bims-glecem 2022-05-08 papers

bims-glecem

Biomed News

on Glycogen metabolism in exercise, cancer and energy metabolism

Issue of 2022–05–08
thirteen papers selected by
Dipsikha Biswas, Københavns Universitet

Regulatory phosphorylation event of Phosphoglucomutase 1 tunes its activity to regulate glycogen metabolism.
The expression of HSP70 in skeletal muscle is not associated with glycogen availability during recovery following prolonged exercise in elite endurance athletes.
[Progress in the role of endometrial glucose metabolism in embryo implantation].
Effects of a Very High-Carbohydrate Diet and Endurance Exercise Training on Pancreatic Amylase Activity and Intestinal Glucose Transporter Content in Rats.
Effect of Trehalose on Oligomeric State and Anti-Aggregation Activity of αB-Crystallin.
PLK2 targets GSK3β to protect against cisplatin-induced acute kidney injury.
Efficacy and safety of empagliflozin in glycogen storage disease type Ib: Data from an international questionnaire.
Lariciresinol displays anti-diabetic activity through inhibition of α-glucosidase and activation and enhancement of insulin signaling.
Prejuveniles of Mugil liza (Actinopterygii; Fam. Mugilidae) show digestive and metabolic flexibility upon different postprandial times and refeeding.
Riluzole Promotes Neurite Growth in Rats after Spinal Cord Injury through the GSK-3β/CRMP-2 Pathway.
Comparative Genomics of Members of the Genus Defluviicoccus With Insights Into Their Ecophysiological Importance.
Understanding the Correlation between Metabolic Regulator SIRT1 and Exosomes with CA-125 in Ovarian Cancer: A Clinicopathological Study.
Electrical stimulated GLUT4 signalling attenuates critical illness-associated muscle wasting.

FEBS J. 2022 May 04.

Regulatory phosphorylation event of Phosphoglucomutase 1 tunes its activity to regulate glycogen metabolism.

Sofía Doello, Niels Neumann, Karl Forchhammer.

  Regulation of glycogen metabolism is of vital importance in organisms of all three kingdoms of life. Although the pathways involved in glycogen synthesis and degradation are well known, many regulatory aspects around the metabolism of this polysaccharide remain undeciphered. Here, we used the unicellular cyanobacterium Synechocystis as a model to investigate how glycogen metabolism is regulated in nitrogen-starved dormant cells, which entirely rely on glycogen catabolism to resume growth upon nitrogen repletion. We identified phosphoglucomutase 1 (PGM1) as a key regulatory point in glycogen metabolism, and post-translational modification as an essential mechanism for controlling its activity. We could show that PGM1 is phosphorylated at a residue in the regulatory latch domain (Ser 47) during nitrogen starvation, which inhibits its activity. Inactivation of PGM1 by phosphorylation at Ser 47 prevents premature degradation of the glycogen stores and appears to be essential for survival of Synechocystis in the dormant state. Remarkably, this regulatory mechanism seems to be evolutionary conserved in PGM1 enzymes, from bacteria to humans.

Keywords:  carbon metabolism; cyanobacteria; glycogen; phosphoglucomutase; phosphorylation

DOI:  https://doi.org/10.1111/febs.16471
Eur J Appl Physiol. 2022 May 05.

The expression of HSP70 in skeletal muscle is not associated with glycogen availability during recovery following prolonged exercise in elite endurance athletes.

Line B Dalgaard, Niels Ørtenblad, Lars G Hvid, Kasper D Gejl.

  The 70-kDa heat shock protein (HSP70) is a ubiquitous molecular chaperone which is highly inducible by cellular stress such as exercise. To investigate the role of muscle glycogen content on the HSP70 expression, muscle glycogen was manipulated by consumption of either water (H2O) or a carbohydrate-enriched diet (CHO) during recovery from 4 h of glycogen-depleting cycling exercise in fourteen elite endurance athletes. Muscle biopsies were obtained pre- and post-exercise, and after 4 and 24 h of recovery, and analyzed for HSP70 mRNA expression, as well as HSP70 protein expression and muscle glycogen within the same skeletal muscle fibers using immunohistochemistry. Exercise reduced glycogen by 59 ± 10% (P < 0.0001). After 4 h of recovery, glycogen approached resting levels in the CHO group (86% of pre, P = 0.28) but remained suppressed in the H2O group (41% of pre, P < 0.001) (group × time interaction: P = 0.002). Importantly, both the HSP70 mRNA (+ 1.6-fold (+ 0.28/- 0.24), P = 0.02) and protein expression (+ 147 ± 99%, P < 0.0001) was substantially increased after exercise and remained elevated in both groups after 4 h of recovery, despite clear differences in muscle glycogen content. Thus, muscle glycogen content was not related to the variation in single fiber HSP70 expression at the 4-h time-point (r2 = 0.004). In conclusion, muscle HSP70 expression remained elevated during recovery from prolonged exercise in highly trained skeletal muscle, irrespective of muscle glycogen availability.

