bims-glecem 2023-09-10 papers

bims-glecem

Biomed News

on Glycogen metabolism in exercise, cancer and energy metabolism

Issue of 2023–09–10
eleven papers selected by
Dipsikha Biswas, Københavns Universitet

Glycogen storage diseases.
Increase in brain glycogen levels ameliorates disease phenotype and rescues neurodegeneration in the Drosophila model of Huntington's disease.
Increasing enzyme mannose-6-phosphate levels but not miglustat co-administration enhances the efficacy of enzyme replacement therapy in Pompe mice.
Glycogen storage diseases.
Inhibition of Wnt/β-catenin signaling reduces renal fibrosis in murine glycogen storage disease type Ia.
The recovery of muscle function and glycogen levels following game-play in young elite male ice hockey players.
Monitoring and Management of Respiratory Function in Pompe Disease: Current Perspectives.
PER2/P65-driven glycogen synthase 1 transcription in macrophages modulates gut inflammation and pathogenesis of rectal prolapse.
Muscle ultrasound in patients with late-onset Pompe disease identified by newborn screening.
Impact of glycogen synthase kinase-3ß inhibition on rats' temporomandibular joint collagen-induced rheumatoid arthritis with correlation to miRNA-155/miRNA-24 expression.
Disruption of Hepatic Mitochondrial Pyruvate and Amino Acid Metabolism Impairs Gluconeogenesis and Endurance Exercise Capacity in Mice.

Nat Rev Dis Primers. 2023 Sep 07. 9(1): 46

Glycogen storage diseases.

William B Hannah, Terry G J Derks, Mitchell L Drumm, Sarah C Grünert, Priya S Kishnani, John Vissing.

Glycogen storage diseases (GSDs) are a group of rare, monogenic disorders that share a defect in the synthesis or breakdown of glycogen. This Primer describes the multi-organ clinical features of hepatic GSDs and muscle GSDs, in addition to their epidemiology, biochemistry and mechanisms of disease, diagnosis, management, quality of life and future research directions. Some GSDs have available guidelines for diagnosis and management. Diagnostic considerations include phenotypic characterization, biomarkers, imaging, genetic testing, enzyme activity analysis and histology. Management includes surveillance for development of characteristic disease sequelae, avoidance of fasting in several hepatic GSDs, medically prescribed diets, appropriate exercise regimens and emergency letters. Specific therapeutic interventions are available for some diseases, such as enzyme replacement therapy to correct enzyme deficiency in Pompe disease and SGLT2 inhibitors for neutropenia and neutrophil dysfunction in GSD Ib. Progress in diagnosis, management and definitive therapies affects the natural course and hence morbidity and mortality. The natural history of GSDs is still being described. The quality of life of patients with these conditions varies, and standard sets of patient-centred outcomes have not yet been developed. The landscape of novel therapeutics and GSD clinical trials is vast, and emerging research is discussed herein.

DOI: https://doi.org/10.1038/s41572-023-00456-z
Dis Model Mech. 2023 Sep 08. pii: dmm.050238. [Epub ahead of print]

Increase in brain glycogen levels ameliorates disease phenotype and rescues neurodegeneration in the Drosophila model of Huntington's disease.

Akanksha Onkar, Deepashree Sheshadri, Anupama Rai, Arjit Kant Gupta, Nitin Gupta, Subramaniam Ganesh.

  Under normal physiological conditions, the mammalian brain contains very little glycogen, most of which is stored in astrocytes. However, the aging brain and subareas of the brain in patients with neurodegenerative disorders tend to accumulate glycogen, the cause and significance of which remain largely unexplored. Using cellular models, we have recently demonstrated a neuroprotective role for neuronal glycogen and glycogen synthase in the context of Huntington's disease. To gain insight into the role of brain glycogen in regulating proteotoxicity, we utilized a Drosophila model of Huntington's disease in which glycogen synthase was either knocked down or expressed ectopically. Enhancing glycogen synthesis in the brains of flies with Huntington's disease decreased mutant Huntingtin aggregation and reduced oxidative stress by activating auto-lysosomal functions. Further, the overexpression of glycogen synthase in the brain rescues photoreceptor degeneration, improves locomotor deficits, and increases fitness traits in Huntington's disease model. We thus provide in vivo evidence for the neuroprotective functions of glycogen synthase and glycogen in neurodegenerative conditions and their role in the neuronal autophagy process.

