bims-glecem 2023-01-15 papers

bims-glecem

Biomed News

on Glycogen metabolism in exercise, cancer and energy metabolism

Issue of 2023‒01‒15
fifteen papers selected by
Dipsikha Biswas, Københavns Universitet

Muscle Glycogen Assessment and Relationship with Body Hydration Status: A Narrative Review.
Urine-Derived Epithelial Cells as a New Model to Study Renal Metabolic Phenotypes of Patients with Glycogen Storage Disease 1a.
Polysaccharides from apple pomace exhibit anti-fatigue activity through increasing glycogen content.
Impact of hematopoietic stem cell transplantation in glycogen storage disease type Ib: A single-subject research design using 13C-glucose breath test.
The new horizons for treatment of Late-Onset Pompe Disease (LOPD).
Induced pluripotent stem cell for modeling Pompe disease.
Xanthosine, a purine glycoside mediates hepatic glucose homeostasis through inhibition of gluconeogenesis and activation of glycogenesis via regulating the AMPK/ FoxO1/AKT/GSK3β signaling cascade.
Long-Term Experience with Anaphylaxis and Desensitization to Alglucosidase Alfa in Pompe Disease.
Dysferlin Deficiency Results in Myofiber-Type Specific Differences in Abundances of Calcium-Handling and Glycogen Metabolism Proteins.
GSK3β Inhibition by Phosphorylation at Ser389 Controls Neuroinflammation.
Concanavalin A-Based Sedimentation Assay to Measure Substrate Binding of Glucan Phosphatases.
The Neurospora crassa PCL-1 cyclin is a PHO85-1 (PGOV) kinase partner that directs the complex to glycogen metabolism and is involved in calcium metabolism regulation.
Acute effects of a single moderate-intensity exercise bout performed in fast or fed states on cell metabolism and signaling: Comparison between lean and obese rats.
P-Rex1 is a novel substrate of the E3 ubiquitin ligase Malin associated with Lafora disease.
Lactate as a Myokine and Exerkine: Drivers and Signals of Physiology and Metabolism.

Nutrients. 2022 Dec 29. pii: 155. [Epub ahead of print]15(1):

Muscle Glycogen Assessment and Relationship with Body Hydration Status: A Narrative Review.

Keisuke Shiose, Hideyuki Takahashi, Yosuke Yamada.

  Muscle glycogen is a crucial energy source for exercise, and assessment of muscle glycogen storage contributes to the adequate manipulation of muscle glycogen levels in athletes before and after training and competition. Muscle biopsy is the traditional and gold standard method for measuring muscle glycogen; alternatively, 13C magnetic resonance spectroscopy (MRS) has been developed as a reliable and non-invasive method. Furthermore, outcomes of ultrasound and bioimpedance methods have been reported to change in association with muscle glycogen conditions. The physiological mechanisms underlying this activity are assumed to involve a change in water content bound to glycogen; however, the relationship between body water and stored muscle glycogen is inconclusive. In this review, we discuss currently available muscle glycogen assessment methods, focusing on 13C MRS. In addition, we consider the involvement of muscle glycogen in changes in body water content and discuss the feasibility of ultrasound and bioimpedance outcomes as indicators of muscle glycogen levels. In relation to changes in body water content associated with muscle glycogen, this review broadens the discussion on changes in body weight and body components other than body water, including fat, during carbohydrate loading. From these discussions, we highlight practical issues regarding muscle glycogen assessment and manipulation in the sports field.

Keywords:  body composition; glycogen; magnetic resonance spectroscopy; performance

DOI:  https://doi.org/10.3390/nu15010155
Int J Mol Sci. 2022 Dec 23. pii: 232. [Epub ahead of print]24(1):

Urine-Derived Epithelial Cells as a New Model to Study Renal Metabolic Phenotypes of Patients with Glycogen Storage Disease 1a.

Livia Lenzini, Elisabetta Iori, Federico Scannapieco, Gianni Carraro, Angelo Avogaro, Nicola Vitturi.