Keywords:  Endurance exercise; Glycogen; HSP70; Metabolic stress; Recovery

DOI:  https://doi.org/10.1007/s00421-022-04955-x
Sheng Li Xue Bao. 2022 Apr 25. 74(2): 255-264

[Progress in the role of endometrial glucose metabolism in embryo implantation].

Yong-Dan Ma, Yi-Cheng Wang, Li-Min Yue.

The synthesis and decomposition of glycogen adjust the blood glucose dynamically to maintain the energy supply required by the cells. As the only hormone that lowers blood sugar in the body, insulin can promote glycogen synthesis by activating the phosphatidylinositol 3-kinase (PI3K)/protein kinase B (Akt) signaling pathway and increasing glucose transporter translocation, and inhibit gluconeogenesis to lower blood glucose. In the endometrium, glycogen metabolism is active, but gluconeogenesis does not occur. The glycogen metabolism in the endometrium is controlled not only by the classical glucose regulating hormones, but also by the ovarian hormones. The functional activities related to implantation of the endometrium during the implantation window require glucose as energy source. A large amount of glucose is used to synthesize glycogen in the endometrium before implantation, which could meet the increased energy demand for embryo implantation. In diabetes, glycogen metabolism in the endometrium is impaired, which frequently leads to implantation failure and early abortion. This article reviews the glycogen metabolism in the endometrium and discusses its role in embryo implantation, which provide new ideas for embryo implantation research and infertility treatment.
J Nutr Sci Vitaminol (Tokyo). 2022 ;68(2): 97-103

Effects of a Very High-Carbohydrate Diet and Endurance Exercise Training on Pancreatic Amylase Activity and Intestinal Glucose Transporter Content in Rats.

Saki Kondo, Takuya Karasawa, Ayumi Fukazawa, Atsuko Koike, Momoko Tsutsui, Shin Terada.

  We previously reported that the combination of a very high-carbohydrate diet and endurance training increased glucose transporter 4 and glycogen concentration in skeletal muscle. However, it remains unclear whether they also affect the digestive and absorptive capacity in the pancreas and small intestine, which are suggested to be rate-limiting steps in the delivery of exogenous carbohydrates to skeletal muscle and muscle glycogen synthesis. Thus, we aimed to evaluate the effects of a very high-carbohydrate diet and endurance training on pancreatic amylase activity and intestinal glucose transporters in rats and to examine the relationship between these adaptations and their influence on muscle glycogen concentration. Male Sprague-Dawley rats (n=29) were fed a high-carbohydrate diet (59% carbohydrate) or a very high-carbohydrate diet (76% carbohydrate) for 4 wk. Half of the rats in each dietary group were subjected to 6-h swimming exercise training (two 3-h sessions separated by 45 min of rest) for 4 wk. Although there was no significant effect of diet or endurance training on sodium-dependent glucose transporter 1 and glucose transporter 2 contents in the intestine, the rats fed a very high-carbohydrate diet in combination with endurance training had substantially higher pancreatic amylase activity and muscle glycogen concentration. Furthermore, there was a positive correlation between pancreatic amylase activity and muscle glycogen concentration (r=0.599, p=0.001). In conclusion, intake of a very high-carbohydrate diet and endurance training synergistically elevated carbohydrate digestive capacity, which partially accounted for the higher muscle glycogen accumulation.

Keywords:  GLUT2; SGLT1; amylase; exercise training; glycogen; pancreas; skeletal muscle; small intestine; very high-carbohydrate diet

DOI:  https://doi.org/10.3177/jnsv.68.97
Biochemistry (Mosc). 2022 Feb;87(2): 121-130

Effect of Trehalose on Oligomeric State and Anti-Aggregation Activity of αB-Crystallin.

