bims-glecem 2023-03-05 papers

bims-glecem

Biomed News

on Glycogen metabolism in exercise, cancer and energy metabolism

Issue of 2023–03–05
eight papers selected by
Dipsikha Biswas, Københavns Universitet

Immune dysregulation in Glycogen Storage Disease 1b - a CyTOF approach.
Severe Liver Injury Secondary to COVID-19-Induced Rhabdomyolysis in McArdle Disease.
Enzyme Replacement Therapy (ERT) on Heart Function Changes the Outcome in Patients with Infantile-Onset Pompe Disease: A Familial History.
Outside the fiber: Endomysial stromal and capillary pathology in skeletal muscle may impede infusion therapy in infantile-onset Pompe disease.
Acanthopanax trifoliatus (L.) Merr polysaccharides ameliorates hyperglycemia by regulating hepatic glycogen metabolism in type 2 diabetic mice.
High-sucrose diet-fed male rats show affectations in pubococcygeus reflex activation and myofiber content.
Generation and comprehensive analysis of Synechococcus elongatus-Aspergillus nidulans co-culture system for polyketide production.
Carbohydrate-Protein drink is effective for restoring endurance capacity in masters class athletes after a two-Hour recovery.

Res Sq. 2023 Feb 23. pii: rs.3.rs-2598829. [Epub ahead of print]

Immune dysregulation in Glycogen Storage Disease 1b - a CyTOF approach.

Arne Gehlhaar, Dror Shouval, Eduardo Gonzalez Santiago, Galina Ling, Blake McCourt, Lael Werner, Baruch Yerushalmi, Liza Konnikova.

Glycogen Storage Disease type 1b (GSD1b) is a rare disease manifesting as hypoglycemia, recurrent infections and neutropenia, resulting from deleterious mutations in the SLC37A4 gene encoding the glucose-6-phosphate transporter. The susceptibility to infections is thought to be attributed not only to the neutrophil defect, though extensive immunophenotyping characterization is currently missing. Here we apply a systems immunology approach utilizing Cytometry by Time Of Flight (CyTOF) to map the peripheral immune landscape of 6 GSD1b patients. When compared to control subjects, those with GSD1b had a significant reduction in anti-inflammatory macrophages, CD16 + macrophages, and Natural Killer cells. Additionally, there was a preference towards a central versus an effector memory phenotype in multiple T cell populations, which may suggest that these changes stem from an inability of activated immune cell populations to undergo the appropriate switch to glycolytic metabolism in the hypoglycemic conditions associated with GSD1b. Furthermore, we identified a global reduction of CD123, CD14, CCR4, CD24 and CD11b across several populations and a multi-cluster upregulation of CXCR3, hinting at a potential role of impaired immune cell trafficking in the context of GSD1b. Taken together, our data indicates that that the immune impairment observed in GSD1b patients extends far beyond neutropenia and encompasses innate and adaptive compartments, which may provide novel insights into the pathogenesis of this disorder.

DOI: https://doi.org/10.21203/rs.3.rs-2598829/v1
Cureus. 2023 Jan;15(1): e34160

Severe Liver Injury Secondary to COVID-19-Induced Rhabdomyolysis in McArdle Disease.

Ana P Urena Neme, Carol Fernandez Hazim, Gustavo Duarte, Michael Victoria Guerrero, Miguel A Rodriguez Guerra.

  Severe liver injury is an uncommon condition caused by non-traumatic rhabdomyolysis. This rare correlation is more commonly seen in the aspartate aminotransferase (AST) than in the alanine transaminase (ALT) level elevation. We report a case of a 27-year-old male with a history of McArdle disease who presented with generalized muscle aches associated with dark urine. His workup showed SARS-CoV-2 positive, severe rhabdomyolysis (creatinine kinase [CK] > 40000 U/L) and acute kidney injury (AKI) followed by severe liver injury (AST/ALT: 2122/383 U/L). He was started on aggressive intravenous hydration. After multiple boluses, he became overloaded, fluids were re-adjusted and continued, his renal function, CK, and liver enzymes improved, and the patient was discharged; during his visit at the post-discharge, the patient was asymptomatic and no clinical or laboratory abnormalities were found. The glycogen storage diseases are challenging, but prompt and accurate assessment is determinant in recognizing potential life-threatening complications of SARS-CoV-2. The failure to identify complicated rhabdomyolysis could lead to the patient's rapid deterioration, ending in multiorgan failure.

