bims-glecem Biomed News
on Glycogen metabolism in exercise, cancer and energy metabolism
Issue of 2022‒07‒17
twenty-two papers selected by
Dipsikha Biswas, Københavns Universitet



  1. J Am Soc Nephrol. 2022 Jul 12. pii: ASN.2021070935. [Epub ahead of print]
      Background: Mutations in SLC37A4, which encodes the intracellular glucose transporter G6PT, cause the rare glycogen storage disease type 1b (GSD1b). A long-term consequence of GSD1b is kidney failure, which requires kidney replacement therapy. The main protein markers of proximal tubule function, including NaPi2A, NHE3, SGLT2, GLUT2, and AQP1, are downregulated as part of the disease phenotype. Methods: We utilized an inducible mouse model of GSD1b, TM-G6PT-/-, to show that glycogen accumulation plays a crucial role in altering proximal tubule morphology and function. To limit glucose entry into proximal tubule cells and, thus, to prevent glycogen accumulation, we administered a SGLT2-inhibitor, dapagliflozin, to TM-G6PT-/- mice. Results: In proximal tubule cells, G6PT suppression stimulates the upregulation and activity of hexokinase I, which increases availability of the reabsorbed glucose for intracellular metabolism. Dapagliflozin prevented glycogen accumulation and improved kidney morphology by promoting a metabolic switch from glycogen synthesis towards lysis and restored expression levels of the main proximal tubule functional markers. Conclusion: We provide proof of concept for the efficacy of dapagliflozin in preserving kidney function in GSD1b mice. Our findings could represent the basis for repurposing this drug to treat GSD1b patients.
    DOI:  https://doi.org/10.1681/ASN.2021070935
  2. JIMD Rep. 2022 Jul;63(4): 309-315
      Glycogen storage disease type Ib (GSD-Ib) is a rare inborn error of glycogen metabolism uniquely associated with neutropenia and neutrophil dysfunction, causing severe infections, inflammatory bowel disease (IBD), and impaired wound healing. Recently, kidney sodium-glucose co-transporter-2 (SGLT2) inhibitors such as empagliflozin known to reduce plasma levels of 1,5-anhydroglucitol (1,5-AG) and its toxic derivatives in neutrophils, have been described as a new treatment option in case reports of patients with GSD-Ib from Europe and Asia. We report our experience with an 11-year-old girl with GSD-Ib presenting with short fasting hypoglycemia, neutropenia with neutrophil dysfunction, recurrent infections, suboptimal growth, iron-deficiency anemia, and IBD. Treatment with daily empagliflozin improved neutrophil counts and function with a significant reduction in G-CSF needs. Significant improvement in IBD has led to weight gain with improved nutritional markers and improved fasting tolerance. Reduction of maximum empagliflozin dose was needed due to arthralgia. No other significant side effects of empagliflozin were observed. This report uniquely highlights the novel use of untargeted metabolomics profiling for monitoring plasma levels of 1,5-AG to assess empagliflozin dose responsiveness and guide dietary management and G-CSF therapy. Clinical improvement correlated to rapid normalization of 1,5-AG levels in plasma sustained after dose reduction. In conclusion, empagliflozin appeared to be a safe treatment option for GSD-Ib-associated neutropenia and neutrophil dysfunction. Global untargeted metabolomics is an efficient method to assess biochemical responsiveness to treatment.
    Keywords:  global metabolomics; hypoglycemia; inborn errors of metabolism; inflammatory bowel disease; neutropenia
    DOI:  https://doi.org/10.1002/jmd2.12304
  3. JIMD Rep. 2022 Jul;63(4): 303-308
      Glycogen storage disease type Ib (GSD Ib) is caused by biallelic variants in SLC37A4. GSD Ib is characterized by hepatomegaly, recurrent hypoglycemia, neutropenia, and neutrophil dysfunction. Only seven pregnancies in four women with GSD Ib have been reported so far. We report on two further successful pregnancies in two patients with GSD Ib. One of these pregnancies was managed with empagliflozin, an SGLT2 inhibitor, repurposed for the treatment of neutropenia in GSD Ib. Both pregnancies were unremarkable and resulted in healthy offspring. Gestational care and pre- and perinatal management in GSD Ib are challenging and require close interdisciplinary metabolic and obstetric monitoring. In our patient, the use of empagliflozin during pregnancy was successful in the prevention of neutropenic symptoms and infections and enabled good wound healing after Cesarean section, while no adverse effects were observed.