Natalia A Chebotareva, Tatiana B Eronina, Valeriya V Mikhaylova, Svetlana G Roman, Kristina V Tugaeva, Boris I Kurganov.

  αB-Crystallin (αB-Cr), one of the main crystalline lens proteins, along with other crystallins maintains lens transparency suppressing protein aggregation and thus preventing cataractogenesis. αB-Cr belongs to the class of molecular chaperones; being expressed in many tissues it has a dynamic quaternary structure, which is essential for its chaperone-like activity. Shift in the equilibrium between ensembles of oligomers of different size allows regulating the chaperone activity. Trehalose is known to inhibit protein aggregation in vivo and in vitro, and it is widely used in biotechnology. The results of studying the effect of trehalose on the chaperone-like activity of crystallins can serve as a basis for the design of drugs delaying cataractogenesis. We have studied the trehalose effect on the quaternary structure and anti-aggregation activity of αB-Cr using muscle glycogen phosphorylase b (Phb) as a target protein. According to the dynamic light scattering data, trehalose affects the nucleation stage of Phb thermal aggregation at 48°C, and an increase in the αB-Cr adsorption capacity (AC0) is the main effect of trehalose on the aggregation process in the presence of the protein chaperone (AC0 increases 1.5-fold in the presence of 66 mM trehalose). According to the sedimentation analysis data, trehalose stabilizes the dimeric form of Phb at the stages of denaturation and dissociation and enhances the interaction of αB-Cr with the target protein. Moreover, trehalose shifts the equilibrium between the αB-Cr oligomers towards the smaller forms. Thus, trehalose affects the quaternary structure of αB-Cr and increases its anti-aggregation activity at the nucleation stage.

Keywords:  analytical ultracentrifugation; anti-aggregation activity; dynamic light scattering; glycogen phosphorylase b; trehalose; αB-crystallin

DOI:  https://doi.org/10.1134/S0006297922020043
Exp Cell Res. 2022 May 03. pii: S0014-4827(22)00174-4. [Epub ahead of print] 113181

PLK2 targets GSK3β to protect against cisplatin-induced acute kidney injury.

Xiaona Wei, Jianping Wu, Jiajia Li, Qiongqiong Yang.

  Cisplatin-induced acute kidney injury (AKI), which is accompanied by a rapid decline in renal function and a high risk of death, is a complex critical illness with no effective or specific treatment. Polo-like kinase 2 (PLK2), a serine/threonine kinase, is involved in the progression of multiple diseases, including cancers, cardiac fibrosis, diabetic nephropathy, etc. Here, by integrating two Gene Expression Omnibus (GEO) datasets of cisplatin-induced AKI animal models, we identified PLK2 as a significantly up-regulated gene in AKI renal tissues, which was then verified in different AKI animal models and cell models. Suppressing PLK2 using siRNAs or inhibitors could enhance cisplatin-induced AKI by inducing severe apoptosis and oxidative stress damage, while enforced PLK2 expression could prevent renal dysfunction induced by cisplatin. We further discovered that PLK2 might phosphorylate glycogen synthase kinase 3β (GSK3β) in the pathogenesis of AKI. In conclusion, our results show that PLK2 play a protective role in cisplatin-induced AKI and may be a new protective target of cisplatin nephrotoxicity.

Keywords:  Acute kidney injury; Apoptosis; Cisplatin; Glycogen synthase kinase 3β; Oxidative stress; Polo-like kinase 2

DOI:  https://doi.org/10.1016/j.yexcr.2022.113181
Genet Med. 2022 May 02. pii: S1098-3600(22)00718-3. [Epub ahead of print]

Efficacy and safety of empagliflozin in glycogen storage disease type Ib: Data from an international questionnaire.