Keywords:  acute liver failure (alf); aki outcome; covid 19; glycogen storage disorder; mcardle disease; rhabdomyolysis; sars covid-19

DOI:  https://doi.org/10.7759/cureus.34160
Case Rep Pediatr. 2023 ;2023 8470341

Enzyme Replacement Therapy (ERT) on Heart Function Changes the Outcome in Patients with Infantile-Onset Pompe Disease: A Familial History.

Marco Lecis, Katia Rossi, Maria Elena Guerzoni, Ilaria Mariotti, Lorenzo Iughetti.

Background: Lysosomal acid alpha-glucosidase (GAA) deficiency, also known as Pompe disease, is an autosomal recessive disorder that leads to the accumulation of glycogen in lysosomes and cytoplasm, resulting in tissue destruction. Infantile-onset GAA deficiency is characterized by cardiomyopathy and severe generalized hypotonia. Without treatment, most patients die within the first two years of life. The demonstration of reduced GAA activity, followed by sequencing of the GAA gene, confirms the disease. GAA deficiency is currently treated with enzyme replacement therapy (ERT) with improved clinical outcomes and survival. Case Presentation. We describe the case of DGAA in two siblings, in which the diagnostic time point, treatment, and outcomes were completely different. The girl was diagnosed with DGAA at the age of 6 months during investigations for poor weight gain and excessive sleepiness. The finding of severe cardiomyopathy through EKG and echocardiography led to the suspicion of storage disease, and the GAA deficiency was later confirmed by genetic analysis. The girl died of complications due to the clinical picture before starting ERT. Conversely, her younger brother had the opportunity to receive an early diagnosis and the rapid onset of ERT. He is showing a regression of cardiac hypertrophy.
Conclusion: The advent of ERT improved clinical outcomes and survival in infantile-onset PD. Its impact on cardiac function is still under study, but different reports in the literature have shown encouraging data. Early recognition of DGAA and prompt initiation of ERT is therefore crucial to prevent the progression of the disease and improve the outcomes.

DOI: https://doi.org/10.1155/2023/8470341
J Neuropathol Exp Neurol. 2023 Mar 02. pii: nlad012. [Epub ahead of print]

Outside the fiber: Endomysial stromal and capillary pathology in skeletal muscle may impede infusion therapy in infantile-onset Pompe disease.

Anne F Buckley, Ankit K Desai, Christine I Ha, Maureen A Petersen, Januario C Estrada, Justin R Waterﬁeld, Edward H Bossen, Priya S Kishnani.

  The survival of infantile-onset Pompe disease (IOPD) patients has improved dramatically since the introduction of enzyme replacement therapy (ERT) with a1glucosidase alfa. However, long-term IOPD survivors on ERT demonstrate motor deficits indicating that current therapy cannot completely prevent disease progression in skeletal muscle. We hypothesized that in IOPD, skeletal muscle endomysial stroma and capillaries would show consistent changes that could impede the movement of infused ERT from blood to muscle fibers. We retrospectively examined 9 skeletal muscle biopsies from 6 treated IOPD patients using light and electron microscopy. We found consistent ultrastructural endomysial stromal and capillary changes. The endomysial interstitium was expanded by lysosomal material, glycosomes/glycogen, cellular debris, and organelles, some exocytosed by viable muscle fibers and some released on fiber lysis. Endomysial scavenger cells phagocytosed this material. Mature fibrillary collagen was seen in the endomysium, and both muscle fibers and endomysial capillaries showed basal laminar reduplication and/or expansion. Capillary endothelial cells showed hypertrophy and degeneration, with narrowing of the vascular lumen. Ultrastructurally defined stromal and vascular changes likely constitute obstacles to movement of infused ERT from capillary lumen to muscle fiber sarcolemma, contributing to the incomplete efficacy of infused ERT in skeletal muscle. Our observations can inform approaches to overcoming these barriers to therapy.

Keywords:  Capillary; Endomysium; Glycogen; Muscle; Pompe; Stroma; Ultrastructure

DOI:  https://doi.org/10.1093/jnen/nlad012
Front Nutr. 2023 ;10 1111287

Acanthopanax trifoliatus (L.) Merr polysaccharides ameliorates hyperglycemia by regulating hepatic glycogen metabolism in type 2 diabetic mice.

Yuzi Lin, Jinghua Pan, Yue Liu, Huiwen Yang, Guoyu Wu, Yufang Pan.