    Keywords:  GSD Ib; G‐CSF; SLC37A4; empagliflozin; glucose‐6‐phosphate transporter; glycogen storage disease type Ib; pregnancy
    DOI:  https://doi.org/10.1002/jmd2.12295
  4. JHEP Rep. 2022 Aug;4(8): 100512
      Background & Aims: Glycogen storage disease type Ia (GSDIa) is an inborn error of carbohydrate metabolism caused by pathogenic variants in the glucose-6-phosphatase catalytic subunit 1 (G6PC1) gene and is associated with hepatocellular adenoma (HCA) formation. Data on risk factors for HCA occurrence in GSDIa are scarce. We investigated HCA development in relation to sex, G6PC1 genotype, and serum triglyceride concentration (TG).Methods: An observational study of patients with genetically confirmed GSDIa ≥12 years was performed. Patients were categorised for sex; presence of 2, 1, or 0 predicted severe G6PC1 variant (PSV); and median TG during childhood (<12 years; stratified for above/below 5.65 mmol/L, i.e. 500 mg/dl).
    Results: Fifty-three patients (23 females) were included, of which 26 patients developed HCA at a median (IQR) age of 21 (17-25) years. At the age of 25 years, 48% of females and 30% of males had developed HCA (log-rank p = 0.045). Two-thirds of patients with GSDIa carried 2 PSVs, 20% carried 1, and 13% carried none. Neither the number of PSVs nor any specific G6PC1 variants were associated with HCA occurrence. Childhood TG was 3.4 (3.0-4.2) mmol/L in males vs. 5.6 (4.0-7.9) mmol/L in females (p = 0.026). Childhood TG >5.65 mmol/L was associated with HCA development at younger age, compared with patients with childhood TG <5.65 mmol/L (18 vs. 33 years; log-rank p = 0.001). Cox regression analysis including TG, sex, and TG-sex interaction correction revealed childhood TG >5.65 mmol/L as an independent risk factor for HCA development (hazard ratio [HR] 6.0; 95% CI 1.2-29.8; p = 0.028).
    Conclusions: In patients with GSDIa, high childhood TG was associated with an increased risk of HCA, and earlier onset of HCA development, independent of sex-associated hypertriglyceridaemia, and G6PC1 genotype.
    Lay summary: Glycogen storage disease type Ia (GSDIa) is a rare, inherited metabolic disease that can be complicated by liver tumours (hepatocellular adenomas), which in turn may cause bleeding or progress to liver cancer. Risk factors associated with hepatocellular adenoma formation in patients with GSDIa are largely unknown. In our study, we found that high serum triglyceride concentrations during childhood, but not specific genetic variants, were associated with increased risk of hepatocellular adenoma diagnosis later in life.
    Keywords:  Benign neoplasm; G6PC1, glucose-6-phosphatase catalytic subunit 1; G6Pase, glucose-6-phosphatase; GSDIa, glycogen storage disease type Ia; Glucose-6-phosphatase triglycerides; Glycogen storage disease type Ia; HCA, hepatocellular adenoma; HR, hazard ratio; Hepatic adenoma; MRI, magnetic resonance imaging; Metabolic disorder; PSV, predicted severe variant; TG, serum triglyceride concentration
    DOI:  https://doi.org/10.1016/j.jhepr.2022.100512
  5. Biomed Res Int. 2022 ;2022 2304494
      Glycogen storage disease (GSD) is a rare disease that can cause life-threatening problems owing to metabolic errors in storing or using glycogen. The disease course of GSD remains unknown, despite medical technology advances. We determined the prevalence and complications of GSD using data from the National Health Insurance Service database. Data were collected and analyzed for the entire South Korean population with GSD during 2007-2018. GSD was defined as a combination of disease code E74.0 and rare incurable disease insurance code V117, a unique disease code combination for GSD in South Korea. Overall, 23,055 patients had the E74 disease code; 404 had an additional V117 insurance code. Most GSD patients were aged <10 years. Many complications were identified, the most common being hepatomegaly, hyperuricemia, and elevated liver enzyme levels. The most prescribed drug was α-glucosidase, followed by allopurinol. Seventy-two percent of patients were treated in pediatrics. Twenty-five patients underwent liver transplantation, and 14 died after GSD diagnosis. In South Korea, more patients than expected had GSD diagnosis and were managed accordingly. GSD causes many complications and hospitalizations, resulting in high medical expenses. Serious complications can result in liver transplantation and, eventually, death in some cases. Although the patients' condition was identified only by the disease code, this is the first study to present the current situation of GSD patients in South Korea. Because GSD patients can have dangerous medical conditions, they should be managed consistently while minimizing various complications that may occur with optimal metabolic control.