  Glycogen storage diseases (GSDs) represent a model of pathological accumulation of glycogen disease in the kidney that, in animal models, results in nephropathy due to abnormal autophagy and mitochondrial function. Patients with Glycogen Storage Disease 1a (GSD1a) accumulate glycogen in the kidneys and suffer a disease resembling diabetic nephropathy that can progress to renal failure. In this study, we addressed whether urine-derived epithelial cells (URECs) from patients with GSD1a maintain their biological features, and whether they can be used as a model to study the renal and metabolic phenotypes of this genetic condition. Studies were performed on cells extracted from urine samples of GSD1a and healthy subjects. URECs were characterized after the fourth passage by transmission electron microscopy and immunofluorescence. Reactive oxygen species (ROS), at different glucose concentrations, were measured by fluorescent staining. We cultured URECs from three patients with GSD1a and three healthy controls. At the fourth passage, URECs from GSD1a patients maintained their massive glycogen content. GSD1a and control cells showed the ciliary structures of renal tubular epithelium and the expression of epithelial (E-cadherin) and renal tubular cells (aquaporin 1 and 2) markers. Moreover, URECs from both groups responded to changes in glucose concentrations by modulating ROS levels. GSD1a cells were featured by a specific response to the low glucose stimulus, which is the condition that more resembles the metabolic derangement of patients with GSD1a. Through this study, we demonstrated that URECs might represent a promising experimental model to study the molecular mechanisms leading to renal damage in GSD1a, due to pathological glycogen storage.

Keywords:  glycogen storage disease; reactive oxygen species; urine-derived cells

DOI:  https://doi.org/10.3390/ijms24010232
J Food Sci Technol. 2023 Jan;60(1): 283-291

Polysaccharides from apple pomace exhibit anti-fatigue activity through increasing glycogen content.

Chunguang Li, Xinjun Zhu, Jingxia Zhang, Tisen Xu, Hong Zhang, Zhiping Zheng, Ramasamy Rajesh Kumar.

  The polysaccharides were isolated from apple pomace by hot-water extraction, and their anti-fatigue activity was evaluated in C2C12 muscle myoblasts and male Kunming mice. The purified polysaccharides from apple pomace (PAP) have a molecular weight of 1.74 × 105 Da and were composed of mannose, rhamnose, glucose, galactose and arabinose. In C2C12 myoblasts, PAP showed no cytotoxicity in the concentrations of 0-300 μg/ml. PAP treatment increased the glycogen content, while the ATP content was not affected in C2C12 myoblasts. Further investigation found that the activity and gene expression of glycogen synthase, rather than glycogen phosphorylase, were upregulated by PAP treatment. The studies in vivo showed that PAP treatment did not affect the food intake and weight again in mice. Importantly, PAP prolonged the exhaustive swimming time, increased hepatic and skeletal muscle glycogen levels, and effectively inhibited the accumulation of blood lactic and blood urea nitrogen in mice. Taken together, the results suggested that PAP exhibit anti-fatigue activity in vitro and in vivo through increasing glycogen content.

Keywords:  Anti-fatigue activity; Apple pomace; Glycogen content; Polysaccharides

DOI:  https://doi.org/10.1007/s13197-022-05613-y
Mol Genet Metab Rep. 2023 Mar;34 100955

Impact of hematopoietic stem cell transplantation in glycogen storage disease type Ib: A single-subject research design using 13C-glucose breath test.

Abrar Turki, Sylvia Stockler, Sandra Sirrs, Kathleen Duddy, Gloria Ho, Rajavel Elango.