Keywords:  Aging; Autophagy; Glycogen synthase; Neurodegenerative disorders; Oxidative stress

DOI:  https://doi.org/10.1242/dmm.050238
J Pharmacol Exp Ther. 2023 Sep 07. pii: JPET-AR-2023-001593. [Epub ahead of print]

Increasing enzyme mannose-6-phosphate levels but not miglustat co-administration enhances the efficacy of enzyme replacement therapy in Pompe mice.

Allyson Anding, Sofia Kinton, Kaitlyn Baranowski, Alexander Brezzani, Hilde De Busser, Michael R Dufault, Patrick Finn, Kelly Keefe, Tanya Tetrault, Yi Li, Weiliang Qiu, Katrien Raes, Olivier Vitse, Mindy Zhang, Robin Ziegler, S Pablo Sardi, Bridge Hunter, Kelly George.

  Pompe disease is a rare glycogen storage disorder caused by a deficiency in the lysosomal enzyme acid α-glucosidase, which leads to muscle weakness, cardiac and respiratory failure, and early mortality. Alglucosidase alfa, a recombinant human acid α-glucosidase, was the first approved treatment for Pompe disease, but its uptake into skeletal muscle via the cation-independent mannose-6-phosphate (M6P) receptor (CIMPR) is limited. Avalglucosidase alfa has received marketing authorization in several countries for infantile-onset and/or late-onset Pompe disease. This recently approved enzyme replacement therapy (ERT) was glycoengineered to maximize CIMPR binding through high-affinity interactions with ~7 bis-M6P moieties. Recently, small molecules like the glucosylceramide synthase inhibitor miglustat were reported to increase the stability of recombinant human acid α-glucosidase and it was suggested that an increased serum half-life would result in better glycogen clearance. Here, the effects of miglustat on alglucosidase alfa and avalglucosidase alfa stability, activity, and efficacy in Pompe mice were evaluated. While miglustat increased the stability of both enzymes in fluorescent protein thermal shift assays and when incubated in neutral pH buffer over time, it reduced their enzymatic activity by ~50%. Improvement in tissue glycogen clearance and transcriptional dysregulation in Pompe mice correlated with M6P levels, but not with miglustat co-administration. These results further substantiate the crucial role of CIMPR binding in lysosomal targeting of ERTs. Significance Statement This work describes important new insights into the treatment of Pompe disease using currently approved ERTs co-administered with miglustat. Though miglustat increased the stability of ERTs in vitro, there was no positive impact to glycogen clearance and transcriptional correction in Pompe mice. However, increasing M6P levels resulted in increased cell uptake in vitro, and increased glycogen clearance and transcriptional correction in Pompe mice, further underscoring the crucial role of CIMPR-mediated lysosomal targeting for ERTs.

Keywords:  Autophagy; Transcriptional regulation; animal/nonclinical/preclinical; chaperones; molecular drug targeting; recombinant proteins

DOI:  https://doi.org/10.1124/jpet.123.001593
Nat Rev Dis Primers. 2023 Sep 07. 9(1): 47

Glycogen storage diseases.

DOI: https://doi.org/10.1038/s41572-023-00462-1
Biochim Biophys Acta Mol Basis Dis. 2023 Sep 04. pii: S0925-4439(23)00240-5. [Epub ahead of print]1870(1): 166874

Inhibition of Wnt/β-catenin signaling reduces renal fibrosis in murine glycogen storage disease type Ia.

Cheol Lee, Kunal Pratap, Lisa Zhang, Hung Dar Chen, Sudeep Gautam, Irina Arnaoutova, Mahadevan Raghavankutty, Matthew F Starost, Michael Kahn, Brian C Mansfield, Janice Y Chou.

  Glycogen storage disease type Ia (GSD-Ia) is caused by a deficiency in the enzyme glucose-6-phosphatase-α (G6Pase-α or G6PC) that is expressed primarily in the gluconeogenic organs, namely liver, kidney cortex, and intestine. Renal G6Pase-α deficiency in GSD-Ia is characterized by impaired gluconeogenesis, nephromegaly due to elevated glycogen accumulation, and nephropathy caused, in part, by renal fibrosis, mediated by activation of the renin-angiotensin system (RAS). The Wnt/β-catenin signaling regulates the expression of a variety of downstream mediators implicated in renal fibrosis, including multiple genes in the RAS. Sustained activation of Wnt/β-catenin signaling is associated with the development and progression of renal fibrotic lesions that can lead to chronic kidney disease. In this study, we examined the molecular mechanism underlying GSD-Ia nephropathy. Damage to the kidney proximal tubules is known to trigger acute kidney injury (AKI) that can, in turn, activate Wnt/β-catenin signaling. We show that GSD-Ia mice have AKI that leads to activation of the Wnt/β-catenin/RAS axis. Renal fibrosis was demonstrated by increased renal levels of Snail1, α-smooth muscle actin (α-SMA), and extracellular matrix proteins, including collagen-Iα1 and collagen-IV. Treating GSD-Ia mice with a CBP/β-catenin inhibitor, ICG-001, significantly decreased nuclear translocated active β-catenin and reduced renal levels of renin, Snail1, α-SMA, and collagen-IV. The results suggest that inhibition of Wnt/β-catenin signaling may be a promising therapeutic strategy for GSD-Ia nephropathy.