    DOI:  https://doi.org/10.1155/2022/2304494
  6. Arch Pharm (Weinheim). 2022 Jul 14. e2200156
      Alzheimer's disease (AD) is a chronic and progressive neurodegenerative disease, characterized by irreversible cognitive impairment, memory loss, and behavioral disturbances, ultimately resulting in death. The critical roles of glycogen synthase kinase-3β (GSK-3β) in tau pathology have also received considerable attention. Based on molecular docking studies, a series of novel α-carboline derivatives were designed, synthesized, and evaluated as GSK-3β inhibitors for their various biological activities. Among them, compound ZCH-9 showed the most potent inhibitory activity against GSK-3β, with an IC50 value of 1.71 ± 0.09 µM. The cytotoxicity assay showed that ZCH-9 had low cytotoxicity toward the cell lines SH-SY5Y, HepG2, and HL-7702. Moreover, Western blot analysis indicated that ZCH-9 effectively inhibited hyperphosphorylation of the tau protein in okadaic acid-treated SH-SY5Y cells. The binding mode between ZCH-9 and GSK-3β was analyzed and further clarified throughout the molecular dynamics simulations. In general, these results suggested that the α-carboline-based small-molecule compounds could serve as potential candidates targeting GSK-3β for the treatment of AD.
    Keywords:  alkaloids; bioorganic chemistry; kinases; molecular dynamics
    DOI:  https://doi.org/10.1002/ardp.202200156
  7. Front Mol Neurosci. 2022 ;15 932939
      Exposure to a heroin-associated conditioned stimulus can reactivate drug reward memory, trigger drug cravings, and induce relapse in heroin addicts. The amygdala, a brain region related to emotions and motivation, is involved in processing rewarding stimulus. Recent evidence demonstrated that disrupting the reconsolidation of the heroin drug memories attenuated heroin seeking which was associated with the basolateral amygdala (BLA). Meanwhile, neural functions associated with learning and memory, like synaptic plasticity, are regulated by glycogen synthase kinase 3 beta (GSK-3β). In addition, GSK-3β regulated memory processes, like retrieval and reconsolidation of cocaine-induced memory. Here, we used a heroin intravenous self-administration (SA) paradigm to illustrate the potential role of GSK-3β in the reconsolidation of drug memory. Therefore, we used SB216763 as a selective inhibitor of GSK-3β. We found that injecting the selective inhibitor SB216763 into the BLA, but not the central amygdala (CeA), immediately after heroin-induced memory retrieval disrupted reconsolidation of heroin drug memory and significantly attenuated heroin-seeking behavior in subsequent drug-primed reinstatement, suggesting that GSK-3β is critical for reconsolidation of heroin drug memories and inhibiting the activity of GSK-3β in BLA disrupted heroin drug memory and reduced relapse. However, no retrieval or 6 h after retrieval, administration of SB216763 into the BLA did not alter heroin-seeking behavior in subsequent heroin-primed reinstatement, suggesting that GSK-3β activity is retrieval-dependent and time-specific. More importantly, a long-term effect of SB216763 treatment was observed in a detectable decrease in heroin-seeking behavior, which lasted at least 28 days. All in all, this present study demonstrates that the activity of GSK-3β in BLA is required for reconsolidation of heroin drug memory, and inhibiting GSK-3β activity of BLA disrupts reconsolidation and attenuates heroin relapse.
    Keywords:  GSK-3β; addiction; amygdala; heroin; reconsolidation; self-administration
    DOI:  https://doi.org/10.3389/fnmol.2022.932939
  8. J Strength Cond Res. 2022 Jul 08.
      ABSTRACT: Matsuda, T, Takahashi, H, Nakamura, M, Ogata, H, Kanno, M, Ishikawa, A, and Sakamaki-Sunaga, M. Influence of the menstrual cycle on muscle glycogen repletion after exhaustive exercise in eumenorrheic women. J Strength Cond Res XX(X): 000-000, 2022-The purpose of this study was to investigate the effect of the menstrual cycle on muscle glycogen repletion postexercise. Eleven women with regular menstrual cycles (age: 20.2 ± 1.3 years, height: 161.1 ± 4.8 cm, and body mass: 55.5 ± 5.7 kg) were assessed in 3 phases of the cycle: the early follicular phase (E-FP), late follicular phase (L-FP), and luteal phase (LP). Each test day began with glycogen-depleting exercise, followed by 5 hours of recovery. Muscle glycogen concentrations, using 13C-magnetic resonance spectroscopy, and estradiol, progesterone, blood glucose, blood lactate, free fatty acid (FFA), and insulin concentrations were measured at t = 0, 120, and 300 minutes postexercise. During the 5-hour recovery period, subjects consumed 1.2g·(kg body mass)-1·h-1 of carbohydrates every 30 minutes. The muscle glycogen concentrations increased at t = 120 and t = 300 minutes postexercise (p < 0.01) but were not significantly different between the menstrual cycle phases (p = 0.30). Blood lactate concentrations were significantly higher in the L-FP and LP than in the E-FP (p < 0.05). Nonetheless, the blood glucose, FFA, insulin concentrations, and the exercise time until exhaustion in the E-FP, L-FP, and LP were similar (blood glucose, p = 0.17; FFA, p = 0.50; insulin, p = 0.31; exercise time, p = 0.67). In conclusion, the menstrual cycle did not influence muscle glycogen repletion after exercise.