  Background: Glycogen storage disease type Ib (GSD Ib) is an autosomal recessively inherited deficiency of the glucose-6-phosphate translocase (G6PT). Clinical features include a combination of a metabolic phenotype (fasting hypoglycemia, lactic acidosis, hepatomegaly) and a hematologic phenotype with neutropenia and neutrophil dysfunction. Dietary treatment involves provision of starches such as uncooked cornstarch (UCCS) and Glycosade® to provide prolonged enteral supply of glucose. Granulocyte colony-stimulating factor (G-CSF) is the treatment of choice for neutropenia. Because long-term stimulation of hematopoiesis with G-CSF causes serious complications such as splenomegaly, hypersplenism, and osteopenia; hematopoietic stem cell transplantation (HSCT) has been considered in some patients with GSD Ib to correct neutropenia and avoid G-CSF related adverse effects. Whether HSCT also has an effect on the metabolic phenotype and utilization of carbohydrate sources has not been determined.Objective: Our objective was to measure the utilization of starch in a patient with GSD Ib before and after HSCT using the minimally invasive 13C-glucose breath test (13C-GBT).
Design: A case of GSD Ib (18y; female) underwent 13C-GBT four times: UCCS (pre-HSCT), UCCS (3, 5 months post-HSCT) and Glycosade® (6 months post-HSCT) with a dose of 80 g administered via nasogastric tube after a 4 h fast according to our patient's fasting tolerance. Breath samples were collected at baseline and every 30 min for 240 min. Rate of CO2 production was measured at 120 min using indirect calorimetry. Finger-prick blood glucose was measured using a glucometer hourly to test hypoglycemia (glucose <4 mmol/L). Biochemical and clinical data were obtained from the medical records as a post-hoc chart review.
Results: UCCS utilization was significantly higher in GSD Ib pre-HSCT, which reduced and stabilized 5 months post-HSCT. UCCS and Glycosade® utilizations were low and not different at 5 and 6 months post-HSCT. Blood glucose concentrations were not significantly different at any time point.
Conclusions: Findings show that HSCT stabilized UCCS utilization, as reflected by lower and stable glucose oxidation. The results also illustrate the application of 13C-GBT to examine glucose metabolism in response to various carbohydrate sources after other treatment modalities like HSCT in GSD Ib.

Keywords:  13C-GBT, 13C-glucose breath test; 13C-glucose; ALT, alanine aminotransferase; AML, acute myeloid leukemia; ANOVA, analysis of variance; AST, aspartate aminotransferase; AUC, area under the curve; BIA, bioelectrical impedance analysis; BMI, body mass index; Breath test; CF-IRMS, continuous flow isotope ratio mass spectrometer; CGM, continuous glucose monitor; CRP, C-reactive protein; Cmax, maximum peak enrichment in 13CO2 oxidation; ER, endoplasmic reticulum; FFM, fat free mass; FM, fat mass; G-CSF, granulocyte colony-stimulating factor; G6P, glucose-6-phosphate; G6PT, glucose-6-phosphate translocase; G6Pase-ß, glucose-6-phosphatase-β; G6Pase-α, glucose-6-phosphatase-α; GGT, gamma glutamyltransferase; GSD I, glycogen storage disease type I; GSD III, glycogen storage disease type III; GSD Ia, glycogen storage disease type Ia; GSD Ib, glycogen storage disease type Ib; Glycogen storage disease type Ib; Glycosade®; HSCT/BMT, hematopoietic stem cell transplantation / bone marrow transplantation; Hematopoietic stem cell transplantation; IBD, inflammatory bowel disease; IM, intramuscular; NG, nasogastric; TBW, total body water; UCCS, uncooked cornstarch; Uncooked cornstarch; VCO2, rate of carbon dioxide production.; tmax, time to reach maximum 13CO2 oxidation

DOI:  https://doi.org/10.1016/j.ymgmr.2023.100955
Rev Neurol (Paris). 2023 Jan 04. pii: S0035-3787(22)00847-5. [Epub ahead of print]

The new horizons for treatment of Late-Onset Pompe Disease (LOPD).

C Guémy, P Laforêt.

  Late-onset Pompe disease (LOPD) is a genetic myopathy causing skeletal muscle weakness and severe respiratory impairment, due to the deficiency of the lysosomal enzyme acid alpha-glucosidase (GAA) leading to lysosomal glycogen accumulation along with other complex pathophysiological processes. A major step for treatment of Pompe disease was reached in 2006 with the marketing of alglucosidase alfa, a first enzyme replacement therapy (ERT) that showed a significant motor and respiratory benefit. However, efficacy of alglucosidase alfa is limited in LOPD with a loss of efficacy over time, promoting research on new treatments. Next-generation ERT are new enzymes biochemically modified to increase the uptake of exogenous enzyme by target tissues, and the benefit of two recombinant enzymes (avalglucosidase alfa and cipaglucosidase alfa) has been recently studied in large phase III clinical trials, the latest combined with miglustat. Several innovative therapies, based on GAA gene transfer, antisense oligonucleotides or inhibition of glycogen synthesis with substrate reduction therapy, are currently under study, but are still at an early stage of development. Overall, active research for new treatments raises hope for LOPD patients but challenges remain for the clinician with the need for reliable efficacy assessment tools, long-term registry data, and evidence-based recommendations for the best use of these new molecules recently available or under development.

