bims-glecem 2023-09-03 papers

Issue of 2023–09–03
seven papers selected by
Dipsikha Biswas, Københavns Universitet

Trends Endocrinol Metab. 2023 Aug 24. pii: S1043-2760(23)00152-2. [Epub ahead of print]

Lysosomal glucose sensing and glycophagy in metabolism.

Melina C Mancini, Robert C Noland, J Jason Collier, Susan J Burke, Krisztian Stadler, Timothy D Heden.

Lysosomes are cellular organelles that function to catabolize both extra- and intracellular cargo, act as a platform for nutrient sensing, and represent a core signaling node integrating bioenergetic cues to changes in cellular metabolism. Although lysosomal amino acid and lipid sensing in metabolism has been well characterized, lysosomal glucose sensing and the role of lysosomes in glucose metabolism is unrefined. This review will highlight the role of the lysosome in glucose metabolism with a focus on lysosomal glucose and glycogen sensing, glycophagy, and lysosomal glucose transport and how these processes impact autophagy and energy metabolism. Additionally, the role of lysosomal glucose metabolism in genetic and metabolic diseases will be briefly discussed.

Keywords: autophagy; carbohydrate sensing; glycogen; nutrient sensing

DOI: https://doi.org/10.1016/j.tem.2023.07.008

PLoS One. 2023 ;18(8): e0290832

Elevated liver glycogenolysis mediates higher blood glucose during acute exercise in Barth syndrome.

George G Schweitzer, Grace L Ditzenberger, Curtis C Hughey, Brian N Finck, Michael R Martino, Christina A Pacak, Barry J Byrne, William Todd Cade.

Barth syndrome (BTHS) is an X-linked recessive genetic disorder due to mutations in the Tafazzin (TAFAZZIN) gene that lead to cardiac and skeletal muscle mitochondrial dysfunction. Previous studies in humans with BTHS demonstrate that the defects in muscle mitochondrial oxidative metabolism result in an enhanced reliance on anaerobic metabolism during exercise to meet energy demands of muscular work. During exercise, the liver normally increases glucose production via glycogenolysis and gluconeogenesis to match the elevated rate of muscle glucose uptake and meet the ATP requirements of working muscle. However, the impact of Tafazzin deficiency on hepatic glucose production and the pathways contributing to hepatic glucose production during exercise is unknown. Therefore, the purpose of this study was to quantify in vivo liver gluconeogenesis and glycogenolysis in Tafazzin knockdown mice at rest and during acute exercise.
METHODS: Male TAFAZZIN shRNA transgenic (TG) and wild-type (WT) mice completed exhaustive treadmill running protocols to test exercise tolerance. Mice underwent 2H- and 13C-stable isotope infusions at rest and during a 30-minute treadmill running bout to quantify hepatic glucose production and associated nutrient fluxes under sedentary conditions and during acute exercise. Circulating and tissue (skeletal muscle and liver) samples were obtained during and following exercise to assess static metabolite levels.
RESULTS: TG mice reached exhaustion sooner during exhaustive treadmill running protocols and exhibited higher plasma lactate concentrations after exhaustive exercise compared to WT mice. Arterial glucose levels were comparable between genotypes at rest, but higher in TG mice compared to WT mice during exercise. Consistent with the higher blood glucose, TG mice showed increased endogenous glucose production owing to elevated glycogenolysis compared to WT mice during exercise. Total gluconeogenesis, gluconeogenesis from glycerol, gluconeogenesis from phosphoenolpyruvate, pyruvate cycling, total cataplerosis, and anaplerotic fluxes were similar between TG and WT mice at rest and during exercise. However, lactate dehydrogenase flux and TCA cycle fluxes trended higher in TG mice during exercise. Liver glycogen content in TG was higher in TG vs. controls.
CONCLUSION: Our data in the Tafazzin knockdown mouse suggest that elevated anaerobic metabolism during rest and exercise previously reported in humans with BTHS are supported by the finding of higher hepatic glycogenolysis.

DOI: https://doi.org/10.1371/journal.pone.0290832

Niger J Clin Pract. 2023 Jul;26(7): 1045-1049

A first in literature: anesthesia management in kidney transplant surgery of a patient with McArdle disease.

E A Bicak.

McArdle disease is an inherited myopathy that autosomal recessive inheritance and is also known as glycogen storage disease type 5. Myoglobinuria, increase in serum CK level and darkening of urine color secondary to myoglobinuria are typical. Patients may have symptoms associated with increased rhabdomyolysis secondary acute renal failure or hyperkalemia after long and strenuous exercise periods. Today, many studies in the literature have shown that transplantation is superior to dialysis in patients with end-stage renal disease. Our case is a 53-year-old male patient with the diagnosis of McArdle syndrome who was going to have a kidney transplant. The patient had essential hypertension and history of HBsAg+. Total intravenous anesthesia technique was chosen as the anesthesia technique because inhaled anesthetic agents may trigger malignant hyperthermia in the patient. We didn't experience any perioperative complications in our patient. In conclusion, renal transplantation performed with total intravenous in a McArdle syndrome patient may be a simple and effective technique.

