and even their genetic regulations remained relatively conserved. Glycogen and fat are universal energy reserves used in all animal phyla and several of their endocrine regulators, such as the insulin pathway, are highly evolutionarily conserved. Nevertheless, some of the factors inducing catabolism of energy stores have diverged significantly during evolution. Moreover, even within a single insect species, D. melanogaster, there are substantial developmental and context-dependent variances in the regulation of energy stores. These differences include, among others, the endocrine pathways that govern the catabolic events or the predominant fuel which is utilized for the given process. For example, many catabolic regulators that control energy reserves in adulthood seem to be largely dispensable for energy mobilization during development. In this review, we focus on a selection of the most important catabolic regulators from the group of peptide hormones (Adipokinetic hormone, Corazonin), catecholamines (octopamine), steroid hormones (20-hydroxyecdysone), and other factors (extracellular adenosine, regulators of lipase Brummer). We discuss their roles in the mobilization of energy reserves for processes such as development through non-feeding stages, flight or starvation survival. Finally, we conclude with future perspectives on the energy balance research in the fly model.

Keywords:  Carbohydrates; Catabolism; Development; Drosophila melanogaster; Lipids; Metabolism

DOI:  https://doi.org/10.1016/j.semcdb.2022.03.034
Front Pharmacol. 2022 ;13 813272

Honokiol Inhibits Atrial Metabolic Remodeling in Atrial Fibrillation Through Sirt3 Pathway.

Guang Zhong Liu, Wei Xu, Yan Xiang Zang, Qi Lou, Peng Zhou Hang, Qiang Gao, Hang Shi, Qi Yun Liu, Hong Wang, Xin Sun, Cheng Liu, Peng Zhang, Hua Dong Liu, Shao Hong Dong.

  Background and Purpose: Atrial metabolic remodeling plays a critical role in the pathogenesis of atrial fibrillation (AF). Sirtuin3 (Sirt3) plays an important role in energy homeostasis. However, the effect of Sirt3 agonist Honokiol (HL) on AF is unclear. Therefore, the aim of this study is to determine the effect of HL on atrial metabolic remodeling in AF and to explore possible mechanisms. Experimental Approach: irt3 and glycogen deposition in left atria of AF patients were examined. Twenty-one rabbits were divided into sham, P (pacing for 3 weeks), P + H treatment (honokiol injected with pacing for 3 weeks). The HL-1 cells were subjected to rapid pacing at 5 Hz for 24 h, in the presence or absence of HL and overexpression or siRNA of Sirt3 by transfection. Metabolic factors, circulating metabolites, atrial electrophysiology, ATP level, and glycogens deposition were detected. Acetylated protein and activity of its enzymes were detected. Key Results: Sirt3 was significantly down-regulated in AF patients and rabbit/HL-1cell model, resulting in the abnormal expression of its downstream metabolic key factors, which were significantly restored by HL. Meanwhile, AF induced an increase of the acetylation level in long-chain acyl-CoA dehydrogenase (LCAD), AceCS2 and GDH, following decreasing of activity of it enzymes, resulting in abnormal alterations of metabolites and reducing of ATP, which was inhibited by HL. The Sirt3 could regulate acetylated modification of key metabolic enzymes, and the increase of Sirt3 rescued AF induced atrial metabolic remodeling. Conclusion and Implications: HL inhibited atrial metabolic remodeling in AF via the Sirt3 pathway. The present study may provide a novel therapeutical strategy for AF.

Keywords:  Honokiol; acetylation; atrial fibrillation; metabolism remodeling; sirt3

DOI:  https://doi.org/10.3389/fphar.2022.813272
Endocrines. 2021 Sep;2(3): 266-283

The Physiological Role of Irisin in the Regulation of Muscle Glucose Homeostasis.

Naohiro Yano, Yu Tina Zhao, Ting C Zhao.

  Irisin is a myokine that primarily targets adipose tissue, where it increases energy expenditure and contributes to the beneficial effects of exercise through the browning of white adipose tissue. As our knowledge has deepened in recent years, muscle has been found to be a major target organ for irisin as well. Several studies have attempted to characterize the role of irisin in muscle to improve glucose metabolism through mechanisms such as reducing insulin resistance. Although they are very intriguing reports, some contradictory results make it difficult to grasp the whole picture of the action of irisin on muscle. In this review, we attempted to organize the current knowledge of the role of irisin in muscle glucose metabolism. We discussed the direct effects of irisin on glucose metabolism in three types of muscle, that is, skeletal muscle, smooth muscle, and the myocardium. We also describe irisin's effects on mitochondria and its interactions with other hormones. Furthermore, to consider the relationship between the irisin-induced improvement of glucose metabolism in muscle and systemic disorders of glucose metabolism, we reviewed the results from animal interventional studies and human clinical studies.

Keywords:  glucose homeostasis; irisin; metabolic disorders; myokine; type 2 diabetes mellitus

DOI:  https://doi.org/10.3390/endocrines2030025