bims-glecem 2023-11-26 papers

Issue of 2023–11–26
six papers selected by
Dipsikha Biswas, Københavns Universitet

Mol Metab. 2023 Nov 21. pii: S2212-8778(23)00172-2. [Epub ahead of print] 101838

Hepatic ChREBP orchestrates intrahepatic carbohydrate metabolism to limit hepatic glucose 6-phosphate and glycogen accumulation in a mouse model for acute Glycogen Storage Disease type Ib (6675 words).

K A Krishnamurthy, M G S Rutten, J A Hoogerland, T H Van Dijk, T Bos, M Koehorst, M P De Vries, N J Kloosterhuis, H Havinga, B V Schomakers, M van Weeghel, J C Wolters, B M Bakker, M H Oosterveer.

OBJECTIVE: Carbohydrate Response Element Binding Protein (ChREBP) is a glucose 6-phosphate (G6P)-sensitive transcription factor that acts as a metabolic switch to maintain intracellular glucose and phosphate homeostasis. Hepatic ChREBP is well-known for its regulatory role in glycolysis, the pentose phosphate pathway, and de novo lipogenesis. The physiological role of ChREBP in hepatic glycogen metabolism and blood glucose regulation has not been assessed in detail, and ChREBP's contribution to carbohydrate flux adaptations in hepatic Glycogen Storage Disease type 1 (GSD I) requires further investigation.
METHODS: The current study aimed to investigate the role of ChREBP as a regulator of glycogen metabolism in response to hepatic G6P accumulation, using a model for acute hepatic GSD type Ib. The immediate biochemical and regulatory responses to hepatic G6P accumulation were evaluated upon G6P transporter inhibition by the chlorogenic acid S4048 in mice that were either treated with a short hairpin RNA (shRNA) directed against ChREBP (shChREBP) or a scrambled shRNA (shSCR). Complementary stable isotope experiments were performed to quantify hepatic carbohydrate fluxes in vivo.
RESULTS: ShChREBP treatment normalized the S4048-mediated induction of hepatic ChREBP target genes to levels observed in vehicle- and shSCR-treated controls. In parallel, hepatic shChREBP treatment in S4048-infused mice resulted in a more pronounced accumulation of hepatic glycogen and further reduction of blood glucose levels compared to shSCR treatment. Hepatic ChREBP knockdown modestly increased glucokinase (GCK) flux in S4048-treated mice while it enhanced UDP-glucose turnover as well as glycogen synthase and phosphorylase fluxes. Hepatic GCK mRNA and protein levels were induced by shChREBP treatment in both vehicle- and S4048-treated mice, while glycogen synthase 2 (GYS2) and glycogen phosphorylase (PYGL) mRNA and protein levels were reduced. Finally, knockdown of hepatic ChREBP expression reduced starch domain binding protein 1 (STBD1) mRNA and protein levels while it inhibited acid alpha-glucosidase (GAA) activity, suggesting reduced capacity for lysosomal glycogen breakdown.
CONCLUSIONS: Our data show that ChREBP activation controls hepatic glycogen and blood glucose levels in acute hepatic GSD Ib through concomitant regulation of glucose phosphorylation, glycogenesis, and glycogenolysis. ChREBP-mediated control of GCK enzyme levels aligns with corresponding adaptations in GCK flux. In contrast, ChREBP activation in response to acute hepatic GSD Ib exerts opposite effects on GYS2/PYGL enzyme levels and their corresponding fluxes, indicating that GYS2/PYGL expression levels are not limiting to their respective fluxes under these conditions.

Keywords: ChREBP; Glycogen Storage Disease type Ib; glucokinase; glycophagy; hepatic glycogen metabolism; stable isotope tracing

DOI: https://doi.org/10.1016/j.molmet.2023.101838

Res Sq. 2023 Nov 08. pii: rs.3.rs-3526342. [Epub ahead of print]

Neuronal Glycogen Breakdown Mitigates Tauopathy via Pentose Phosphate Pathway-Mediated Oxidative Stress Reduction.

Pankaj Kapahi, Sudipta Bar, Kenneth Wilson, Tyler Hilsabeck, Sydney Alderfer, Eric Dammer, Jordan Burton, Samah Shah, Anja Holtz, Enrique Carrera, Jennifer Beck, Jackson Chen, Grant Kauwe, Tara Tracy, Nicholas Seyfried, Birgit Schilling, Lisa Ellerby.

Tauopathies encompass a range of neurodegenerative disorders, such as Alzheimer's disease (AD) and frontotemporal dementia (FTD). Unfortunately, current treatment approaches for tauopathies have yielded limited success, underscoring the pressing need for novel therapeutic strategies. We observed distinct signatures of impaired glycogen metabolism in the Drosophila brain of the tauopathy model and the brain of AD patients, indicating a link between tauopathies and glycogen metabolism. We demonstrate that the breakdown of neuronal glycogen by activating glycogen phosphorylase (GlyP) ameliorates the tauopathy phenotypes in flies and induced pluripotent stem cell (iPSC) derived neurons from FTD patients. We observed that glycogen breakdown redirects the glucose flux to the pentose phosphate pathway to alleviate oxidative stress. Our findings uncover a critical role for increased GlyP activity in mediating the neuroprotection benefit of dietary restriction (DR) through the cAMP-mediated protein kinase A (PKA) activation. Our studies identify impaired glycogen metabolism as a key hallmark for tauopathies and offer a promising therapeutic target in tauopathy treatment.