    DOI:  https://doi.org/10.1519/JSC.0000000000004306
  9. Nat Struct Mol Biol. 2022 Jul;29(7): 628-638
      Glycogen synthase (GYS1) is the central enzyme in muscle glycogen biosynthesis. GYS1 activity is inhibited by phosphorylation of its amino (N) and carboxyl (C) termini, which is relieved by allosteric activation of glucose-6-phosphate (Glc6P). We present cryo-EM structures at 3.0-4.0 Å resolution of phosphorylated human GYS1, in complex with a minimal interacting region of glycogenin, in the inhibited, activated and catalytically competent states. Phosphorylations of specific terminal residues are sensed by different arginine clusters, locking the GYS1 tetramer in an inhibited state via intersubunit interactions. The Glc6P activator promotes conformational change by disrupting these interactions and increases the flexibility of GYS1, such that it is poised to adopt a catalytically competent state when the sugar donor UDP-glucose (UDP-glc) binds. We also identify an inhibited-like conformation that has not transitioned into the activated state, in which the locking interaction of phosphorylation with the arginine cluster impedes subsequent conformational changes due to Glc6P binding. Our results address longstanding questions regarding the mechanism of human GYS1 regulation.
    DOI:  https://doi.org/10.1038/s41594-022-00799-3
  10. Brain Commun. 2022 ;4(4): fcac168
      Lafora disease is a fatal neurodegenerative childhood dementia caused by loss-of-function mutations in either the laforin or malin gene. The hallmark of the disease is the accumulation of abnormal glycogen aggregates known as Lafora bodies (LBs) in the brain and other tissues. These aggregates are responsible for the pathological features of the disease. As a monogenic disorder, Lafora disease is a good candidate for gene therapy-based approaches. However, most patients are diagnosed after the appearance of the first symptoms and thus when LBs are already present in the brain. In this context, it was not clear whether the restoration of a normal copy of the defective gene (either laforin or malin) would prove effective. Here we evaluated the effect of restoring malin in a malin-deficient mouse model of Lafora disease as a proof of concept for gene replacement therapy. To this end, we generated a malin-deficient mouse in which malin expression can be induced at a certain time. Our results reveal that malin restoration at an advanced stage of the disease arrests the accumulation of LBs in brain and muscle, induces the degradation of laforin and glycogen synthase bound to the aggregates, and ameliorates neuroinflammation. These results identify malin restoration as the first therapeutic strategy to show effectiveness when applied at advanced stages of Lafora disease.
    Keywords:  Lafora disease; gene therapy; glycogen; neurodegeneration; neuroinflammation
    DOI:  https://doi.org/10.1093/braincomms/fcac168
  11. Cancer Gene Ther. 2022 Jul 11.
      GSK3B is the mRNA form of glycogen synthase kinase 3 beta (GSK-3β), which is a critical repressor of Wnt/β-catenin signaling pathway and generally inhibited in cancer cells. Plenty of researches have disclosed that circular RNAs, namely circRNAs exert important functions in the progression of various human malignancies including lung adenocarcinoma (LUAD). Therefore, we attempted to explore whether there existed certain circRNAs that could mediate LUAD development by regulating GSK3B expression and Wnt/β-catenin pathway. In the present research, circ-GSK3B (hsa_circ_0066903) was found to be significantly down-regulated in LUAD tissues and cells and it suppressed the proliferation, migration and stemness of LUAD cells. Furthermore, it was discovered that circ-GSK3B competitively sponged miR-3681-3p and miR-3909 to elevate GSK3B expression. Circ-GSK3B could impair the binding ability of FKBP51 to GSK-3β to inhibit the phosphorylation of GSK-3βS9, resulting in the inactivation of Wnt/β-catenin signaling. In addition, the regulatory effect of circ-GSK3B on LUAD tumorigenesis and cell progression was testified through in vitro and in vivo rescue experiments. In conclusion, circ-GSK3B suppressed LUAD development through up-regulating and activating GSK3B.
    DOI:  https://doi.org/10.1038/s41417-022-00489-8
  12. PLoS One. 2022 ;17(7): e0270373
      Glycogen storage disorders occur due to enzyme deficiencies in the glycogenolysis and gluconeogenesis pathway, encoded by 26 genes. GSD's present with overlapping phenotypes with variable severity. In this series, 57 individuals were molecularly confirmed for 7 GSD subtypes and their demographic data, clinical profiles and genotype-phenotype co-relations are studied. Genomic DNA from venous blood samples was isolated from clinically affected individuals. Targeted gene panel sequencing covering 23 genes and Sanger sequencing were employed. Various bioinformatic tools were used to predict pathogenicity for new variations. Close parental consanguinity was seen in 76%. Forty-nine pathogenic variations were detected of which 27 were novel. Variations were spread across GSDIa, Ib, III, VI, IXa, b and c. The largest subgroup was GSDIII in 28 individuals with 24 variations (12 novel) in AGL. The 1620+1G>C intronic variation was observed in 5 with GSDVI (PYGL). A total of eleven GSDIX are described with the first Indian report of type IXb. This is the largest study of GSDs from India. High levels of consanguinity in the local population and employment of targeted sequencing panels accounted for the range of GSDs reported here.