Keywords: Anesthesia; McArdle disease; kidney transplant

DOI: https://doi.org/10.4103/njcp.njcp_895_22

Cell Rep. 2023 Aug 25. pii: S2211-1247(23)01041-0. [Epub ahead of print]42(9): 113030

GSK3 and lamellipodin balance lamellipodial protrusions and focal adhesion maturation in mouse neural crest migration.

Lisa Dobson, William B Barrell, Zahra Seraj, Steven Lynham, Sheng-Yuan Wu, Matthias Krause, Karen J Liu.

Neural crest cells are multipotent cells that delaminate from the neuroepithelium, migrating throughout the embryo. Aberrant migration causes developmental defects. Animal models are improving our understanding of neural crest anomalies, but in vivo migration behaviors are poorly understood. Here, we demonstrate that murine neural crest cells display actin-based lamellipodia and filopodia in vivo. Using neural crest-specific knockouts or inhibitors, we show that the serine-threonine kinase glycogen synthase kinase-3 (GSK3) and the cytoskeletal regulator lamellipodin (Lpd) are required for lamellipodia formation while preventing focal adhesion maturation. Lpd is a substrate of GSK3, and phosphorylation of Lpd favors interactions with the Scar/WAVE complex (lamellipodia formation) at the expense of VASP and Mena interactions (adhesion maturation and filopodia formation). This improved understanding of cytoskeletal regulation in mammalian neural crest migration has general implications for neural crest anomalies and cancer.

Keywords: CP: Cell biology; focal adhesions; glycogen synthase kinase 3; gsk3; lamellipodia; lamellipodin; mouse; neural crest

DOI: https://doi.org/10.1016/j.celrep.2023.113030

Curr Opin Neurol. 2023 Jul 20.

Current avenues of gene therapy in Pompe disease.

Carmen Leon-Astudillo, Prasad D Trivedi, Ramon C Sun, Matthew Gentry, Barry J Byrne, Manuela Corti.

PURPOSE OF THE REVIEW: Pompe disease is a rare, inherited, devastating condition that causes progressive weakness, cardiomyopathy and neuromotor disease due to the accumulation of glycogen in striated and smooth muscle, as well as neurons. While enzyme replacement therapy has dramatically changed the outcome of patients with the disease, this strategy has several limitations. Gene therapy in Pompe disease constitutes an attractive approach due to the multisystem aspects of the disease and need to address the central nervous system manifestations. This review highlights the recent work in this field, including methods, progress, shortcomings, and future directions.
RECENT FINDINGS: Recombinant adeno-associated virus (rAAV) and lentiviral vectors (LV) are well studied platforms for gene therapy in Pompe disease. These products can be further adapted for safe and efficient administration with concomitant immunosuppression, with the modification of specific receptors or codon optimization. rAAV has been studied in multiple clinical trials demonstrating safety and tolerability.
SUMMARY: Gene therapy for the treatment of patients with Pompe disease is feasible and offers an opportunity to fully correct the principal pathology leading to cellular glycogen accumulation. Further work is needed to overcome the limitations related to vector production, immunologic reactions and redosing.

DOI: https://doi.org/10.1097/WCO.0000000000001187

World J Mens Health. 2023 Aug 09.

Regulation of Phosphorylation of Glycogen Synthase Kinase 3α and the Correlation with Sperm Motility in Human.

Seung Hyun Park, Young-Pil Kim, Jeong Min Lee, Dong-Wook Park, Ju Tae Seo, Myung Chan Gye.

PURPOSE: To unravel the mechanism regulating the phosphorylation of glycogen synthase kinase 3 (GSK3) and the correlation between the inhibitory phosphorylation of GSK3α and sperm motility in human.
MATERIALS AND METHODS: The phosphorylation and priming phosphorylated substrate-specific kinase activity of GSK3 were examined in human spermatozoa with various motility conditions.
RESULTS: In human spermatozoa, GSK3α/β was localized in the head, midpiece, and principal piece of tail and p-GSK3α(Ser21) was enriched in the midpiece. The ratio of p-GSK3α(Ser21)/GSK3α was positively coupled with normal sperm motility criteria of World Health Organization. In high-motility spermatozoa, p-GSK3α(Ser21) phosphotyrosine (p-Tyr) proteins but p-GSK3α(Tyr279) markedly increased together with decreased kinase activity of GSK3 after incubation in Ca2+ containing medium. In high-motility spermatozoa, p-GSK3α(Ser21) levels were negatively coupled with kinase activity of GSK3, and which was deregulated in low-motility spermatozoa. In high-motility spermatozoa, 6-bromo-indirubin-3'-oxime, an inhibitor of kinase activity of GSK3 increased p-GSK3α(Ser21) and p-Tyr proteins. p-GSK3α(Ser21) and p-Tyr protein levels were decreased by inhibition of PKA and Akt. Calyculin A, a protein phosphatase-1/2A inhibitor, markedly increased the p-GSK3α(Ser21) and p-Tyr proteins, and significantly increased the motility of low-motility human spermatozoa.
CONCLUSIONS: Down regulation of kinase activity of GSK3α by inhibitory phosphorylation was positively coupled with human sperm motility, and which was regulated by Ca2+, PKA, Akt, and PP1. Small-molecule inhibitors of GSK3 and PP1 can be considered to potentiate human sperm motility.

Keywords: Glycogen synthase kinase 3; Humans; Phosphorylation; Sperm motility

DOI: https://doi.org/10.5534/wjmh.230004