Sarah C Grünert, Terry G J Derks, Katarina Adrian, Khalid Al-Thihli, Diana Ballhausen, Joanna Bidiuk, Andrea Bordugo, Monica Boyer, Drago Bratkovic, Michaela Brunner-Krainz, Alberto Burlina, Anupam Chakrapani, Willemijn Corpeleijn, Alison Cozens, Charlotte Dawson, Helena Dhamko, Maja Djordjevic Milosevic, Hernan Eiroa, Yael Finezilber, Carolina Fischinger Moura de Souza, Maria Concepción Garcia-Jiménez, Serena Gasperini, Dorothea Haas, Johannes Häberle, Rebecca Halligan, Law Hiu Fung, Alexandra Hörbe-Blindt, Laura Maria Horka, Martina Huemer, Sema Kalkan Uçar, Bozica Kecman, Sebile Kilavuz, Gergely Kriván, Martin Lindner, Natalia Lüsebrink, Konstantinos Makrilkakis, Anne Mei-Kwun Kwok, Esther M Maier, Arianna Maiorana, Shawn E McCandless, John James Mitchell, Hiroshi Mizumoto, Helen Mundy, Carlos Ochoa, Kathryn Pierce, Pilar Quijada Fraile, Debra Regier, Alessandro Rossi, René Santer, Hester C Schuman, Piotr Sobieraj, Johannes Spenger, Ronen Spiegel, Karolina M Stepien, Galit Tal, Mojca Zerjav Tanšek, Ana Drole Torkar, Michel Tchan, Santhosh Thyagu, Samantha A Schrier Vergano, Erika Vucko, Natalie Weinhold, Petra Zsidegh, Saskia B Wortmann.

   PURPOSE: This paper aims to report collective information on safety and efficacy of empagliflozin drug repurposing in individuals with glycogen storage disease type Ib (GSD Ib).
METHODS: This is an international retrospective questionnaire study on the safety and efficacy of empagliflozin use for management of neutropenia/neutrophil dysfunction in patients with GSD Ib, conducted among the respective health care providers from 24 countries across the globe.
RESULTS: Clinical data from 112 individuals with GSD Ib were evaluated, representing a total of 94 treatment years. The median age at start of empagliflozin treatment was 10.5 years (range = 0-38 years). Empagliflozin showed positive effects on all neutrophil dysfunction-related symptoms, including oral and urogenital mucosal lesions, recurrent infections, skin abscesses, inflammatory bowel disease, and anemia. Before initiating empagliflozin, most patients with GSD Ib were on G-CSF (94/112; 84%). At the time of the survey, 49 of 89 (55%) patients previously treated with G-CSF had completely stopped G-CSF, and another 15 (17%) were able to reduce the dose. The most common adverse event during empagliflozin treatment was hypoglycemia, occurring in 18% of individuals.
CONCLUSION: Empagliflozin has a favorable effect on neutropenia/neutrophil dysfunction-related symptoms and safety profile in individuals with GSD Ib.

Keywords:  GSD Ib; Glycogen storage disease type Ib; Neutropenia; SGLT2 inhibitors; SLC37A4

DOI:  https://doi.org/10.1016/j.gim.2022.04.001
Mol Nutr Food Res. 2022 May 01. e2100751

Lariciresinol displays anti-diabetic activity through inhibition of α-glucosidase and activation and enhancement of insulin signaling.

Md Badrul Alam, Jeong-Sic Ra, Ji-Young Lim, Bo-Rim Song, Ahsan Javed, Sang-Han Lee.

   SCOPE: The aim of this study was to investigate the antidiabetic effect of lariciresinol (LSR) in C2C12 myotubes and STZ-induced diabetic mice.
METHODS AND RESULTS: To investigate antidiabetic potential of LSR, α-glucosidase inhibitory assay, molecular docking, glucose uptake assay, western blot assay on antidiabetic biomarkers were performed. STZ-induced diabetic model was used for in vivo study by calculating oral glucose tolerance test, histochemical examination, and glycogen assay. LSR inhibited α-glucosidase activity with an IC50 value of 6.97 ± 0.37 μM and acts as a competitive inhibitor with an inhibitory constant (Ki) value of 0.046 μM. In C2C12 cells, LSR activated insulin signaling leading to glucose transporter 4 (GLUT4) translocation and augmented glucose uptake. Furthermore, in Streptozotocin (STZ)-treated diabetic mice, three weeks of oral LSR administration (10 mg kg-1 ) considerably decreased blood glucose levels, while increasing insulin levels in an oral glucose tolerance test, improved pancreatic islet size, increased GLUT4 expression, and significantly enhanced insulin signaling in skeletal muscle. LSR treatment also activated GSK-3β resulting in improved glycogen content.
CONCLUSION: Our findings indicate a potential usefulness for oral LSR in the management and prevention of diabetes by enhancing glucose homeostasis. This article is protected by copyright. All rights reserved.

