The Entner-Doudoroff Pathway Contributes to Glycogen Breakdown During High to Low CO2 Shifts in the Cyanobacterium Synechocystis sp. PCC 6803

Cyanobacteria perform plant-like oxygenic photosynthesis to convert inorganic carbon into organic compounds and can also use internal carbohydrate reserves under specific conditions. A mutant collection with defects in different routes for sugar catabolism was studied to analyze which of them is preferentially used to degrade glycogen reserves in light-exposed cells of Synechocystis sp. PCC 6803 shifted from high to low CO2 conditions. Mutants defective in the glycolytic Embden–Meyerhof–Parnas pathway or in the oxidative pentose-phosphate (OPP) pathway showed glycogen levels similar to wild type under high CO2 (HC) conditions and were able to degrade it similarly after shifts to low CO2 (LC) conditions. In contrast, the mutant Δeda, which is defective in the glycolytic Entner-Doudoroff (ED) pathway, accumulated elevated glycogen levels under HC that were more slowly consumed during the LC shift. In consequence, the mutant Δeda showed a lowered ability to respond to the inorganic carbon shifts, displayed a pronounced lack in the reactivation of growth when brought back to HC, and differed significantly in its metabolite composition. Particularly, Δeda accumulated enhanced levels of proline, which is a well-known metabolite to maintain redox balances via NADPH levels in many organisms under stress conditions. We suggest that deletion of eda might promote the utilization of the OPP shunt that dramatically enhance NADPH levels. Collectively, the results point at a major regulatory contribution of the ED pathway for the mobilization of glycogen reserves during rapid acclimation to fluctuating CO2 conditions.

Lithium enhances exercise-induced glycogen breakdown and insulin-induced AKT activation to facilitate glucose uptake in rodent skeletal muscle

The purpose of this study was to investigate the effect of lithium on glucose disposal in a high-fat diet-induced type 2 diabetes mellitus (T2DM) and streptozotocin-induced type 1 diabetes mellitus (T1DM) animal model along with low-volume exercise and low-dose insulin. Lithium decreased body weight, fasting plasma glucose, and insulin levels when to treat with low-volume exercise training; however, there were no adaptive responses like an increase in GLUT4 content and translocation factor levels. We discovered that lithium enhanced glucose uptake by acute low-volume exercise-induced glycogen breakdown, which was facilitated by the dephosphorylation of serine 473-AKT (Ser473-AKT) and serine 9-GSK3β. In streptozotocin-induced T1DM mice, Li/low-dose insulin facilitates glucose uptake through increase the level of exocyst complex component 7 (Exoc7) and Ser473-AKT. Thus, lithium enhances acute exercise-induced glycogen breakdown and insulin-induced AKT activation and could serve as a candidate therapeutic target to regulate glucose level of DM patients.

Preclinical Research in Glycogen Storage Diseases: A Comprehensive Review of Current Animal Models

GSD are a group of disorders characterized by a defect in gene expression of specific enzymes involved in glycogen breakdown or synthesis, commonly resulting in the accumulation of glycogen in various tissues (primarily the liver and skeletal muscle). Several different GSD animal models have been found to naturally present spontaneous mutations and others have been developed and characterized in order to further understand the physiopathology of these diseases and as a useful tool to evaluate potential therapeutic strategies. In the present work we have reviewed a total of 42 different animal models of GSD, including 26 genetically modified mouse models, 15 naturally occurring models (encompassing quails, cats, dogs, sheep, cattle and horses), and one genetically modified zebrafish model. To our knowledge, this is the most complete list of GSD animal models ever reviewed. Importantly, when all these animal models are analyzed together, we can observe some common traits, as well as model specific differences, that would be overlooked if each model was only studied in the context of a given GSD.

Exogenous ketosis impacts neither performance nor muscle glycogen breakdown in prolonged endurance exercise

Exogenous ketosis produced by oral ketone ester ingestion during the early phase of prolonged endurance exercise and against the background of adequate carbohydrate intake neither causes muscle glycogen sparing nor improves performance in the final stage of the event. However, such exogenous ketosis may decrease buffering capacity in the approach of the final episode of the event. Furthermore, ketone ester intake during exercise may reduce appetite immediately after exercise.