    DOI:  https://doi.org/10.1371/journal.pone.0270373
  13. Cancer Biol Ther. 2022 12 31. 23(1): 417-423
      GSK-3β is a serine/threonine kinase implicated in tumorigenesis and chemotherapy resistance. GSK-3β blockade downregulates the NF-κB pathway, modulates immune cell PD-1 and tumor cell PD-L1 expression, and increases CD8 + T cell and NK cell function. We report a case of adult T-cell leukemia/lymphoma (ATLL) treated with 9-ING-41, a selective GSK-3β inhibitor in clinical development, who achieved a durable response. A 43-year-old male developed diffuse lymphadenopathy, and biopsy of axillary lymph node showed acute-type ATLL. Peripheral blood flow cytometry revealed a circulating clonal T cell population, and CSF was positive for ATLL involvement. After disease progression on the 3rd line of treatment, he started treatment with 9-ING-41 monotherapy in a clinical trial (NCT03678883). CT imaging after seven months showed a partial response. Sustained reduction of peripheral blood ATLL cells lasted 15 months. Treatment of patient-derived CD8 + T cells with 9-ING-41 increased the secretion of IFN-γ, granzyme B, and tumor necrosis factor-related apoptosis-inducing ligand (TRAIL). In conclusion, treatment of a patient with refractory ATLL with the GSK-3β inhibitor 9-ING-41 resulted in a prolonged response. Ongoing experiments are investigating the hypothesis that 9-ING-41-induced T cell activation and immunomodulation contributes to its clinical activity. Further clinical investigation of 9-ING-41 for treatment of ATLL is warranted.
    Keywords:  9-ING-41; ATLL; GSK-3; GSK-3b; glycogen synthase kinase 3
    DOI:  https://doi.org/10.1080/15384047.2022.2088984
  14. Aging Cell. 2022 Jul 10. e13667
      Dysfunctional adipocyte precursors have emerged as key determinants for obesity- and aging-related inflammation, but the mechanistic basis remains poorly understood. Here, we explored the dysfunctional adipose tissue of elderly and obese individuals focusing on the metabolic and inflammatory state of human adipose-derived mesenchymal stromal cells (hASCs), and on sirtuins, which link metabolism and inflammation. Both obesity and aging impaired the differentiation potential of hASCs but had a different impact on their proliferative capacity. hASCs from elderly individuals (≥65 years) showed an upregulation of glycolysis-related genes, which was accompanied by increased lactate secretion and glycogen storage, a phenotype that was exaggerated by obesity. Multiplex protein profiling revealed that the metabolic switch to glycogenesis was associated with a pro-inflammatory secretome concomitant with a decrease in the protein expression of SIRT1 and SIRT6. siRNA-mediated knockdown of SIRT1 and SIRT6 in hASCs from lean adults increased the expression of pro-inflammatory and glycolysis-related markers, and enforced glycogen deposition by overexpression of protein targeting to glycogen (PTG) led to a downregulation of SIRT1/6 protein levels, mimicking the inflammatory state of hASCs from elderly subjects. Overall, our data point to a glycogen-SIRT1/6 signaling axis as a driver of age-related inflammation in adipocyte precursors.
    Keywords:  Aging; SIRT1; SIRT6; adipose-derived mesenchymal stromal cells; glycogen; glycolysis; inflammation; obesity
    DOI:  https://doi.org/10.1111/acel.13667
  15. Dev Comp Immunol. 2022 Jul 10. pii: S0145-305X(22)00154-9. [Epub ahead of print] 104492
      D-lactic acidosis is a metabolic disease of cattle caused by the digestive overgrowth of bacteria that are highly producers of d-lactate, a metabolite that then reaches and accumulates in the bloodstream. d-lactate is a proinflammatory agent in cattle that induces the formation of extracellular traps (ETs) in polymorphonuclear leucocytes (PMN), although information on PMN metabolic requirements for this response mechanism is insufficient. In the present study, metabolic pathways involved in ET formation induced by d-lactate were studied. We show that d-lactate but not l-lactate induced ET formation in cattle PMN. We analyzed the metabolomic changes induced by d-lactate in bovine PMN using gas chromatography-mass spectrometry (GC-MS). Several metabolic pathways were altered, including glycolysis/gluconeogenesis, amino sugar and nucleotide sugar metabolism, galactose metabolism, starch and sucrose metabolism, fructose and mannose metabolism, and pentose phosphate pathway. d-lactate increased intracellular levels of glucose and glucose-6-phosphate, and increased uptake of the fluorescent glucose analog 2-NBDG, suggesting improved glycolytic activity. In addition, using an enzymatic assay and transmission electron microscopy (TEM), we observed that d-lactate was able to decrease intracellular glycogen levels and the presence of glycogen granules. Relatedly, d-lactate increased the expression of enzymes of glycolysis, gluconeogenesis and glycogen metabolism. In addition, 2DG (a hexokinase inhibitor), 3PO (a 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase 3 inhibitor), MB05032 (inhibitor of fructose-1,6-bisphosphatase) and CP-91149 (inhibitor of glycogen phosphorylase) reduced d-lactate-triggered ETosis. Taken together, these results suggest that d-lactate induces a metabolic rewiring that increases glycolysis, gluconeogenesis and glycogenolysis, all of which are required for d-lactate-induced ET release in cattle PMN.