Keywords:  GLUT4; glycogen; insulin receptor substrate 1; lariciresinol; α-glucosidase

DOI:  https://doi.org/10.1002/mnfr.202100751
J Comp Physiol B. 2022 May 05.

Prejuveniles of Mugil liza (Actinopterygii; Fam. Mugilidae) show digestive and metabolic flexibility upon different postprandial times and refeeding.

Albanesi Camila, González-Castro Mariano, López-Mañanes Alejandra.

  Many animals face periods of feeding restrictions implying fasting and refeeding. The determination of digestive/metabolic and body condition parameters at different times of food deprivation and after refeeding allows to evaluate the postprandial dynamics, the transition from feeding to fasting and the capacity to reverse digestive and metabolic alterations. In spite of its physiological importance, studies on estuarine-dependent detritivore fish are lacking. We determined total mass (TM), relative intestine length (RIL), hepatosomatic index (HSI), digestive enzymes activities in the intestine and energy reserves in liver and muscle at 0, 24, 72, 144 and 240 h after feeding and at 72 h after refeeding in prejuveniles of Mugil liza (Mugilidae) as a model species. After feeding, a decrease occurred in: TM (144 h, 25%), RIL (144 h, 23%); amylase and maltase (72 h, 45 and 35%), sucrase (24 h, 40%) and lipase (24 h, 70%) in intestine; glycogen and free glucose (72 h, 90 and 92%) in liver. In muscle, glycogen (72-144 h) and free glucose (144 h) (170% and 165%, respectively) peak increased; triglycerides decreased at 24-240 h (50%). After refeeding TM, RIL, carbohydrases activities in intestine, glycogen and free glucose in liver were recovered. In muscle, glycogen and free glucose were similar to 0 h; lipase activity and triglycerides were not recovered. Trypsin and APN in intestine, triglycerides in liver, protein in liver and muscle and HSI did not change. The differential modulation of key components of carbohydrates and lipid metabolism after feeding/refeeding would allow to face fasting and recover body condition. Our results improve lacking knowledge about digestive and metabolic physiology of detritivore fish.

Keywords:  Detritivore fish; Digestive enzymes; Energy reserves; Feeding; Mugil liza

DOI:  https://doi.org/10.1007/s00360-022-01438-5
Biol Pharm Bull. 2022 ;45(5): 569-575

Riluzole Promotes Neurite Growth in Rats after Spinal Cord Injury through the GSK-3β/CRMP-2 Pathway.

Songjie Xu, Qichao Wu, Wenkai Zhang, Tao Liu, Yanjun Zhang, Wenxiu Zhang, Yan Zhang, Xueming Chen.

  Spinal cord injury (SCI) is a disastrous event that often leads to permanent neurological deficits involving motor, sensory, and autonomic dysfunctions in patients. Accumulating research has demonstrated that riluzole may play crucial roles in the process of spinal tissue repair, but the underlying mechanisms remain elusive. This study verified the effectiveness of riluzole and speculated that a riluzole-afforded protection mechanism may be associated with the glycogen synthase kinase-3 beta (GSK-3β)/collapsin response mediator protein-2 (CRMP-2) pathway in rats after spinal cord injury. Here, a modified Allen's weight dropping model was generated and riluzole at 4 mg/kg was injected intraperitoneally after surgery and twice a day for 7 consecutive days. At 6 weeks after SCI, we found that riluzole treatment reduced the central cavity size of the spinal cord and improved neurological functions. Meanwhile, riluzole-treated rats exhibited shorter latency and larger amplitude in motor evoked potentials and somatosensory evoked potentials, compared with vehicle-treated rats. Furthermore, Western blotting and immunofluorescence data revealed that the expression levels of GSK-3β and phosphorylated-GSK-3β were lower in riluzole-treated SCI rats compared with vehicle-treated rats. We next detected the expression CRMP-2 and phosphorylated CRMP-2 and found that the expression of CRMP-2 showed no difference between the riluzole-treated and vehicle-treated groups; however, administration of riluzole downregulated phosphorylated CRMP-2 expression. The current findings suggest that after SCI, administration of riluzole promotes neurological functional restoration, which may be associated, in part, with its activation of the GSK-3β/CRMP-2 signaling pathway.

Keywords:  collapsin response mediator protein-2; glycogen synthase kinase-3 beta; neurofilament; riluzole; spinal cord injury

DOI:  https://doi.org/10.1248/bpb.b21-00693
Front Microbiol. 2022 ;13 834906

Comparative Genomics of Members of the Genus Defluviicoccus With Insights Into Their Ecophysiological Importance.

