Lactate Supplementation Research Articles

33. Effects of betaine supplementation in summer lactation and weaning-to-remating interval on subsequent reproductive performance of sows

33. Effects of betaine supplementation in summer lactation and weaning-to-remating interval on subsequent reproductive performance of sows

Warburg-associated acidification represses lactic fermentation independently of lactate, contribution from real-time NMR on cell-free systems

Lactate accumulation and acidification in tumours are a cancer hallmark associated with the Warburg effect. Lactic acidosis correlates with cancer malignancy, and the benefit it offers to tumours has been the subject of numerous hypotheses. Strikingly, lactic acidosis enhances cancer cell survival to environmental glucose depletion by repressing high-rate glycolysis and lactic fermentation, and promoting an oxidative metabolism involving reactivated respiration. We used real-time NMR to evaluate how cytosolic lactate accumulation up to 40 mM and acidification up to pH 6.5 individually impact glucose consumption, lactate production and pyruvate evolution in isolated cytosols. We used a reductive cell-free system (CFS) to specifically study cytosolic metabolism independently of other Warburg-regulatory mechanisms found in the cell. We assessed the impact of lactate and acidification on the Warburg metabolism of cancer cytosols, and whether this effect extended to different cytosolic phenotypes of lactic fermentation and cancer. We observed that moderate acidification, independently of lactate concentration, drastically reduces the glucose consumption rate and halts lactate production in different lactic fermentation phenotypes. In parallel, for Warburg-type CFS lactate supplementation induces pyruvate accumulation at control pH, and can maintain a higher cytosolic pyruvate pool at low pH. Altogether, we demonstrate that intracellular acidification accounts for the direct repression of lactic fermentation by the Warburg-associated lactic acidosis.

Zinc lactate alleviates oxidative stress by modulating crosstalk between constitutive androstane receptor signaling pathway and gut microbiota profile in weaned piglets

This study aimed to determine the regulatory mechanism of dietary zinc lactate (ZL) supplementation on intestinal oxidative stress damage in a paraquat (PQ)-induced piglet model. Twenty-eight piglets (mean body weight 9.51 ± 0.23 kg) weaned at 28 d of age were randomly divided into control, ZL, PQ, and ZL + PQ groups (n = 7 in each group). The ZL-supplemented diet had little effect on growth performance under normal physiological conditions. However, under PQ challenge, ZL supplementation significantly improved average daily gain (P < 0.05) and reduced the frequency of diarrhea. ZL improved intestinal morphology and ultrastructure by significantly increasing the expression level of the jejunal tight junction protein, zonula occludens-1 (ZO-1) (P < 0.05), and intestinal zinc transport and absorption in PQ-induced piglets, which reduced intestinal permeability. ZL supplementation also enhanced the expression of antioxidant and anti-inflammatory factor-related genes and decreased inflammatory cytokine expression and secretion in PQ-induced piglets. Furthermore, ZL treatment significantly inhibited the activation of constitutive androstane receptor (CAR) signaling (P < 0.01) in PQ-induced piglets and altered the structure of the gut microbiota, especially by significantly increasing the abundance of beneficial gut microbes, including UCG_002, Ruminococcus, Rikenellaceae_RC9_gut_group, Christensenellaceae_R_7_group, Treponema, unclassified_Christensenellaceae, and unclassified_Erysipelotrichaceae (P < 0.05). These data reveal that pre-administration of ZL to piglets can suppress intestinal oxidative stress by improving antioxidant and anti-inflammatory capacity and regulating the crosstalk between CAR signaling and gut microbiota.

PFKFB3-driven vascular smooth muscle cell glycolysis promotes vascular calcification via the altered FoxO3 and lactate production.