DOI: https://doi.org/10.21203/rs.3.rs-3526342/v1

J Cachexia Sarcopenia Muscle. 2023 Nov 20.

MicroRNA-92b in the skeletal muscle regulates exercise capacity via modulation of glucose metabolism.

Shu Yang, Guangyan Yang, Xinyu Wang, Lixing Li, Yanchun Li, Jiaqing Xiang, Lin Kang, Zhen Liang.

BACKGROUND: Exercise mimetics is a proposed class of therapeutics that specifically mimics or enhances the therapeutic effects of exercise. Muscle glycogen and lactate extrusion are critical for physical performance. The mechanism by which glycogen and lactate metabolism are manipulated during exercise remains unclear. This study aimed to assess the effect of miR-92b on the upregulation of exercise training-induced physical performance.
METHODS: Adeno-associated virus (AAV)-mediated skeletal muscle miR-92b overexpression in C57BLKS/J mice, and global knockout of miR-92b mice were used to explore the function of miR-92b in glycogen and lactate metabolism in skeletal muscle. AAV-mediated UGP2 or MCT4 knockdown in WT or miR-92 knockout mice was used to confirm whether miR-92b regulates glycogen and lactate metabolism in skeletal muscle through UGP2 and MCT4. Body weight, muscle weight, grip strength, running time and distance to exhaustion, and muscle histology were assessed. The expression levels of muscle mass-related and function-related proteins were analysed by immunoblotting or immunostaining.
RESULTS: Global knockout of miR-92b resulted in normal body weight and insulin sensitivity, but higher glycogen content before exercise exhaustion (0.8538 ± 0.0417 vs. 1.043 ± 0.040, **P = 0.0087), lower lactate levels after exercise exhaustion (4.133 ± 0.2589 vs. 3.207 ± 0.2511, *P = 0.0279), and better exercise capacity (running distance to exhaustion, 3616 ± 86.71 vs. 4231 ± 90.29, ***P = 0.0006; running time to exhaustion, 186.8 ± 8.027 vs. 220.8 ± 3.156, **P = 0.0028), as compared with those observed in the control mice. Mice skeletal muscle overexpressing miR-92b (both miR-92b-3p and miR-92b-5p) displayed lower glycogen content before exercise exhaustion (0.6318 ± 0.0231 vs. 0.535 ± 0.0194, **P = 0.0094), and higher lactate accumulation after exercise exhaustion (4.5 ± 0.2394 vs. 5.467 ± 0.1892, *P = 0.01), and poorer exercise capacity (running distance to exhaustion, 4005 ± 81.65 vs. 3228 ± 149.8, ***P<0.0001; running time to exhaustion, 225.5 ± 7.689 vs. 163 ± 6.476, **P = 0.001). Mechanistic analysis revealed that miR-92b-3p targets UDP-glucose pyrophosphorylase 2 (UGP2) expression to inhibit glycogen synthesis, while miR-92b-5p represses lactate extrusion by directly target monocarboxylate transporter 4 (MCT4). Knockdown of UGP2 and MCT4 reversed the effects observed in the absence of miR-92b in vivo.
CONCLUSIONS: This study revealed regulatory pathways, including miR-92b-3p/UGP2/glycogen synthesis and miR-92b-5p/MCT4/lactate extrusion, which could be targeted to control exercise capacity.

Keywords: Exercise capacity; Glycogen synthesis; Lactate extrusion; Skeletal muscle; miR-92b

DOI: https://doi.org/10.1002/jcsm.13377

Biochem Pharmacol. 2023 Nov 18. pii: S0006-2952(23)00516-6. [Epub ahead of print]218 115923

New insights into glycogen synthase kinase-3: A common target for neurodegenerative diseases.

Chengfeng Wang, Yu Cui, Tong Xu, Yu Zhou, Rong Yang, Ting Wang.

Glycogen synthase kinase 3 (GSK-3) is a highly conserved protein serine/threonine kinase that plays a central role in a wide variety of cellular processes to coordinate catabolic and anabolic pathways and regulate cell growth and fate. There is increasing evidence showing that abnormal glycogen synthase kinase 3 (GSK-3) is associated with the pathogenesis and progression of many disorders, such as cancer, diabetes, psychiatric diseases, and neurodegenerative diseases. In this review, we summarize recent findings about the regulatory role of GSK-3 in the occurrence and development of multiple neurodegenerative diseases, mainly focusing on Alzheimer's disease, Parkinson's disease, and amyotrophic lateral sclerosis. The aim of this study is to provide new insight into the shared working mechanism of GSK-3 as a therapeutic target of multiple neurodegenerative diseases.