Keywords:  Antisense oligonucleotides; Enzyme replacement therapy; Gene therapy; Glycogen storage disease II; Pompe disease; Substrate reduction therapy

DOI:  https://doi.org/10.1016/j.neurol.2022.12.004
Front Cardiovasc Med. 2022 ;9 1061384

Induced pluripotent stem cell for modeling Pompe disease.

Wenjun Huang, Yanmin Zhang, Rui Zhou.

  Pompe disease (PD) is a rare, autosomal recessive, inherited, and progressive metabolic disorder caused by α-glucosidase defect in lysosomes, resulting in abnormal glycogen accumulation. Patients with PD characteristically have multisystem pathological disorders, particularly hypertrophic cardiomyopathy, muscle weakness, and hepatomegaly. Although the pathogenesis and clinical outcomes of PD are well-established, disease-modeling ability, mechanism elucidation, and drug development targeting PD have been substantially limited by the unavailable PD-relevant cell models. This obstacle has been overcome with the help of induced pluripotent stem cell (iPSC) reprogramming technology, thus providing a powerful tool for cell replacement therapy, disease modeling, drug screening, and drug toxicity assessment. This review focused on the exciting achievement of PD disease modeling and mechanism exploration using iPSC.

Keywords:  GAA; Pompe disease; disease modeling; glycogen storage disease type II; induced pluripotent stem cell

DOI:  https://doi.org/10.3389/fcvm.2022.1061384
Chem Biol Interact. 2023 Jan 07. pii: S0009-2797(23)00014-5. [Epub ahead of print] 110347

Xanthosine, a purine glycoside mediates hepatic glucose homeostasis through inhibition of gluconeogenesis and activation of glycogenesis via regulating the AMPK/ FoxO1/AKT/GSK3β signaling cascade.

Semim Akhtar Ahmed, Pranamika Sarma, Sagar Ramrao Barge, Deepsikha Swargiary, Gurumayum Shalini Devi, Jagat Chandra Borah.

  Type 2 Diabetes Mellitus (T2DM) is characterized by hepatic insulin resistance, which results in increased glucose production and reduced glycogen storage in the liver. There is no previous study in the literature that has explored the role of Xanthosine in hepatic insulin resistance. Moreover, mechanistic explanation for the beneficial effects of Xanthosine in lowering glucose production in diabetes is yet to be determined. This study for the first time investigated the beneficial effects of Tribulus terrestris (TT) and its active constituent, Xanthosine on gluconeogenesis and glycogenesis in Free Fatty Acid (FFA)-induced CC1 hepatocytes and streptozotocin (STZ)-induced Wistar rats. Xanthosine enhanced glucose uptake and decreased glucose production through phosphorylation of AMP-activated protein kinase (AMPK) and forkhead box transcription factor O1 (FoxO1), and downregulation of two rate limiting enzymes of gluconeogenesis, phosphoenolpyruvate carboxykinase (PEPCK) and glucose-6-phosphatase (G6Pase) expression in FFA-induced CC1 cells. Xanthosine also prevented FFA-induced decreases in the phosphorylation of AKT/Protein kinase B, glycogen synthase kinase-3β (GSK3β), and increased glycogen synthase (GS) phosphorylation to increase the glycogen content in the hepatocytes. Moreover, in STZ-induced diabetic rats, oral administration of TT n-butanol fraction (TTBF) enriched with compound Xanthosine (10, 50 & 100 mg/kg body weight) improved insulin sensitivity, reduced fasting blood glucose levels, improved glucose homeostasis by reducing gluconeogenesis via AMPK/FoxO1-mediated PEPCK and G6Pase down-regulation and increasing glycogenesis via AKT/GSK3β-mediated GS activation. Overall, Xanthosine may be developed further for treating insulin resistance and hyperglycemia in T2DM.