Carl and Gerty Cori: A collaboration that changed the face of biochemistry

Carl Cori and Gerty Cori elucidated basic biochemical mechanisms involved in the utilization of energy by muscle and liver, first at Roswell Park Cancer Institute and then at Washington University. In 1929, they formulated the Cori cycle, the process by which glycogen is converted to glucose in liver and is then reconverted to glycogen in muscle. They later found that glycogen breakdown yielded glucose-1-phosphate (Cori ester) and lactate, key intermediates in the cycle; they also established that lactic acid provided the energy employed in muscle contraction. They later discovered phosphorylase, the enzyme that catalyzed glycogen breakdown. After purifiying and crystallizing muscle phosphorylase, they identified two forms of the enzyme and defined their respective roles in metabolic regulation. These studies emboldened other scientists to advance our knowledge of fundamental regulatory processes such as the adenylate cyclase-cyclic AMP system and enzyme phosphorylation. The Coris also built a world-renowned Department of Biochemistry at Washington University, which included seven future Nobelists. In 1947, the Coris were awarded the Nobel Prize, with Gerty Cori being the first American woman to win this prestigious honor.

Glioma and Neurokinin-1 Receptor Antagonists: A New Therapeutic Approach

Background: In adults, the most lethal and frequent primary brain tumor is glioblastoma. Despite multimodal aggressive therapies, the median survival time after diagnosis is around 15 months. In part, this is due to the blood-brain barrier that restricts common treatments (e.g., chemotherapy). Unfortunately, glioma recurs in 90% of patients. New therapeutic strategies against glioma are urgently required. Substance P (SP), through the neurokinin (NK)-1 receptor, controls cancer cell proliferation by activating c-myc, mitogenactivated protein kinases, activator protein 1 and extracellular signal-regulated kinases 1 and 2. Glioma cells overexpress NK-1 receptors when compared with normal cells. The NK-1 receptor/SP system regulates the proliferation/migration of glioma cells and stimulates angiogenesis, triggering inflammation which contributes to glioma progression. In glioma cells, SP favors glycogen breakdown, essential for glycolysis. By contrast, in glioma, NK-1 receptor antagonists block the proliferation of tumor cells and the breakdown of glycogen and also promote the death (apoptosis) of these cells. These antagonists also inhibit angiogenesis and exert antimetastatic and anti-inflammatory actions. Objective: This review updates the involvement of the NK-1 receptor/SP system in the development of glioma and the potential clinical application of NK-1 receptor antagonists as antiglioma agents. Conclusion: The NK-1 receptor plays a crucial role in glioma and NK-1 receptor antagonists could be used as anti-glioma drugs.

Triheptanoin alters [U-13C6]-glucose incorporation into glycolytic intermediates and increases TCA cycling by normalizing the activities of pyruvate dehydrogenase and oxoglutarate dehydrogenase in a chronic epilepsy mouse model

Triheptanoin is anticonvulsant in several seizure models. Here, we investigated changes in glucose metabolism by triheptanoin interictally in the chronic stage of the pilocarpine mouse epilepsy model. After injection of [U-13C6]-glucose (i.p.), enrichments of 13C in intermediates of glycolysis and the tricarboxylic acid (TCA) cycle were quantified in hippocampal extracts and maximal activities of enzymes in each pathway were measured. The enrichment of 13C glucose in plasma was similar across all groups. Despite this, we observed reductions in incorporation of 13C in several glycolytic intermediates compared to control mice suggesting glucose utilization may be impaired and/or glycogenolysis increased in the untreated interictal hippocampus. Triheptanoin prevented the interictal reductions of 13C incorporation in most glycolytic intermediates, suggesting it increased glucose utilization or – as an additional astrocytic fuel – it decreased glycogen breakdown. In the TCA cycle metabolites, the incorporation of 13C was reduced in the interictal state. Triheptanoin restored the correlation between 13C enrichments of pyruvate relative to most of the TCA cycle intermediates in “epileptic” mice. Triheptanoin also prevented the reductions of hippocampal pyruvate dehydrogenase and 2-oxoglutarate dehydrogenase activities. Decreased glycogen breakdown and increased glucose utilization and metabolism via the TCA cycle in epileptogenic brain areas may contribute to triheptanoin's anticonvulsant effects.