Irina Bessarab, Abdul Majid Maszenan, Mindia A S Haryono, Krithika Arumugam, Nay Min Min Thaw Saw, Robert J Seviour, Rohan B H Williams.

  Members of the genus Defluviicoccus occur often at high abundances in activated sludge wastewater treatment plants designed to remove phosphorus, where biomass is subjected to alternating anaerobic feed/aerobic famine conditions, believed to favor the proliferation of organisms like Ca. Accumulibacter and other phosphate-accumulating organisms (PAO), and Defluviicoccus. All have a capacity to assimilate readily metabolizable substrates and store them intracellularly during the anaerobic feed stage so that under the subsequent famine aerobic stage, these can be used to synthesize polyphosphate reserves by the PAO and glycogen by Defluviicoccus. Consequently, Defluviicoccus is described as a glycogen-accumulating organism or GAO. Because they share a similar anaerobic phenotype, it has been proposed that at high Defluviicoccus abundance, the PAO are out-competed for assimilable metabolites anaerobically, and hence aerobic P removal capacity is reduced. Several Defluviicoccus whole genome sequences have been published (Ca. Defluviicoccus tetraformis, Defluviicoccus GAO-HK, and Ca. Defluviicoccus seviourii). The available genomic data of these suggest marked metabolic differences between them, some of which have ecophysiological implications. Here, we describe the whole genome sequence of the type strain Defluviicoccus vanusT , the only cultured member of this genus, and a detailed comparative re-examination of all extant Defluviicoccus genomes. Each, with one exception, which appears not to be a member of this genus, contains the genes expected of GAO members, in possessing multiple copies of those for glycogen biosynthesis and catabolism, and anaerobic polyhydroxyalkanoate (PHA) synthesis. Both 16S rRNA and genome sequence data suggest that the current recognition of four clades is insufficient to embrace their phylogenetic biodiversity, but do not support the view that they should be re-classified into families other than their existing location in the Rhodospirillaceae. As expected, considerable variations were seen in the presence and numbers of genes encoding properties associated with key substrate assimilation and metabolic pathways. Two genomes also carried the pit gene for synthesis of the low-affinity phosphate transport protein, pit, considered by many to distinguish all PAO from GAO. The data re-emphasize the risks associated with extrapolating the data generated from a single Defluviicoccus population to embrace all members of that genus.

Keywords:  Defluviicoccus; Defluviicoccus vanus; activated sludge; enhanced biological phosphorus removal (EBPR); glycogen accumulating organisms

DOI:  https://doi.org/10.3389/fmicb.2022.834906
Biomed Res Int. 2022 ;2022 5346091

Understanding the Correlation between Metabolic Regulator SIRT1 and Exosomes with CA-125 in Ovarian Cancer: A Clinicopathological Study.

Sraddhya Roy, Ananya Das, Manisha Vernekar, Syamsundar Mandal, Nabanita Chatterjee.

Background: Ovarian cancer (OvCa), the deadliest gynaecological malignancy, is associated with poor prognosis and high mortality rate. Ovarian cancer has been related with CA-125 and metabolic reprogramming by SIRT1 leading to metastasis with the involvement of exosomes.
Methods: Clinicopathological data of OvCa patients were collected to perform the analysis. Patients' samples were collected during surgery for immunohistochemistry and flow cytometric analysis of SIRT1, HIF-1α, exosomal markers (CD81 and CD63), ki-67, and PAS staining for glycogen deposition. Adjacent normal and tumor tissues were collected as per the CA-125 levels.
Results: CA-125, a vital diagnostic marker, has shown significant correlation with body mass index (BMI) (P = 0.0153), tumor type (P = 0.0029), ascites level, ascites malignancy, degree of dissemination, tumor differentiation, FIGO stage, TNM stage, laterality, and tumor size at P < 0.0001. Since significant correlation was associated with BMI and degree of dissemination, as disclosed by IHC analysis, metabolic marker SIRT1 (P = 0.0003), HIF-1α (P < 0.0001), exosomal marker CD81 (P < 0.0001), ki-67 status (P = 0.0034), and glycogen deposition (P <0.0001) were expressed more in tumor tissues as compared to the normal ones. ROC analysis of CA-125 had shown 327.7 U/ml has the best cutoff point with 82.4% sensitivity and specificity of 52.3%. In addition, Kaplan-Meier plots of CA-125 (P < 0.0001), BMI (P = 0.001), degree of dissemination (P < 0.0001), and ascites level (P <0.0001) reflected significant correlation with overall survival (OS). Upon multivariate Cox-regression analysis for overall survival (OS), BMI (P = 0.008, HR 1.759, 95% CI 1.156-2.677), ascites malignancy (P = 0.032, HR 0.336, 95% CI 0.124-0.911), and degree of dissemination (P = 0.004, HR 1.994, 95% CI 1.251-3.178) were significant proving to be independent indicators of the disease.
Conclusion: Clinicopathological parameters like BMI, degree of dissemination, and ascites level along with CA-125 can be prognostic factors for the disease. Levels of CA-125 can depict the metabolic and metastatic factors. Thus, by targeting SIRT1 and assessing exosomal concentrations to overcome metastasis and glycogen deposition, individualized treatment strategy could be designed. In-depth studies are still required.

