bims-glecem 2022-11-13 papers

Issue of 2022‒11‒13
five papers selected by
Dipsikha Biswas, Københavns Universitet

J Physiol. 2022 Nov 12.

Muscle glycogen unavailability and fat oxidation rate during exercise: Insights from McArdle disease.

Carlos Rodriguez-Lopez, Alfredo Santalla, Pedro L Valenzuela, Alberto Real-Martínez, Mónica Villarreal-Salazar, Irene Rodriguez-Gomez, Tomàs Pinós, Ignacio Ara, Alejandro Lucia.

KEY POINTS: Physically active McArdle patients shown an exceptional fat oxidation capacity. Maximal fat oxidation rate occurs near-maximal exercise capacity in these patients. McArdle patients' exercise tolerance might rely on maximal fat oxidation rate capacity. Hyperpnoea patients might, however, cloud substrate oxidation measurements in some patients. An animal model revealed overall no higher molecular markers of lipid transport/metabolism.ABSTRACT: Carbohydrate availability affects fat metabolism during exercise; however, the effects of complete muscle glycogen unavailability on maximal fat oxidation (MFO) rate remain unknown. Our purpose was to examine MFO rate in patients with McArdle disease-an inherited condition caused by complete blockade of muscle glycogen metabolism-compared to healthy controls. Nine patients (3 women, 36 ± 12yrs) and 12 healthy controls (4 women, 40 ± 13yrs) were studied. Several molecular markers of lipid transport/metabolism were also determined in skeletal muscle (gastrocnemius) and white adipose tissue of McArdle (Pygm p.50R*/p.50R*) and wild-type mice. Peak oxygen uptake (VO2 peak), MFO rate, the exercise intensity eliciting MFO rate (FATmax), and the MFO rate-associated workload were determined by indirect calorimetry during an incremental cycle-ergometer test. Despite having a much lower V̇O2 peak (24.7 ± 4 vs. 42.5 ± 11.4 ml·kg-1 ·min-1 , respectively; P < 0.0001), patients showed considerably higher values of MFO rate (0.53 ± 0.12 vs. 0.33 ± 0.10 g·min-1 , P = 0.001), FATmax (94.4 ± 7.2 vs. 41.3 ± 9.1 % of V̇O2 peak, P < 0.0001) and MFO rate-associated workload (1.33 ± 0.35 vs. 0.81 ± 0.54 watts·kg-1 , P = 0.020) than controls. No between-group differences were found overall in molecular markers of lipid transport/metabolism in mice. In summary, patients with McArdle disease show an exceptionally high MFO rate, which they attained at near-maximal exercise capacity. Pending more mechanistic explanations, these findings support the influence of glycogen availability on MFO rate and suggest that these patients develop a unique fat oxidation capacity, possibly as an adaptation to compensate for the inherited blockade in glycogen metabolism, and point to MFO rate as a potential limiting factor of exercise tolerance in this disease. Abstract figure legend McArdle disease is caused by inherited blockade of glycogen breakdown in skeletal muscle fibers, with subsequent intolerance to most exercise tasks as well as a substantial impairment of peak aerobic capacity. This study supports that the exercise capacity of these patients is mainly sustained by fat oxidation, with active patients showing an exceptional maximal fat oxidation rate (similar in fact to athletes) during endurance exercise, possibly as an adaptation to muscle glycogen unavailability. On the other hand, data in the (untrained) mouse model of the disease revealed overall no major differences at baseline in molecular markers of lipid transport/metabolism, compared with wild-type mice.
ABBREVIATIONS: AMPK, AMP-activated protein kinase; CD36, transmembrane glycoprotein cluster of differentiation 36; HADH, 3-hydroxyacyl-CoA dehydrogenase; HSL, hormone-sensitive lipase (total or phosphorylated); MFO, maximum fat oxidation; NS, 'no significant' (for between-group comparisons). pAMPK, phosphorylated AMPK; pATGL, phosphorylated adipose triglyceride lipase; Plin5, perilipin 5; VO2 peak, peak oxygen uptake. Data presented as mean (SD). This article is protected by copyright. All rights reserved.

Keywords: anaplerotic; fatty acids; glycogen depletion; glycogen store disease; lactate; muscle fatigue; substrate oxidation; tricarboxylic acid cycle

DOI: https://doi.org/10.1113/JP283743

Eur J Immunol. 2022 Nov 09.

Targeting glycogen synthase kinase 3 with CHIR99021 negatively regulates allergen-induced mast cell activation.