A link between increased glycolysis and vascular calcification has recently been reported, but it remains unclear how increased glycolysis contributes to vascular calcification. We therefore investigated the role of PFKFB3, a critical enzyme of glycolysis, in vascular calcification. We found that PFKFB3 expression was upregulated in calcified mouse VSMCs and arteries. We showed that expression of miR-26a-5p and miR-26b-5p in calcified mouse arteries was significantly decreased, and a negative correlation between Pfkfb3 mRNA expression and miR-26a-5p or miR-26b-5p was seen in these samples. Overexpression of miR-26a/b-5p significantly inhibited PFKFB3 expression in VSMCs. Intriguingly, pharmacological inhibition of PFKFB3 using PFK15 or knockdown of PFKFB3 ameliorated vascular calcification in vD3 -overloaded mice in vivo or attenuated high phosphate (Pi)-induced VSMC calcification in vitro. Consistently, knockdown of PFKFB3 significantly reduced glycolysis and osteogenic transdifferentiation of VSMCs, whereas overexpression of PFKFB3 in VSMCs induced the opposite effects. RNA-seq analysis and subsequent experiments revealed that silencing of PFKFB3 inhibited FoxO3 expression in VSMCs. Silencing of FoxO3 phenocopied the effects of PFKFB3 depletion on Ocn and Opg expression but not Alpl in VSMCs. Pyruvate or lactate supplementation, the product of glycolysis, reversed the PFKFB3 depletion-mediated effects on ALP activity and OPG protein expression in VSMCs. Our results reveal that blockade of PFKFB3-mediated glycolysis inhibits vascular calcification in vitro and in vivo. Mechanistically, we show that FoxO3 and lactate production are involved in PFKFB3-driven osteogenic transdifferentiation of VSMCs. PFKFB3 may be a promising therapeutic target for the treatment of vascular calcification.

Maternal tributyrin supplementation in late pregnancy and lactation improves offspring immunity, gut microbiota, and diarrhea rate in a sow model.

Several studies have evaluated the effects of tributyrin on sow reproductive performance; however, none of these studies have investigated the effects of tributyrin on sow gut microbiota and its potential interactions with immune systems and milk composition. Therefore, we speculated that tributyrin, the combination of butyrate and mono-butyrin without odor, would reach the hindgut and affect the intestinal microbiota composition and play a better role in regulating sow reproductive performance, gut flora, and health. Thirty sows (Landrace × Yorkshire) were randomly divided into two groups: the control group (CON) and the tributyrin group (TB), which received basal diet supplemented with 0.05% tributyrin. The experimental period lasted for 35 days from late pregnancy to lactation. The results showed that TB supplementation significantly shortened the total parturition time and reduced the diarrhea rate in suckling piglets. On day 20 of lactation, the milk fat and protein levels increased by 9 and 4%, respectively. TB supplementation significantly improved the digestibility of dry material, gross energy, and crude fat in the sow diet, but had no significant effect on crude protein digestibility. Furthermore, TB supplementation increased the levels of IL-10, IL-6, and IgA in the blood of weaned piglets, but had no effect on maternal immunity. Analysis of the fecal microbial composition revealed that the addition of TB during late gestation and lactation increased the microbiota diversity in sows and piglets. At the phylum level, sows in the TB group had a slight increase in the relative abundance of Bacteroidota and Spirochaetota and a decrease in Firmicutes. At the order level, the relative abundance of Lactobacillales was increased in piglets and sows, and the TB group showed increased relative abundance of Enterobacterales and significantly decreased relative abundance of Oscillospirales in piglets. At family level, the relative abundance of Lactobacillaceae, Oscillospiraceae, and Christensenellaceae increased in sows, and the relative abundance of Enterobacteriaceae and Lactobacillaceae increased in piglets. At genus level, the relative abundance of Lactobacillus increased in sows and piglets, but the relative abundance of Subdoligranulum and Eubacterium_fissicatena_group decreased in piglets in the TB group. In conclusion, tributyrin supplementation shortened the farrowing duration and reduced the diarrhea rate of piglets by improving the inflammatory response and composition of gut microbiota in piglets and sows.

Lactate dehydrogenase A mediated histone lactylation induced the pyroptosis through targeting HMGB1.

Cerebral ischemia (CI), as the cerebrovascular disease with the highest incidence rate, is treated by limited intravenous thrombolysis and intravascular therapy to recanalize the embolized vessels. Recently, the discovery of histone lactylation proposes a potential molecular mechanism for the role of lactate in physiological and pathological processes. This study aimed to analyze the lactate dehydrogenase A (LDHA) mediated histone lactylation in CI reperfusion (CI/R) injury. Oxygen-glucose deprivation/reoxygenation (OGD/R) treated N2a cells and middle cerebral artery occlusion (MCAO) treated rats was used as the CI/R model in vivo and in vitro. Cell viability and pyroptosis was assessed using CCK-8 and flow cytometry. RT-qPCR was performed to detect the relative expression. The relationship between histone lactylation and HMGB1 was verified by CHIP assay. LDHA, HMGB1, lactate and histone lactylation was up-regulated in the OGD/R treated N2a cells. Additionally, LDHA knockdown decreased HMGB1 levels in vitro, and relieved CI/R injury in vivo. Besides, LDHA silencing declined the histone lactylation mark enrichment on HMGB1 promoter, and lactate supplement rescued it. What?s more, LDHA knockdown decreased the IL-18 and IL-1β contents, and the cleaved-caspase-1 and GSDMD-N protein levels in the OGD/R treated N2a cells, which was reversed by HMGB1 overexpression. Knockdown of LDHA suppressed the pyroptosis in the N2a cells induced by OGD/R, which was reversed by HMGB1 overexpression. Mechanistically, LDHA mediated the histone lactylation induced pyroptosis through targeting HMGB1 in the CI/R injury.