DOI: https://doi.org/10.1155/2022/5346091
J Cachexia Sarcopenia Muscle. 2022 May 03.

Electrical stimulated GLUT4 signalling attenuates critical illness-associated muscle wasting.

Alex B Addinsall, Nicola Cacciani, Anders Backéus, Yvette Hedström, Ganna Shevchenko, Jonas Bergquist, Lars Larsson.

   BACKGROUND: Critical illness myopathy (CIM) is a debilitating condition characterized by the preferential loss of the motor protein myosin. CIM is a by-product of critical care, attributed to impaired recovery, long-term complications, and mortality. CIM pathophysiology is complex, heterogeneous and remains incompletely understood; however, loss of mechanical stimuli contributes to critical illness-associated muscle atrophy and weakness. Passive mechanical loading and electrical stimulation (ES) therapies augment muscle mass and function. While having beneficial outcomes, the mechanistic underpinning of these therapies is less known. Therefore, here we aimed to assess the mechanism by which chronic supramaximal ES ameliorates CIM in a unique experimental rat model of critical care.
METHODS: Rats were subjected to 8 days of critical care conditions entailing deep sedation, controlled mechanical ventilation, and immobilization with and without direct soleus ES. Muscle size and function were assessed at the single cell level. RNAseq and western blotting were employed to understand the mechanisms driving ES muscle outcomes in CIM.
RESULTS: Following 8 days of controlled mechanical ventilation and immobilization, soleus muscle mass, myosin : actin ratio, and single muscle fibre maximum force normalized to cross-sectional area (CSA; specific force) were reduced by 40-50% (P < 0.0001). ES significantly reduced the loss of soleus muscle fibre CSA and myosin : actin ratio by approximately 30% (P < 0.05) yet failed to effect specific force. RNAseq pathway analysis revealed downregulation of insulin signalling in the soleus muscle following critical care, and GLUT4 trafficking was reduced by 55% leading to an 85% reduction of muscle glycogen content (P < 0.01). ES promoted phosphofructokinase and insulin signalling pathways to control levels (P < 0.05), consistent with the maintenance of GLUT4 translocation and glycogen levels. AMPK, but not AKT, signalling pathway was stimulated following ES, where the downstream target TBC1D4 increased 3 logFC (P = 0.029) and AMPK-specific P-TBC1D4 levels were increased approximately two-fold (P = 0.06). Reduction of muscle protein degradation rather than increased synthesis promoted soleus CSA, as ES reduced E3 ubiquitin proteins, Atrogin-1 (P = 0.006) and MuRF1 (P = 0.08) by approximately 50%, downstream of AMPK-FoxO3.
CONCLUSIONS: ES maintained GLUT4 translocation through increased AMPK-TBC1D4 signalling leading to improved muscle glucose homeostasis. Soleus CSA and myosin content was promoted through reduced protein degradation via AMPK-FoxO3 E3 ligases, Atrogin-1 and MuRF1. These results demonstrate chronic supramaximal ES reduces critical care associated muscle wasting, preserved glucose signalling, and reduced muscle protein degradation in CIM.

Keywords:  Critical illness myopathy; E3 ligase; GLUT4 signalling; Muscle wasting; TBC1D4

DOI:  https://doi.org/10.1002/jcsm.12978