Robert W E Crozier, Val A Fajardo, Adam J MacNeil.

Mast cells are granulated immune sentinels responsible for allergic inflammation. Allergen-induced FcεRI-signaling leads to rapid degranulation in the early-phase and sustained production and release of pro-inflammatory mediators in the late-phase. Glycogen synthase kinase 3 (GSK3) is a constitutively active serine/threonine kinase and a central molecular convergence point for several pro-inflammatory pathways. GSK3 inhibition has been shown to reduce inflammation but has not yet been fully characterized in mast cell activation. Therefore, the objective of this study was to evaluate GSK3 as a putative therapeutic target in allergic inflammation using the GSK3 inhibitor, CHIR99021. Here, we found that GSK3 inhibition impaired ROS production and degranulation. Through modulation of MKK4-JNK, c-jun, and NFκB signaling, GSK3 inhibition reduced the production/release of IL-6, IL-13, TNF and CCL1, while only the release of CCL2 and CCL3 was impaired. Furthermore, CHIR99021-mediated GSK3 inhibition altered the pro-inflammatory phenotype of mast cells, reducing c-kit receptor levels. This implicated GSK3 in FcεRI signaling, reducing release of IL-6, TNF and CCL1 when stimulated through FcεRI, while CCL2 and CCL3 remained unaffected, and were increased when stimulated with SCF only. These results identify GSK3 as a potential therapeutic target of utility warranting further consideration in contexts of pathological mast cell activation. This article is protected by copyright. All rights reserved.

Keywords: Fc-epsilon-RI (FcεRI); GSK3; allergy; immunoglobulin E (IgE); mast cell

DOI: https://doi.org/10.1002/eji.202250104

JACC Basic Transl Sci. 2022 Oct;7(10): 1001-1017

Acute Glycogen Synthase Kinase-3 Inhibition Modulates Human Cardiac Conduction.

Gang Li, Brittany D Brumback, Lei Huang, David M Zhang, Tiankai Yin, Catherine E Lipovsky, Stephanie C Hicks, Jesus Jimenez, Patrick M Boyle, Stacey L Rentschler.

Glycogen synthase kinase 3 (GSK-3) inhibition has emerged as a potential therapeutic target for several diseases, including cancer. However, the role for GSK-3 regulation of human cardiac electrophysiology remains ill-defined. We demonstrate that SB216763, a GSK-3 inhibitor, can acutely reduce conduction velocity in human cardiac slices. Combined computational modeling and experimental approaches provided mechanistic insight into GSK-3 inhibition-mediated changes, revealing that decreased sodium-channel conductance and tissue conductivity may underlie the observed phenotypes. Our study demonstrates that GSK-3 inhibition in human myocardium alters electrophysiology and may predispose to an arrhythmogenic substrate; therefore, monitoring for adverse arrhythmogenic events could be considered.

Keywords: ABC, active β-catenin; APD, action potential duration; BDM, 2,3-butanedione monoxime; CV, conduction velocity; Cx43, connexin 43; GNa, sodium-channel conductance; GOF, gain of function; GSK-3 inhibitor; GSK-3, glycogen synthase kinase 3; INa, sodium current; LV, left ventricle; NaV1.5, pore-forming α-subunit protein of the voltage-gated cardiac sodium channel; PCR, polymerase chain reaction; RMP, resting membrane potential; RT-qPCR, reverse transcription-quantitative polymerase chain reaction; SB2, SB216763; SB216763; cDNA, complementary DNA; dVm/dtmax, maximum upstroke velocity; electrophysiology; human cardiac slices

DOI: https://doi.org/10.1016/j.jacbts.2022.04.007

J Ethnopharmacol. 2022 Nov 03. pii: S0378-8741(22)00938-2. [Epub ahead of print] 115899

Hypericum perforatum L. extract exerts insulinotropic effects and inhibits gluconeogenesis in diabetic rats by regulating AMPK expression and PKCε concentration.

Elena Rafailovska, Oliver Tushevski, Kristiana Shijakova, Sonja Gadzovska Simic, Suzana Dinevska Kjovkarovska, Biljana Miova.