    Keywords:  Bovine PMN; Extracellular traps; Glucose metabolism; d-lactate
    DOI:  https://doi.org/10.1016/j.dci.2022.104492
  16. Front Pharmacol. 2022 ;13 903488
      Background: A high prevalence of infantile-onset Pompe disease (IOPD) in the Chinese population has been noted, but there are currently no reported clinical trials of enzyme replacement therapy (ERT) for IOPD in this population. The purpose of this study was to evaluate the efficacy and safety of alglucosidase alfa in Chinese patients with IOPD. Materials and Methods: A multicentre, single-arm, prospective, open-label clinical trial was performed at 4 sites in China. Eligible Chinese subjects with IOPD received an infusion of alglucosidase alfa at a dose of 20 mg/kg every 2 weeks for up to 52 weeks. The primary endpoints of clinical efficacy were the survival rate and changes in the left ventricular mass index (LVMI). The safety assessment was based on the incidence of adverse events (AEs). Results: A total of 10 eligible subjects were enrolled in the study. The mean age at the start of ERT was 5.36 ± 1.56 months. Nine subjects had survived after 52 weeks of treatment. One subject discontinued the study and died after mechanical ventilation was withdrawn. The intent-to-treat analysis demonstrated that the survival rate was 90.0% (95% confidence interval: 55.5-99.7%). The mean LVMI at week 52 was 70.59 ± 39.93 g/m2 compared to that of 298.02 ± 178.43 g/m2 at baseline, with a difference of -227.60 ± 155.99 g/m2. All subjects had left ventricular mass (LVM) Z scores >10 at baseline, and eight subjects (80%) achieved Z scores <5 at week 52. No treatment-related AEs were observed, and no AEs led to the discontinuation of treatment. Conclusions: This clinical trial is the first study of ERT for IOPD in China, indicating that alglucosidase alfa has favourable efficacy and safety for the treatment of Chinese patients with IOPD (ClinicalTrials.gov number, NCT03687333).
    Keywords:  Pompe disease; alglucosidase alfa; enzyme replacement therapy; glycogen storage disease type II; left ventricular mass index; survival rate
    DOI:  https://doi.org/10.3389/fphar.2022.903488
  17. Eur Radiol. 2022 Jul 13.
      OBJECTIVES: To evaluate changes in diaphragmatic function in Pompe disease using MRI over time, both during natural disease course and during treatment with enzyme replacement therapy (ERT).METHODS: In this prospective study, 30 adult Pompe patients and 10 healthy controls underwent pulmonary function tests and spirometry-controlled MRI twice, with an interval of 1 year. In the sagittal view of 3D gradient echo breath-hold acquisitions, diaphragmatic motion (cranial-caudal ratio between end-inspiration and end-expiration) and curvature (diaphragm height and area ratio) were calculated using a machine learning algorithm based on convolutional neural networks. Changes in outcomes after 1 year were compared between Pompe patients and healthy controls using the Mann-Whitney test.
    RESULTS: Pulmonary function outcomes and cranial-caudal ratio in Pompe patients did not change significantly over time compared to healthy controls. Diaphragm height ratio increased by 0.04 (-0.38 to 1.79) in Pompe patients compared to -0.02 (-0.18 to 0.25) in healthy controls (p = 0.02). An increased diaphragmatic curvature over time was observed in particular in untreated Pompe patients (p = 0.03), in those receiving ERT already for over 3 years (p = 0.03), and when severe diaphragmatic weakness was found on the initial MRI (p = 0.01); no progression was observed in Pompe patients who started ERT less than 3 years ago and in Pompe patients with mild diaphragmatic weakness on their initial MRI.
    CONCLUSIONS: MRI enables to detect small changes in diaphragmatic curvature over 1-year time in Pompe patients. It also showed that once severe diaphragmatic weakness has occurred, improvement of diaphragmatic muscle function seems unlikely.