   Introduction: Drug monotherapy was inadequate in controlling blood glucose levels and other comorbidities. An agent that selectively tunes multiple targets was regarded as a new therapeutic strategy for type 2 diabetes. Acanthopanax trifoliatus (L.) Merr polysaccharide (ATMP) is a bio-macromolecule isolated from Acanthopanax trifoliatus (L.) Merr and has therapeutic potential for diabetes management due to its anti-hyperglycemia activity.
Methods: Type 2 diabetes mellitus was induced in mice using streptozotocin, and 40 and 80 mg/kg ATMP was administered daily via the intragastric route for 8 weeks. Food intake, water intake, and body weight were recorded. The fasting blood glucose (FBG), fasting insulin (FINS) and an oral glucose tolerance test (OGTT) were performed. Histological changes in the liver and pancreas were analyzed by H&E staining. The mRNA and the protein levels of key factors involved in glycogen synthesis, glycogenolysis, and gluconeogenesis were measured by quantitative real time PCR and Western blotting.
Results: In this study, we found that ATMP could effectively improve glucose tolerance and alleviate insulin resistance by promoting insulin secretion and inhibiting glucagon secretion. In addition, ATMP decreases glycogen synthesis by inhibiting PI3K/Akt/GSK3β signaling, reduces glycogenolysis via suppressing cAMP/PKA signaling, and suppresses liver gluconeogenesis by activating AMPK signaling.
Conclusion: Together, ATMP has the potential to be developed as a new multitargets therapeutics for type 2 diabetes.

Keywords:  AMPK; Acanthopanax trifoliatus (L.) Merr; PI3K/Akt/GSK3β; cAMP/PKA; liver glucose metabolism; type 2 diabetes mellitus

DOI:  https://doi.org/10.3389/fnut.2023.1111287
Tissue Cell. 2023 Feb 21. pii: S0040-8166(23)00035-6. [Epub ahead of print]82 102047

High-sucrose diet-fed male rats show affectations in pubococcygeus reflex activation and myofiber content.

Carolina Sánchez Sánchez, Omar Lara García, María de Los Ángeles Carrasco Ruiz, Pablo Pacheco, Margarita Martínez-Gómez, Dora Luz Corona-Quintanilla, Jorge Rodríguez-Antolín, Francisco Castelán, Leticia Nicolás-Toledo.

  In males, the function of the pubococcygeus muscle (Pcm) shows a high androgen dependency. High sucrose intake increases testosterone levels in pubertal male rats. We aimed to analyze the Pcm reflex activity and fiber type in response to a 30 % sucrose diet. Wistar male rats were assigned into two groups: control and sugar. The Pcm electromyographic activity was recorded during the mechanical stimulation of the scrotal skin and penis. We also determined the relative levels of Glut4 expression, glycogen content, myofiber cross-sectional area (CSA), and the content of glycolytic and oxidative with NADH-TR or fast, intermediate, and slow fibers with alkaline (pH 9.4) ATPase histochemistry. The sugar group showed a short Pcm reflex activity, a higher Glut4 expression, and glycogen content; the CSA fibers showed a significant difference in the percentage of fibers with the different transversal areas. The number of nuclei was positively correlated with the CSA of the Pcm fibers. There was also a decrease in oxidative fibers but an increase in glycolytic fibers, while the content of fast muscle fibers increased to the detriment of intermediate and slow fibers. Thus, a high-sugar diet reduced Pcm reflex activity, fiber type, and dysregulation of skeletal muscle energy metabolism.

Keywords:  Glut4 expression; Glycogen; Glycolytic fibers; Oxidative fibers; Pubertal rats; Reflex activity

DOI:  https://doi.org/10.1016/j.tice.2023.102047
Biotechnol Biofuels Bioprod. 2023 Mar 01. 16(1): 32

Generation and comprehensive analysis of Synechococcus elongatus-Aspergillus nidulans co-culture system for polyketide production.

Jie Feng, Jingwei Li, Dongxia Liu, Yuxian Xin, Jingrong Sun, Wen-Bing Yin, Tingting Li.