Lactate trafficking inhibition restores sensitivity to proteasome inhibitors and orchestrates immuno-microenvironment in multiple myeloma.

Metabolic changes of malignant plasma cells (PCs) and adaptation to tumour microenvironment represent one of the hallmarks of multiple myeloma (MM). We previously showed that MM mesenchymal stromal cells are more glycolytic and produce more lactate than healthy counterpart. Hence, we aimed to explore the impact of high lactate concentration on metabolism of tumour PCs and its impact on the efficacy of proteasome inhibitors (PIs). Lactate concentration was performed by colorimetric assay on MM patient's sera. The metabolism of MM cell treated with lactate was assessed by seahorse and real time Polymerase Chain Reaction (PCR). Cytometry was used to evaluate mitochondrial reactive oxygen species (mROS), apoptosis and mitochondrial depolarization. Lactate concentration resulted increased in MM patient's sera. Therefore, PCs were treated with lactate and we observed an increase of oxidative phosphorylation-related genes, mROS and oxygen consumption rate. Lactate supplementation exhibited a significant reduction in cell proliferation and less responsive to PIs. These data were confirmed by pharmacological inhibition of monocarboxylate transporter 1 (MCT1) by AZD3965 which was able to overcame metabolic protective effect of lactate against PIs. Consistently, high levels of circulating lactate caused expansion of Treg and monocytic myeloid derived suppressor cells and such effect was significantly reduced by AZD3965. Overall, these findings showed that targeting lactate trafficking in TME inhibits metabolic rewiring of tumour PCs, lactate-dependent immune evasion and thus improving therapy efficacy.

Dietary lactate supplementation can alleviate DSS-induced colitis in piglets

Colitis is a common and complex intestinal inflammatory disease in which lactate, a metabolite of anaerobic glycolysis, plays a crucial role. Our study aimed to investigate the alleviated effect of lactate in colitis, and to provide a nutritional measure to alleviate colitis injury. The variations in colonic lactate in piglets with DSS-induced colitis were investigated in Experiment 1 (Exp.1). Thirty weaned pigs were allotted into three groups and sampled at different stages of DSS-induced colitis (days 0, 5, and 7). The colonic level of lactate and interleukin 10 (IL-10) was significantly decreased on day 5 when compared to day 0. Colonic lactate, IL-10, and G protein receptor 81 (GPR81) levels were significantly increased on day 7 when compared to day 5. Sixty weaned piglets were assigned to control (basal diet), DSS (basal diet with DSS gavage), or lactate (2% lactate supplementation diet with DSS gavage) groups to investigate the effects of lactate on DSS-induced colitis in Experiment 2 (Exp.2). Lactate reduced the disease activity index (DAI), DSS-induced impairment of colonic structure in response to the critical inflammatory cytokines interleukin 1β (IL-1β) and interleukin 18 (IL-18) when compared with the DSS group. Furthermore, GPR-81 levels, colonic M2 macrophages, and IL-10 levels, the colonic antioxidant capacity, colonic butyrate levels were increased, and eventually improved growth performance post-colitis. The results of this study show that lactate was decreased at the peak of colitis, accumulated in subsidized colitis. Furthermore, dietary lactate supplementation helped to alleviate DSS-induced colitis injury.