Keywords: GSK-3; GSK-3 inhibitors; Neurodegeneration; Neuroprotection; Phosphorylation

DOI: https://doi.org/10.1016/j.bcp.2023.115923

JACC Heart Fail. 2023 Nov 08. pii: S2213-1779(23)00695-9. [Epub ahead of print]

Skeletal Muscle Involvement in Patients With Truncations of Titin and Familial Dilated Cardiomyopathy.

Sofie Vinther Skriver, Bjørg Krett, Nanna Scharf Poulsen, Thomas Krag, Helle Rudkjær Walas, Alex Hørby Christensen, Henning Bundgaard, John Vissing, Christoffer Rasmus Vissing.

BACKGROUND: Genetic variants in titin (TTN) are associated with dilated cardiomyopathy (DCM) and skeletal myopathy. However, the skeletal muscle phenotype in individuals carrying heterozygous truncating TTN variants (TTNtv), the leading cause of DCM, is understudied.
OBJECTIVES: This study aimed to assess the skeletal muscle phenotype associated with TTNtv.
METHODS: Participants with TTNtv were included in a cross-sectional study. Skeletal muscle fat fraction was evaluated by magnetic resonance imaging (compared with healthy controls and controls with non-TTNtv DCM). Muscle strength was evaluated by dynamometry and muscle biopsy specimens were analyzed.
RESULTS: Twenty-five TTNtv participants (11 women, mean age 51 ± 15 years, left ventricular ejection fraction 45% ± 10%) were included (19 had DCM). Compared to healthy controls (n = 25), fat fraction was higher in calf (12.5% vs 9.9%, P = 0.013), thigh (12.2% vs 9.3%, P = 0.004), and paraspinal muscles (18.8% vs 13.9%, P = 0.008) of TTNtv participants. Linear mixed effects modelling found higher fat fractions in TTNtv participants compared to healthy controls (2.5%; 95% CI: 1.4-3.7]; P < 0.001) and controls with non-TTNtv genetic DCM (n = 7; 1.5%; 95% CI: 0.2-2.8; P = 0.025). Muscle strength was within 1 SD of normal values. Biopsy specimens from 21 participants found myopathic features in 13 (62%), including central nuclei. Electron microscopy showed well-ordered Z-lines and T-tubuli but uneven and discontinuous M-lines and excessive glycogen depositions flanked by autophagosomes, lysosomes, and abnormal mitochondria with mitophagy.
CONCLUSIONS: Mild skeletal muscle involvement was prevalent in patients with TTNtv. The phenotype was characterized by an increased muscle fat fraction and excessive accumulation of glycogen, possibly due to reduced autophagic flux. These findings indicate an impact of TTNtv beyond the heart.

Keywords: genotype; inherited cardiomyopathies; phenotype; truncating titin variants

DOI: https://doi.org/10.1016/j.jchf.2023.10.010

Clin Cancer Res. 2023 Nov 20.

Phase 1 study of Elraglusib (9-ING-41), a glycogen synthase kinase-3b inhibitor, as monotherapy or combined with chemotherapy in patients with advanced malignancies.

PURPOSE: The safety, pharmacokinetics and efficacy of elraglusib, a GSK-3b small molecule inhibitor, as monotherapy or combined with chemotherapy, in patients with relapsed or refractory solid tumors or hematologic malignancies was studied.
PATIENTS AND METHODS: Elraglusib (intravenously twice weekly in three-week cycles) monotherapy dose-escalation was followed by dose-escalation with eight chemotherapy regimens (gemcitabine, doxorubicin, lomustine, carboplatin, irinotecan, gemcitabine/nab-paclitaxel, paclitaxel/carboplatin, and pemetrexed/carboplatin) in patients previously exposed to the same chemotherapy.
RESULTS: Patients received monotherapy (n=67) or combination therapy (n=171) elraglusib doses 1-15 mg/kg twice weekly. The initial recommended phase 2 dose (RP2D) of elraglusib was 15 mg/kg twice weekly and was defined, without DLT observation, due to fluid volumes necessary for drug administration. The RP2D was subsequently reduced to 9.3 mg/kg once weekly to reduce elraglusib-associated central/peripheral vascular access catheter blockages. Other common elraglusib-related adverse events (AE) included transient visual changes and fatigue. Grade 3 treatment-emergent AE occurred in 55.2% and 71.3% of patients on monotherapy and combination therapy, respectively. Part 1 monotherapy (n=62) and part 2 combination (n=138) patients were evaluable for response. In part 1, a patient with melanoma had a complete response, and a patient with acute T-cell leukemia/lymphoma had a partial response (PR). In part 2, 7 PRs were observed, and the median progression-free survival and overall survival were 2.1 (95% CI, 2-2.6) and 6.9 (95% CI, 5.7-8.4) months, respectively.
CONCLUSIONS: Elraglusib had a favorable toxicity profile as monotherapy and combined with chemotherapy and was associated with clinical benefit supporting further clinical evaluation in combination with chemotherapy.

DOI: https://doi.org/10.1158/1078-0432.CCR-23-1916