    KEY POINTS: • Changes in diaphragmatic curvature in Pompe patients over time assessed with 3D MRI may serve as an outcome measure to evaluate the effect of treatment on diaphragmatic function. • Diaphragmatic curvature showed a significant deterioration after 1 year in Pompe patients compared to healthy controls, but the curvature seems to remain stable over this period in patients who were treated with enzyme replacement therapy for less than 3 years, possibly indicating a positive effect of ERT. • Improvement of diaphragmatic curvature over time is rarely seen in Pompe patients once diaphragmatic motion shows severe impairment (cranial-caudal inspiratory/expiratory ratio < 1.4).
    Keywords:  Diaphragm; Enzyme replacement therapy; Glycogen storage disease type II; Magnetic resonance imaging; Respiration
    DOI:  https://doi.org/10.1007/s00330-022-08940-y
  18. Mol Genet Metab Rep. 2022 Sep;32 100893
      Infantile onset Pompe disease (IOPD) is a rare devastating disease that presents in early infancy with rapidly progressive hypertrophic cardiomyopathy, severe generalized myopathy and death within the first year of life. The emergence of enzyme replacement therapy (ERT) with recombinant human acid alpha glucosidase (rhGAA) has improved the natural course of IOPD with a significant impact on cardiomyopathy but has a more limited effect on the progression of myopathy and consequently the later deterioration of the disease. Possible reasons for reduced ERT efficacy include insufficient enzyme, partial targeting of skeletal muscle and the development of IgG rhGAA antibodies especially in patients who are cross-reactive immunological material (CRIM) negative. We report a CRIM-negative IOPD female patient who started treatment upon diagnosis at 4.5 months with ERT at 20 mg/kg every other week and a course of combined immunomodulation with rituximab, methotrexate and IVIG according to the published Duke protocol and increased ERT within a month to 40 mg/kg/week. Despite initial good clinical response to ERT and immunomodulation, monthly monitoring identified a gradual increase of serum antibody titers to rhGAA necessitating a second course of immunomodulation with bortezomib and maintenance rituximab and methotrexate. A gradual reduction in frequency of immunotherapy was instituted and over a period of 14 months was discontinued. Serum anti-rhGAA antibody titers remained negative for 5 months since cessation of immunomodulation and the patient is now immune tolerant with recovery of CD19. At the age of 30 months the patient is walking independently and has normal cardiac function and anatomy. We recommend initiating ERT at 40 mg/kg/week in CRIM-negative IOPD patients, concomitant with immunomodulation and monthly monitoring of serum anti-rhGAA IgG titers upon confirmation of the diagnosis.
    Keywords:  Cross reactive immunological material (CRIM); Enzyme replacement therapy; GAA gene; Immunomodulation; Infantile-onset Pompe disease
    DOI:  https://doi.org/10.1016/j.ymgmr.2022.100893
  19. Front Immunol. 2022 ;13 919728
      The female reproductive tract harbors a unique microbiome, especially the vagina. The human vaginal microbiome exhibits a low diversity and is dominated by Lactobacillus species, compared to the microbiome of other organs. The host and vaginal microbiome mutually coexist in the vaginal microenvironment. Host cells provide Lactobacillus glycogen as an energy source, and Lactobacillus produce lactic acid, which lowers vaginal pH thereby preventing growth of other bacteria. Bacterial vaginosis can modulate host immune systems, and is frequently associated with various aspects of disease, including sexually transmitted infection, gynecologic cancer, and poor pregnancy outcomes. Because of this, numerous studies focused on the impact of the vaginal microbiome on women`s health and disease. Furthermore, numerous epidemiologic studies also have demonstrated various host factors regulate the vaginal microbiome. The female reproductive tract undergoes constant fluctuations due to hormonal cycle, pregnancy, and other extrinsic factors. Depending on these fluctuations, the vaginal microbiome composition can shift temporally and dynamically. In this review, we highlight the current knowledge of how host factors modulate vaginal microbiome composition and how the vaginal microbiome contributes to maintaining homeostasis or inducing pathogenesis. A better understanding of relationship between host and vaginal microbiome could identify novel targets for diagnosis, prognosis, or treatment of microbiome-related diseases.