Keywords:  AKT; AMPK; Gluconeogenesis; Glycogenesis; Tribulus terrestris; Type 2 diabetes; Xanthosine

DOI:  https://doi.org/10.1016/j.cbi.2023.110347
Int Arch Allergy Immunol. 2023 Jan 09. 1-6

Long-Term Experience with Anaphylaxis and Desensitization to Alglucosidase Alfa in Pompe Disease.

Gazi University Enzyme Replacement Therapy Hypersensitivity Study Group

  BACKGROUND AND OBJECTIVE: Pompe disease (PD) is an inherited lysosomal storage disease that progresses with glycogen accumulation in many tissues, due to the deficiency of the acid-alpha glucosidase enzyme. Recombinant alglucosidase alfa (rhGAA) is the only disease-specific treatment option, in the form of enzyme replacement therapy (ERT). Anaphylaxis can develop with rhGAA. There is no study evaluating anaphylaxis and its management in PD in the long term. We aimed to evaluate the development of anaphylaxis and rapid drug desensitization (RDD) with rhGAA in children with PD.MATERIALS AND METHODS: All children diagnosed and followed up in our institution with PD over 12 years between January 2009 and September 2021 were evaluated for development of anaphylaxis and RDD with rhGAA from medical records.
RESULTS: Fourteen patients, 64% of whom were female and diagnosed with PD (1 juvenile, 13 infantile types) during the study period included in the study. The median age at diagnosis was 3.2 months (1-40 months). The median follow-up time of the patients was 20 months (1-129 months). Thirteen patients were given rhGAA, one died before ERT. Four (30.8%) patients developed moderate to severe anaphylaxis, and RDD was applied with rhGAA. A total of 390 RDDs have been performed so far without any serious breakthrough reactions during all RDDs.
CONCLUSIONS: Anaphylaxis with rhGAA is not rare and RDD with rhGAA is safe and effective in the long term.

Keywords:  Anaphylaxis; Pompe disease; Rapid drug desensitization; Recombinant alglucosidase alfa

DOI:  https://doi.org/10.1159/000528343
Int J Mol Sci. 2022 Dec 21. pii: 76. [Epub ahead of print]24(1):

Dysferlin Deficiency Results in Myofiber-Type Specific Differences in Abundances of Calcium-Handling and Glycogen Metabolism Proteins.

Erin M Lloyd, Gavin J Pinniger, Miranda D Grounds, Robyn M Murphy.

  Dysferlinopathies are a clinically heterogeneous group of muscular dystrophies caused by a genetic deficiency of the membrane-associated protein dysferlin, which usually manifest post-growth in young adults. The disease is characterized by progressive skeletal muscle wasting in the limb-girdle and limbs, inflammation, accumulation of lipid droplets in slow-twitch myofibers and, in later stages, replacement of muscles by adipose tissue. Previously we reported myofiber-type specific differences in muscle contractile function of 10-month-old dysferlin-deficient BLAJ mice that could not be fully accounted for by altered myofiber-type composition. In order to further investigate these findings, we examined the impact of dysferlin deficiency on the abundance of calcium (Ca2+) handling and glucose/glycogen metabolism-related proteins in predominantly slow-twitch, oxidative soleus and fast-twitch, glycolytic extensor digitorum longus (EDL) muscles of 10-month-old wild-type (WT) C57BL/6J and dysferlin-deficient BLAJ male mice. Additionally, we compared the Ca2+ activation properties of isolated slow- and fast-twitch myofibers from 3-month-old WT and BLAJ male mice. Differences were observed for some Ca2+ handling and glucose/glycogen metabolism-related protein levels between BLAJ soleus and EDL muscles (compared with WT) that may contribute to the previously reported differences in function in these BLAJ muscles. Dysferlin deficiency did not impact glycogen content of whole muscles nor Ca2+ activation of the myofilaments, although soleus muscle from 10-month-old BLAJ mice had more glycogen than EDL muscles. These results demonstrate a further impact of dysferlin deficiency on proteins associated with excitation-contraction coupling and glycogen metabolism in skeletal muscles, potentially contributing to altered contractile function in dysferlinopathy.