Keywords:  Acute kidney injury; Glucose reabsorption; Glucose-6-phosphatase-α; Nephromegaly, ICG-001; von Gierke Disease

DOI:  https://doi.org/10.1016/j.bbadis.2023.166874
Scand J Med Sci Sports. 2023 Sep 05.

The recovery of muscle function and glycogen levels following game-play in young elite male ice hockey players.

Hallur Thorsteinsson, Jeppe F Vigh-Larsen, Jeppe Panduro, Bjørn Fristrup, Daniel Zornow Kruse, Lasse Gliemann, Marte Egeland, Jens L Olesen, Per Aagaard, Morten B Randers, Peter Krustrup, Lars Nybo, Kristian Overgaard, Magni Mohr.

  Despite the frequent occurrence of congested game fixtures in elite ice hockey, the postgame recovery pattern has not previously been investigated. The purpose of the present study was therefore to evaluate the acute decrements and subsequent recovery of skeletal muscle glycogen levels, muscle function and repeated-sprint ability following ice hockey game-play. Sixteen male players from the Danish U20 national team completed a training game with muscle biopsies obtained before, postgame and following ~38 h of recovery (day 2). On-ice repeated-sprint ability and muscle function (maximal voluntary isometric [MVIC] and electrically induced low- (20 Hz) and high-frequency (50 Hz) knee-extensor contractions) were assessed at the same time points, as well as ~20 h into recovery (day 1). Muscle glycogen decreased 31% (p < 0.001) postgame and had returned to pregame levels on day 2. MVIC dropped 11%, whereas 50 and 20 Hz torque dropped 21% and 29% postgame, respectively, inducing a 10% reduction in the 20/50 Hz torque ratio indicative of low-frequency force depression (all p < 0.001). While MVIC torque returned to baseline on day 1, 20 and 50 Hz torque remained depressed by 9%-11% (p = 0.010-0.040), hence restoring the pre-exercise 20/50 Hz ratio. Repeated-sprint ability was only marginally reduced by 1% postgame (p = 0.041) and fully recovered on day 1. In conclusion, an elite youth ice hockey game induces substantial reductions in muscle glycogen content and muscle function, but only minor reductions in repeated-sprint ability and with complete recovery of all parameters within 1-2 days postgame.

Keywords:  fatigue; intermittent exercise; performance; team sport

DOI:  https://doi.org/10.1111/sms.14485
Ther Clin Risk Manag. 2023 ;19 713-729

Monitoring and Management of Respiratory Function in Pompe Disease: Current Perspectives.

Léa El Haddad, Mainur Khan, Rania Soufny, David Mummy, Bastiaan Driehuys, Wissam Mansour, Priya S Kishnani, Mai K ElMallah.

  Pompe disease (PD) is a neuromuscular disorder caused by a deficiency of acid alpha-glucosidase (GAA) - a lysosomal enzyme responsible for hydrolyzing glycogen. GAA deficiency leads to accumulation of glycogen in lysosomes, causing cellular disruption. The severity of PD is directly related to the extent of GAA deficiency - if no or minimal GAA is produced, symptoms are severe and manifest in infancy, known as infantile onset PD (IOPD). If left untreated, infants with IOPD experience muscle hypotonia and cardio-respiratory failure leading to significant morbidity and mortality in the first year of life. In contrast, late-onset PD (LOPD) patients have more GAA activity and present later in life, but also have significant respiratory function decline. Despite FDA-approved enzyme replacement therapy, respiratory insufficiency remains a major cause of morbidity and mortality, emphasizing the importance of early detection and management of respiratory complications. These complications include impaired cough and airway clearance, respiratory muscle weakness, sleep-related breathing issues, and pulmonary infections. This review aims to provide an overview of the respiratory pathology, monitoring, and management of PD patients. In addition, we discuss the impact of novel approaches and therapies on respiratory function in PD.