   BACKGROUND: Artificial microbial consortia composed of heterotrophic and photoautotrophic organisms represent a unique strategy for converting light energy and carbon dioxide into high-value bioproducts. Currently, the types of desired bioproducts are still limited, and microbial fitness benefit rendered by paired partner generally needs to be intensified. Exploring novel artificial microbial consortia at a laboratory scale is an essential step towards addressing this unmet need. This study aimed to conduct and analyze an artificial consortium composed of cyanobacterium Synechococcus elongatus FL130 with the filamentous fungus Aspergillus nidulans TWY1.1 for producing fungi-derived secondary metabolite of polyketide neosartoricin B.
RESULTS: Polyketide-producing A. nidulans TWY1.1 substantially ameliorated the growth and the survival of sucrose-secreting cyanobacterium S. elongatus FL130 in salt-stressed environments. Besides sucrose, comparable amounts of other carbohydrates were released from axenically cultured FL130 cells, which could be efficiently consumed by TWY1.1. Relative to axenically cultured FL130, less glycogen was accumulated in FL130 cells co-cultured with TWY1.1, and the glycogen phosphorylase gene catalyzing the first step for glycogen degradation had two-fold expression. Different from axenically cultured filamentous fungi, abundant vacuoles were observed in fungal hyphae of TWY1.1 co-cultured with cyanobacterium FL130. Meanwhile, FL130 cells displayed a characteristic pattern of interacting with its heterotrophic partner, densely dispersing along certain hyphae of TWY1.1. Finally, polyketide neosartoricin B was produced from TWY1.1 in FL130-TWY1.1 co-cultures, which was tightly adjusted by nitrogen level.
CONCLUSION: Overall, the results thoroughly proved the concept of pairing cyanobacteria with filamentous fungi to build artificial consortia for producing fungi-derived biomolecules.

Keywords:  Aspergillus; Carbohydrate; Co-culture; Cyanobacteria; Glycogen; Secondary metabolite; Sucrose

DOI:  https://doi.org/10.1186/s13068-023-02283-6
J Int Soc Sports Nutr. 2023 Dec;20(1): 2178858

Carbohydrate-Protein drink is effective for restoring endurance capacity in masters class athletes after a two-Hour recovery.

Erica R Goldstein, Jeffrey R Stout, Adam J Wells, Jose Antonio, Ecaterina Vasenina, David H Fukuda.

   BACKGROUND: Carbohydrate (CHO) and carbohydrate-protein co-ingestion (CHO-P) have been shown to be equally effective for enhancing glycogen resynthesis and subsequent same-day performance when CHO intake is suboptimal (≤0.8 g/kg). Few studies have specifically examined the effect of isocaloric CHO vs CHO-P consumption on subsequent high-intensity aerobic performance with limited time to recover (≤2 hours) in masters class endurance athletes.
METHODS: This was a randomized, double-blind between-subject design. Twenty-two male masters class endurance athletes (age 49.1 ± 6.9 years; height 175.8 ± 4.8 cm; body mass 80.7 ± 8.6 kg; body fat (%) 19.1 ± 5.8; VO2peak 48.6 ± 6.7 ml·kg·min-1) were assigned to consume one of three beverages during a 2-hour recovery period: Placebo (PLA; electrolytes and water), CHO (1.2 g/kg bm), or CHO-P (0.8 g/kg bm CHO + 0.4 g/kg bm PRO). All beverages were standardized to one liter (~32 oz.) of total fluid volume regardless of the treatment group. During Visit #1, participants completed graded exercise testing on a cycle ergometer to determine VO2peak and peak power output (PPO, watts). Visit #2 consisted of familiarization with the high-intensity protocol including 5 × 4 min intervals at 70-80% of PPO with 2 min of active recovery at 50 W, followed by a time to exhaustion (TTE) test at 90% PPO. During Visit#3, the same high-intensity interval protocol with TTE was conducted pre-and post-beverage consumption.
RESULTS: A one-way ANCOVA indicated a significant difference among the group means for the posttest TTE (F2,18 = 6.702, p = .007, ƞ2 = .427) values after adjusting for the pretest differences. TTE performance in the second exercise bout improved for the CHO (295.48 ± 24.90) and CHO-P (255.08 ± 25.07 sec) groups. The water and electrolyte solution was not effective in restoring TTE performance in the PLA group (171.13 ± 23.71 sec).
CONCLUSIONS: Both CHO and CHO-P effectively promoted an increase in TTE performance with limited time to recover in this sample of masters class endurance athletes. Water and electrolytes alone were not effective for restoring endurance capacity during the second bout of exhaustive exercise.

Keywords:  Protein; carbohydrate; fatigue; glycogen; post-exercise; recovery

DOI:  https://doi.org/10.1080/15502783.2023.2178858