Keywords:  BLAJ mouse; calcium-handling proteins; dysferlinopathy; glucose/glycogen metabolism proteins; myofiber-types; skeletal muscle contraction

DOI:  https://doi.org/10.3390/ijms24010076
Int J Mol Sci. 2022 Dec 25. pii: 337. [Epub ahead of print]24(1):

GSK3β Inhibition by Phosphorylation at Ser389 Controls Neuroinflammation.

Belen Calvo, Miriam Fernandez, Mercedes Rincon, Pedro Tranque.

  The inhibition of Glycogen Synthase Kinase 3 β (GSK3β) by Ser9 phosphorylation affects many physiological processes, including the immune response. However, the consequences of GSK3β inhibition by alternative Ser389 phosphorylation remain poorly characterized. Here we have examined neuroinflammation in GSK3β Ser389 knock-in (KI) mice, in which the phosphorylation of Ser389 GSK3β is impaired. The number of activated microglia/infiltrated macrophages, astrocytes, and infiltrated neutrophils was significantly higher in these animals compared to C57BL/6J wild-type (WT) counterparts, which suggests that the failure to inactivate GSK3β by Ser389 phosphorylation results in sustained low-grade neuroinflammation. Moreover, glial cell activation and brain infiltration of immune cells in response to lipopolysaccharide (LPS) failed in GSK3β Ser389 KI mice. Such effects were brain-specific, as peripheral immunity was not similarly affected. Additionally, phosphorylation of the IkB kinase complex (IKK) in response to LPS failed in GSK3β Ser389 KI mice, while STAT3 phosphorylation was fully conserved, suggesting that the NF-κB signaling pathway is specifically affected by this GSK3β regulatory pathway. Overall, our findings indicate that GSK3β inactivation by Ser389 phosphorylation controls the brain inflammatory response, raising the need to evaluate its role in the progression of neuroinflammatory pathologies.

Keywords:  NF-κB signaling; astrocytes; flow cytometry; microglia; neuroinflammation; neutrophils

DOI:  https://doi.org/10.3390/ijms24010337
J Vis Exp. 2022 Dec 23.

Concanavalin A-Based Sedimentation Assay to Measure Substrate Binding of Glucan Phosphatases.

Eliana M Wolpaw, Marissa L Frenett, Claudia A Mak, Sloane M Zwanger, Madushi Raththagala.

Glucan phosphatases belong to the larger family of dual specificity phosphatases (DSP) that dephosphorylate glucan substrates, such as glycogen in animals and starch in plants. The crystal structures of glucan phosphatase with model glucan substrates reveal distinct glucan-binding interfaces made of DSP and carbohydrate-binding domains. However, quantitative measurements of glucan-glucan phosphatase interactions with physiologically relevant substrates are fundamental to the biological understanding of the glucan phosphatase family of enzymes and the regulation of energy metabolism. This manuscript reports a Concanavalin A (ConA)-based in vitro sedimentation assay designed to detect the substrate binding affinity of glucan phosphatases against different glucan substrates. As a proof of concept, the dissociation constant (KD) of glucan phosphatase Arabidopsis thaliana Starch Excess4 (SEX4) and amylopectin was determined. The characterization of SEX4 mutants and other members of the glucan phosphatase family of enzymes further demonstrates the utility of this assay to assess the differential binding of protein- carbohydrate interactions. These data demonstrate the suitability of this assay to characterize a wide range of starch and glycogen interacting proteins.

DOI: https://doi.org/10.3791/64700
Front Microbiol. 2022 ;13 1078972

The Neurospora crassa PCL-1 cyclin is a PHO85-1 (PGOV) kinase partner that directs the complex to glycogen metabolism and is involved in calcium metabolism regulation.