Keywords:  Pompe disease; respiratory complications; respiratory monitoring; respiratory therapy

DOI:  https://doi.org/10.2147/TCRM.S362871
J Biol Chem. 2023 Sep 01. pii: S0021-9258(23)02247-0. [Epub ahead of print] 105219

PER2/P65-driven glycogen synthase 1 transcription in macrophages modulates gut inflammation and pathogenesis of rectal prolapse.

Zhao Ding, Wenhao Ge, Xiaodong Xu, Xi Xu, Shiming Wang, Jianfa Zhang.

  Rectal prolapse in serious inflammatory bowel disease is caused by abnormal reactions of the intestinal mucosal immune system. The circadian clock has been implicated in immune defense and inflammatory responses, but the mechanisms by which it regulates gut inflammation remain unclear. In this study, we investigate the role of the rhythmic gene Period2 (Per2) in triggering inflammation in the rectum and its contribution to the pathogenesis of rectal prolapse. We report that Per2 deficiency in mice increased susceptibility to intestinal inflammation and resulted in spontaneous rectal prolapse. We further demonstrated that PER2 was essential for the transcription of glycogen synthase 1 (Gys1) by interacting with the nuclear factor-κB (NF-κB) p65. We show inhibition of Per2 reduced the levels of GYS1 and glycogen synthesis in macrophages, impairing the capacity of pathogen clearance and disrupting the composition of gut microbes. Taken together, our findings identify a novel role for Per2 in regulating the capacity of pathogen clearance in macrophages and gut inflammation, and suggest a potential animal model that more closely resembles human rectal prolapse.

Keywords:  Per2; inflammatory; inflammatory bowel disease; macrophage; rectal prolapse

DOI:  https://doi.org/10.1016/j.jbc.2023.105219
Mol Genet Metab Rep. 2023 Sep;36 100989

Muscle ultrasound in patients with late-onset Pompe disease identified by newborn screening.

David G Jackson, Laura E Case, Erin Huggins, Maggie Holland, Janet Blount, Lisa Hobson Webb, Priya S Kishnani.

   Importance: Implementation of newborn screening (NBS) in the United States now detects infants with late-onset Pompe disease (LOPD), a lysosomal storage disease characterized by slowly progressive muscle weakness, and detailed clinical evaluation has identified early muscle weakness. Biomarkers may be uninformative; thus, non-invasive imaging is needed to assess early LOPD muscle changes. Muscle ultrasound (US) measuring echointensity (EI) is a non-invasive measure of muscle health.
Objective: In this study, we aimed to evaluate if EI can identify characteristic patterns of muscle involvement in LOPD patients identified by NBS.
Design/setting: Prospective, cross-sectional, single time point study.
Setting: One-center study.
Participants: We examined 20 infants with NBS-identified LOPD (ages 5-20 months). All had standardized physical therapy assessments.
Exposures: Creatine Kinase (CK) and Urine Hexose Tetrasaccharide (Glc4) were obtained. Muscle US of deltoid, biceps brachii, forearm flexors, thoracic paraspinals, gluteus maximus, quadriceps, tibialis anterior and medial gastrocnemius was performed.
Main outcomes and measures: Mean EI was calculated for all involved muscle groups. Quantitative EI Sum Scores were calculated as total EI divided by number of muscle groups assessed. We performed a comprehensive literature review to compare our results to previous LOPD muscle ultrasound studies.
Results: Six of 20 participants had elevated CK and 15 had ≥50% of the most common concerning kinematic physical findings; with normal urine Glc4 in all except one. Based upon muscle EI, the most affected muscles were quadriceps and medial gastrocnemius, with notable elevated EI in thoracic paraspinals. Biceps brachii was the most frequently affected upper extremity muscle. EI sum scores correlated moderately with increasing CK. Statistically significant positive correlation was found between posterior pelvic tilt in sitting and EI of gluteus maximus. Sonographic pattern of muscle involvement was similar to previous studies assessing older patients with LOPD.
Conclusions and relevance: In this study, muscle EI was elevated most often in the quadriceps, tibialis anterior, medial gastrocnemius, thoracic paraspinals, and biceps brachii. Involved muscles generally fit the profile of physical and muscle ultrasound/MRI exam findings in LOPD patients. Muscle ultrasound is recommended for rapid, focused muscle assessment in LOPD, especially those identified via NBS. Future studies should focus on this pattern of ultrasonographic abnormality and changes over time.

Keywords:  Newborn screening; Pompe disease; Ultrasound

DOI:  https://doi.org/10.1016/j.ymgmr.2023.100989
Eur Rev Med Pharmacol Sci. 2023 Aug;pii: 33393. [Epub ahead of print]27(16): 7416-7430

Impact of glycogen synthase kinase-3ß inhibition on rats' temporomandibular joint collagen-induced rheumatoid arthritis with correlation to miRNA-155/miRNA-24 expression.