    Keywords:  STI; bacterial vaginosis; estrogen; glycogen; lactobacillus; preterm birth; probiotics; vaginal microbiome
    DOI:  https://doi.org/10.3389/fimmu.2022.919728
  20. Semin Cancer Biol. 2022 Jul 09. pii: S1044-579X(22)00175-4. [Epub ahead of print]
      The evolutionary pressure for life transitioning from extended periods of hypoxia to an increasingly oxygenated atmosphere initiated drastic selections for a variety of biochemical pathways supporting the robust life currently present on the planet. First, we discuss how fermentative glycolysis, a primitive metabolic pathway present at the emergence of life, is instrumental for the rapid growth of cancer, regenerating tissues, immune cells but also bacteria and viruses during infections. The 'Warburg effect', activated via Myc and HIF-1 in response to growth factors and hypoxia, is an essential metabolic and energetic pathway which satisfies nutritional and energetic demands required for rapid genome replication. Second, we present the key role of lactic acid, the end-product of fermentative glycolysis able to move across cell membranes in both directions via monocarboxylate transporting proteins (i.e. MCT1/4) contributing to cell-pH homeostasis but also to the complex immune response via acidosis of the tumour microenvironment. Importantly lactate is recycled in multiple organs as a major metabolic precursor of gluconeogenesis and energy source protecting cells and animals from harsh nutritional or oxygen restrictions. Third, we revisit the Warburg effect via CRISPR-Cas9 disruption of glucose-6-phosphate isomerase (GPI-KO) or lactate dehydrogenases (LDHA/B-DKO) in two aggressive tumours (melanoma B16-F10, human adenocarcinoma LS174T). Full suppression of lactic acid production reduces but does not suppress tumour growth due to reactivation of OXPHOS. In contrast, disruption of the lactic acid transporters MCT1/4 suppressed glycolysis, mTORC1, and tumour growth as a result of intracellular acidosis. Finally, we briefly discuss the current clinical developments of an MCT1 specific drug AZ3965, and the recent progress for a specific in vivo MCT4 inhibitor, two drugs of very high potential for future cancer clinical applications.
    Keywords:  BASIGIN; CRISPR-cas9; GPI; LDHA; LDHB; MCT1; MCT4; OXPHOS; Warburg effect; acidosis; bacteria; cancer; fermentative glycolysis; glycogen; immune evasion; immunity; lactate; pathogens; viruses
    DOI:  https://doi.org/10.1016/j.semcancer.2022.07.004
  21. Front Pharmacol. 2022 ;13 913367
      Nrf2-mediated oxidative stress is a promising target of exhaustive exercise-induced fatigue (EEIF). Trilobatin (TLB) is a naturally occurring food additive with antioxidant effect and Nrf2 activation potency. The present study aimed to investigate the effect of TLB on EEIF and elucidate its underlying mechanism. Our results showed that TLB exerted potent anti-EEIF effect, as reflected by the rope climbing test and exhaustive swimming test. Moreover, TLB also effectively reduced the levels of lactate, creatine kinase, and blood urea nitrogen, and increased liver glycogen and skeletal muscle glycogen in mice after EEIF insult. Additionally, TLB also balanced the redox status as evidenced by decreasing the generation of reactive oxygen species and improving the antioxidant enzyme activities including superoxide dismutase, catalase, and glutathione peroxidase, as well as the level of glutathione both in the tissue of muscle and myocardium. Furthermore, TLB promoted nuclear factor erythroid 2-related factor 2 (Nrf2) from the cytoplasm to the nucleus, and upregulated its downstream antioxidant response element (ARE) including quinone oxidoreductase-1 and heme oxygenase-1. Intriguingly, TLB also upregulated the GPx4 protein expression and reduced iron overload in mice after EEIF insult. Encouragingly, the beneficial effect of TLB on EEIF-induced oxidative stress and ferroptosis were substantially abolished in Nrf2-deficient mice. In conclusion, our findings demonstrate, for the first time, that TLB alleviates EEIF-induced oxidative stress through mediating Nrf2/ARE/ferroptosis axis.
    Keywords:  exhaustive exercise-induced fatigue; ferroptosis; nuclear factor erythroid 2-related factor 2; oxidative stress; trilobatin
    DOI:  https://doi.org/10.3389/fphar.2022.913367
  22. FASEB J. 2022 Aug;36(8): e22461
      Brown adipose tissue (BAT) is an important component of energy expenditure and necessary to maintain body temperature for newborn mammals. In the previous study, we found that L-carnitine was enriched in BAT and promoted BAT adipogenesis and thermogenesis in goat brown adipocytes. However, whether dietary L-carnitine regulates BAT heat production and energy expenditure in lambs remains unclear. In this study, maternal L-carnitine supplementation elevated the rectal temperature, as well as the expression of UCP1 and mitochondrial DNA content to promote BAT thermogenesis in newborn goats. Moreover, maternal L-carnitine supplementation increased the levels of triglycerides (TG), non-esterified fatty acids (NEFA), and lactate in plasma, as well as the content of lipid droplet and glycogen in BAT of newborn goats. Lipidomic analysis showed that maternal L-carnitine supplementation remodeled the lipid composition of BAT in newborn goats. L-carnitine significantly increased the levels of TG and diglyceride (DG) and decreased the levels of glycerophospholipids and sphingolipids in BAT. Further studies showed that L-carnitine promoted TG and glycogen deposition in brown adipocytes through AMPKα. Our results indicate that maternal L-carnitine supplementation promotes BAT development and thermogenesis in newborn goats and provides new evidence for newborn goats to maintain body temperature in response to cold exposure.
    Keywords:  L-carnitine; brown adipose tissue; cold exposure; lipidomics; thermogenesis
    DOI:  https://doi.org/10.1096/fj.202200637R