Jonatas Erick Maimoni Campanella, Thiago de Souza Candido, Luiz Carlos Bertucci Barbosa, Antoniel Augusto Severo Gomes, Carla Andréa Leite, Erika Silva Higashi, Paula Aboud Barbugli, Marcos Roberto de Matos Fontes, Maria Célia Bertolini.

  Cyclins are a family of proteins characterized by possessing a cyclin box domain that mediates binding to cyclin dependent kinases (CDKs) partners. In this study, the search for a partner cyclin of the PHO85-1 CDK retrieved PCL-1 an ortholog of yeast Pcls (for Pho85 cyclins) that performs functions common to Pcls belonging to different cyclin families. We show here that PCL-1, as a typical cyclin, is involved in cell cycle control and cell progression. In addition, PCL-1 regulates glycogen metabolism; Δpcl-1 cells accumulate higher glycogen levels than wild-type cells and the glycogen synthase (GSN) enzyme is less phosphorylated and, therefore, more active in the mutant cells. Together with PHO85-1, PCL-1 phosphorylates in vitro GSN at the Ser636 amino acid residue. Modeling studies identified PHO85-1 and PCL-1 as a CDK/cyclin complex, with a conserved intermolecular region stabilized by hydrophobic and polar interactions. PCL-1 is also involved in calcium and NaCl stress response. Δpcl-1 cells are sensitive to high NaCl concentration; on the contrary, they grow better and overexpress calcium responsive genes under high calcium chloride concentration compared to the wild-type strain. The expression of the calcium-responsive CRZ-1 transcription factor is modulated by PCL-1, and this transcription factor seems to be less phosphorylated in Δpcl-1 cells since exhibits nuclear location in these cells in the absence of calcium. Our results show that PCL-1 locates at different cell regions suggesting that it may determine its activity by controlling its intracellular location and reveal an interesting functional divergence between yeast and filamentous fungus cyclins.

Keywords:  CDK/cyclin complex; CRZ-1 transcription factor; Neurospora crassa; protein phosphorylation; stress response

DOI:  https://doi.org/10.3389/fmicb.2022.1078972
Life Sci. 2023 Jan 09. pii: S0024-3205(22)01057-8. [Epub ahead of print] 121357

Acute effects of a single moderate-intensity exercise bout performed in fast or fed states on cell metabolism and signaling: Comparison between lean and obese rats.

Éverton Lopes Vogt, Maiza Cristina Von Dentz, Débora Santos Rocha, Jorge Felipe Argenta Model, Lucas Stahlhöfer Kowalewski, Diane Silveira, Marjoriane de Amaral, Paulo Ivo Homem de Bittencourt, Luiz Carlos Kucharski, Mauricio Krause, Anapaula Sommer Vinagre.

  AIMS: Although the benefits of exercise can be potentiated by fasting in healthy subjects, few studies evaluated the effects of this intervention on the metabolism of obese subjects. This study investigated the immediate effects of a single moderate-intensity exercise bout performed in fast or fed states on the metabolism of gastrocnemius and soleus of lean and obese rats.MAIN METHODS: Male rats received a high-fat diet (HFD) for twelve weeks to induce obesity or were fed standard diet (SD). After this period, the animals were subdivided in groups: fed and rest (FER), fed and exercise (30 min treadmill, FEE), 8 h fasted and rest (FAR) and fasted and exercise (FAE). Muscle samples were used to investigate the oxidative capacity and gene expression of AMPK, PGC1α, SIRT1, HSF1 and HSP70.
KEY FINDINGS: In relation to lean animals, obese animals' gastrocnemius glycogen decreased 60 %, triglycerides increased 31 %; glucose and alanine oxidation decreased 26 % and 38 %, respectively; in soleus, triglycerides reduced 46 % and glucose oxidation decreased 37 %. Exercise and fasting induced different effects in glycolytic and oxidative muscles of obese rats. In soleus, fasting exercise spared glycogen and increased palmitate oxidation, while in gastrocnemius, glucose oxidation increased. In obese animals' gastrocnemius, AMPK expression decreased 29 % and SIRT1 increased 28 % in relation to lean. The AMPK response was more sensitive to exercise and fasting in lean than obese rats.
SIGNIFICANCE: Exercise and fasting induced different effects on the metabolism of glycolytic and oxidative muscles of obese rats that can promote health benefits in these animals.