R H Al-Serwi, G Othman, A F Dawood, A K Alhumaidan, H S Alharbi, M El-Sherbiny, M E Almadani, D M A Elsherbini.

OBJECTIVE: The current study considered assessing the role of miRNA-155 and miRNA-24 in collagen-induced rheumatoid arthritis (RA) in rats' temporomandibular joint (TMJ). Their role in histological aggressiveness of the disease and therapy response to glycogen synthase kinase (GSK) inhibitor 4-benzyl-2-methyl-1,2,4-thiadiazolidine-3,5-dione (TDZD-8) will be studied.
MATERIALS AND METHODS: Rats were randomly distributed to four groups (8 rats/group): group I negative control, group II collagen-induced rheumatoid arthritis (CIA), group III Control+TDZD-8 treated group, and group IV CIA+TDZD-8 treated group. Then were euthanized 42 days after the start of the experiment. H&E staining, Masson trichrome staining, and immunohistochemical antibodies against S100 were performed. qRT-PCR of miRNA-155 and miRNA-24 were done for frozen synovial tissues.
RESULTS: Histological analysis showed that the most affected structure in induced rheumatoid arthritis of TMJ is the articular disc, condylar head, and subchondral bone. Combined treatment with TDZD-8 improved histological status in the joint. Masson's trichrome (MTC) histochemical staining revealed disarrangement of collagen fibers and adherence between the articular disc and condylar cartilage. Meanwhile, the morphology and collagen composition of the disc and condyle in CIA+ TDZD-8 were similar to those of healthy tissues. Immunohistochemical analysis for S100A4 revealed increased immunoreactivity staining in the CIA group. The immunoreactivity was significantly decreased in CIA+ TDZD-8 treated group. TDZD-8 significantly decreased the levels of miRNA-155 and miRNA-24 in synovial tissue.
CONCLUSIONS: Our results reveal for the first-time correlation of miRNA-155 and miRNA-24 that might be implicated in the onset of TMJ RA. Consequently, the treatment of CIA with GSK inhibitor (TDZD-8) yields encouraging results. We predicted the TDZD-8 might protect against CIA by suppressing miRNA-155, miRNA-24, and S100A4 protein levels.

DOI: https://doi.org/10.26355/eurrev_202308_33393
bioRxiv. 2023 Aug 23. pii: 2023.08.22.554345. [Epub ahead of print]

Disruption of Hepatic Mitochondrial Pyruvate and Amino Acid Metabolism Impairs Gluconeogenesis and Endurance Exercise Capacity in Mice.

Michael R Martino, Mohammad Habibi, Daniel Ferguson, Rita T Brookheart, John P Thyfault, Gretchen A Meyer, Louise Lantier, Curtis C Hughey, Brian N Finck.

Exercise robustly increases the glucose demands of skeletal muscle. This demand is met not only by muscle glycogenolysis, but also by accelerated liver glucose production from hepatic glycogenolysis and gluconeogenesis to fuel mechanical work and prevent hypoglycemia during exercise. Hepatic gluconeogenesis during exercise is dependent on highly coordinated responses within and between muscle and liver. Specifically, exercise increases the rate at which gluconeogenic precursors such as pyruvate/lactate or amino acids are delivered from muscle to the liver, extracted by the liver, and channeled into glucose. Herein, we examined the effects of interrupting gluconeogenic efficiency and capacity on exercise performance by deleting hepatic mitochondrial pyruvate carrier 2 (MPC2) and/or alanine transaminase 2 (ALT2) in mice. We found that deletion of MPC2 or ALT2 alone did not significantly affect time to exhaustion or post-exercise glucose concentrations in treadmill exercise tests, but mice lacking both MPC2 and ALT2 in liver (DKO) reached exhaustion faster and exhibited lower circulating glucose during and after exercise. Use of ²H/¹³C metabolic flux analyses demonstrated that DKO mice exhibited lower endogenous glucose production owing to decreased glycogenolysis and gluconeogenesis at rest and during exercise. The decreased gluconeogenesis was accompanied by lower anaplerotic, cataplerotic, and TCA cycle fluxes. Collectively, these findings demonstrate that the transition of the liver to the gluconeogenic mode is critical for preventing hypoglycemia and sustaining performance during exercise. The results also illustrate the need for interorgan crosstalk during exercise as described by the Cahill and Cori cycles.

DOI: https://doi.org/10.1101/2023.08.22.554345