ETHNOPHARMACOLOGICAL RELEVANCE: Hypericum perforatum L., commonly known as St. John's Wort (SJW), represents one of the best-known and most thoroughly researched medicinal plant species. The ethnobotanical usage and bioactivities related to H. perforatum include treatment of skin diseases, wounds and burns, gastrointestinal problems, urogenital diseases and psychiatric disorders, particularly depression. In the last decade, many studies focused on the bioactive constituents responsible for the antihyperglycemic and antidiabetic activity of SJW extracts. However, the mechanism by which H. perforatum extract exhibits these properties is still unclear. Hence, the current study was designed to gain insight into the underlying biochemical and molecular mechanisms by which wildly growing H. perforatum exerts its antihyperglycemic and antidiabetic activities.MATERIAL AND METHODS: Plant material of H. perforatum was harvested from a natural population in the Republic of North Macedonia during full flowering season. Methanol (80% v/v) was used to extract bioactive components from HH powder.The dissolved HH dry extract (in 0.3% CMC) was given daily as a single treatment (200 mg/kg bw) during 14 days both in healthy and streptozotocin-induced diabetic rats. As a positive control, we applied glibenclamide. The activity of key enzymes involved in carbohydrate methabolisam in the liver were assessed, along with substrate concentration, as well as AMPK mRNA levels, PKCε concentration, plasma insulin level and pancreatic PARP activity.
RESULTS: Compared to diabetic rats, treatment of diabetic rats with HH extract resulted with decreased activity of hepatic enzymes glucose-6-phospatase and fructose-1,6-bisphosphatase, increased liver glycogen and glucose-6-phosphate content, which resulted with reduced blood glucose concentration up to normoglycaemia. Non-significant changes were observed in the activity of hexokinase, glycogen phosphorylase and glucose-6-phospahte dehydrogenase. HH-treatment also caused an increase in plasma insulin concentration and increase in pancreatic PARP activity. Finally, HH treatment of diabetic rats showed significant increase in AMPK expression and decrease of PKCε concentration.
CONCLUSION: We present in vivo evidence that HH- extract exert insulinotropic effects and regulate endogenous glucose production mostly by suppressing liver gluconeogenesis. The HH-treatment did not effected glycogenolysys and glycolysis. Finally, we confirm the antihyperglycemic and antidiabetic effect of HH-extract and the mechanism of this effect involves amelioration of AMPK and PKCε changes in the liver.

Keywords: AMPK; Carbohydrate metabolism; Diabetic rats; Hypericum perforatum L.; PKCε

DOI: https://doi.org/10.1016/j.jep.2022.115899

Am J Physiol Endocrinol Metab. 2022 Nov 09.

Loss of hepatic phosphoenolpyruvate carboxykinase 1 dysregulates metabolic responses to acute exercise but enhances adaptations to exercise training in mice.

Ferrol I Rome, Gregory L Shobert, William C Voigt, David B Stagg, Patrycja Puchalska, Shawn C Burgess, Peter A Crawford, Curtis C Hughey.

Acute exercise increases liver gluconeogenesis to supply glucose to working muscle. Concurrently, elevated liver lipid breakdown fuels the high energetic cost of gluconeogenesis. This functional coupling between liver gluconeogenesis and lipid oxidation has been proposed to underlie the ability of regular exercise to enhance liver mitochondrial oxidative metabolism and decrease liver steatosis in individuals with non-alcoholic fatty liver disease. Herein we tested whether repeated bouts of increased hepatic gluconeogenesis are necessary for exercise training to lower liver lipids. Experiments used diet-induced obese mice lacking hepatic phosphoenolpyruvate carboxykinase 1 (KO) to inhibit gluconeogenesis and wild type (WT) littermates. 2H/13C metabolic flux analysis quantified glucose and mitochondrial oxidative fluxes in untrained mice at rest and during acute exercise. Circulating and tissue metabolite levels were determined during sedentary conditions, acute exercise, and refeeding post-exercise. Mice also underwent six weeks of treadmill running protocols to define hepatic and extrahepatic adaptations to exercise training. Untrained KO mice were unable to maintain euglycemia during acute exercise resulting from an inability to increase gluconeogenesis. Liver triacylglycerides were elevated following acute exercise and circulating β-hydroxybutyrate was higher during post-exercise refeeding in untrained KO mice. In contrast, exercise training prevented liver triacylglyceride accumulation in KO mice. This was accompanied by pronounced increases in indices of skeletal muscle mitochondrial oxidative metabolism in KO mice. Together, these results show that hepatic gluconeogenesis is dispensable for exercise training to reduce liver lipids. This may be due to responses in ketone body metabolism and/or metabolic adaptations in skeletal muscle to exercise.

Keywords: gluconeogenesis; glycogenolysis; ketone bodies; mitochondria; skeletal muscle

DOI: https://doi.org/10.1152/ajpendo.00222.2022