Keywords:  AMPK; Exercise; Fasting; Glycogen; Muscle metabolism; Obesity; SIRT1

DOI:  https://doi.org/10.1016/j.lfs.2022.121357
Neurobiol Dis. 2023 Jan 10. pii: S0969-9961(23)00012-8. [Epub ahead of print] 105998

P-Rex1 is a novel substrate of the E3 ubiquitin ligase Malin associated with Lafora disease.

L Kumarasinghe, M A Garcia-Gimeno, J Ramirez, U Mayor, J L Zugaza, P Sanz.

  Laforin and Malin are two proteins that are encoded by the genes EPM2A and EPM2B, respectively. Laforin is a glucan phosphatase and Malin is an E3-ubiquitin ligase, and these two proteins function as a complex. Mutations occurring at the level of one of the two genes lead to the accumulation of an aberrant form of glycogen meant to cluster in polyglucosans that go under the name of Lafora bodies. Individuals affected by the appearance of these polyglucosans, especially at the cerebral level, experience progressive neurodegeneration and several episodes of epilepsy leading to the manifestation of a fatal form of a rare disease called Lafora disease (LD), for which, to date, no treatment is available. Despite the different dysfunctions described for this disease, many molecular aspects still demand elucidation. An effective way to unknot some of the nodes that prevent the achievement of better knowledge of LD is to focus on the substrates that are ubiquitinated by the E3-ubiquitin ligase Malin. Some substrates have already been provided by previous studies based on protein-protein interaction techniques and have been associated with some alterations that mark the disease. In this work, we have used an unbiased alternative approach based on the activity of Malin as an E3-ubiquitin ligase. We report the discovery of novel bonafide substrates of Malin and have characterized one of them more deeply, namely PIP3-dependent Rac exchanger 1 (P-Rex1). The analysis conducted upon this substrate sets the genesis of the delineation of a molecular pathway that leads to altered glucose uptake, which could be one of the origin of the accumulation of the polyglucosans present in the disease.

Keywords:  Lafora disease; Malin; P-Rex1; Quantitative proteomics; Rac1; Ubiquitination; bioUb

DOI:  https://doi.org/10.1016/j.nbd.2023.105998
J Appl Physiol (1985). 2023 Jan 12.

Lactate as a Myokine and Exerkine: Drivers and Signals of Physiology and Metabolism.

George A Brooks, Adam D Osmond, Jose A Arevalo, Justin J Duong, Casey C Curl, Diana D Moreno-Santillan, Robert G Leija.

  No longer viewed as a metabolic waste product and cause of muscle fatigue, a contemporary view incorporates the roles of lactate in metabolism, sensing and signaling in normal as well as pathophysiological conditions. Lactate exists in millimolar concentrations in muscle, blood and other tissues and can rise more than an order of magnitude as the result of increased production and clearance limitations. Lactate exerts its powerful driver-like influence by mass action, redox change, allosteric binding, and other mechanisms described in this article. Depending on the condition, such as during rest and exercise, following injury, or pathology, lactate can serve as a myokine or exerkine with autocrine-, paracrine-, and endocrine-like functions that have important basic and translational implications. For instance, lactate signaling is: involved in reproductive biology, fueling the heart, muscle and brain, controlling cardiac output and breathing, growth and development, and a treatment for inflammatory conditions. Ironically, lactate can be disruptive of normal processes such as insulin secretion when insertion of lactate transporters into pancreatic Beta-cell membranes is not suppressed and in carcinogenesis. Lactate signaling is important in areas of intermediary metabolism, redox biology, mitochondrial biogenesis, cardiovascular and pulmonary regulation, genomics, neurobiology, gut physiology, appetite regulation, nutrition and overall health and vigor. The various roles of lactate as a myokine and exerkine are reviewed.

Keywords:  Glucose; Glycogen Paradox; Lactate Shuttle; Metabolic Signalling; Physiological Regulation

DOI:  https://doi.org/10.1152/japplphysiol.00497.2022