Calsium Supplementation with Rasbora sp. to Prevent Loss of Bone Mineral Density during Gonadotropin-releasing hormone Agonis Long-term Treatment

Background. Gonadotropin-releasing hormone (GnRH) agonist widely used to induce hypoestrogenic climate overcoming any benign gynecologic abnormalities such as endometriosis, adenomyosis, or various cause of abnormal uterine bleeding. Hypoestrogenic cause some of adverse effect mainly loss of bone mineral density (BMD). Suplementation of calcium improve loss in BMD, hence prevent development of osteoporosis. Certain area of Indonesia shows specific biodiversity, for example South Borneo has its wetland biodiversity in swamp and river. Processed food from fishery like Rasbora sp. (locally called Seluang fish) is local favourite due to access and economical reason.&#x0D; Method. Studies included 24 reproductive age (15-49 years old) female on agonist GnRH leuprolide acetate 11,25 mcg regimen given subcutaneously. Measurement of bone mineral density was done twice within 3 months apart, before and after first agonist GnRH treatment. During observation, subject was divided to one of three daily supplementation belows, placebo containing saccharum lactis, grinded powder of 500 mg of calcium, or grinded powder of dried Rasbora sp containing 500 mg of calcium. Measurement pre- and post- supplementation was count using bone quality index with Osteosys of Sonost 3000.&#x0D; Result. Placebo supplementation group in GnRH agonist has bone mineral density loss of -22,7201 greater than 500 mg grinded powder of lactate calcium dan grinded powder of rasbora sp, respectively -4,4570 and -3,3634 after 3 months of trial. Homogeneity test shown p=0.031 level of significancy and ANOVA resulted a significant difference from three classes. Post Hoc resulted calcium lactate supplementation 18,26 + 3,20 greater (p = 0.001) and grinded powder of Seluang 19,36 + 3,20 greater (p = 0.000). Both form of calcium lactate and fish powder supplementation have no significant differences.&#x0D; Conclusion. Calcium supplementation in both of calcium lactate powder and natural resources help maintaining bone mineral density during GnRH agonist treatment. Seluang fish (Rasbora sp.), abundantly found along Indonesia people especially in South Borneo, has similar potency with pharmaceutical calcium lactate product in same weight. Fishery product, has beneficial trace element for bodies, 84 mg of calcium (Ca), 6,81 % of magnesium (Mg), 13,4 mg of iron (Fe), dan 3.97 % of zinc (Zn).&#x0D; Keyword: Bone mineral density, Calcium supplementation, Agonist GnRH, Rasbora Sp.

Bcl-3 regulates the function of Th17 cells through raptor mediated glycolysis metabolism.

Bcl-3 is an atypical IκB family member that regulates transcription in the nucleus by binding to the p50/p52 homologous dimer subunit. Although various studies illustrate the important role of Bcl-3 in physiological function, its role in metabolism is still unclear. We found that Bcl-3 has a metabolic regulatory effect on autoimmunity. Bcl-3-depleted mice are unable to develop experimental autoimmune encephalomyelitis. The disease resistance was linked to an increase in lactate levels in Th17 cells, and lactate could alleviate EAE development in WT mice. Bcl-3 deficient mice had more differentiated Th17 cells and an increased extracellular acidification rate in these cells. Concurrently, their ultimate respiration rate and respiratory reserve capacity were significantly lower than wild-type mice. However, adding GNE-140 (LADH inhibitor) to Bcl-3-deficient Th17 cells could reverse the phenomenon, and lactate supplementation could increase the glycolysis metabolism of Th17 cells in WT mice. Mechanically, Bcl-3 could interact with Raptor through ANK and RNC domains. Therefore, Bcl-3 regulates Th17 pathogenicity by promoting Raptor mediated energy metabolism, revealing a novel regulation of adaptive immunity.

Acceleration of lactate-utilizing pathway for enhancing biohydrogen production by magnetite supplementation in Clostridium butyricum

A conductive metal compound can be used as a catalyst for enhancing hydrogen production by dark fermentation. This study aimed to identify mechanisms of enhanced hydrogen production by magnetite supplementation. Experiments were performed with lactate and/or magnetite supplementation to confirm that the lactate-utilizing pathway is the key cause of enhanced hydrogen production. Also, ribonucleic acid sample was collected for monitoring gene regulation under each condition. Hydrogen production was significantly enhanced by approximately 25.6% and 58.9%, respectively, via magnetite alone and with lactate. Moreover, the expression of genes involved in hydrogen production, including pyruvate ferredoxin oxidoreductase, hydrogenase, and ferredoxin, via magnetite alone and with lactate was upregulated by 0.26, 0.71, and 3.50 and 1.06, 2.14, and 1.94 times, respectively.

Lactate promotes the growth of patient-derived organoids from hepatopancreatobiliary cancers via ENO1/HIF1\u03b1 pathway and does not affect their drug sensitivities

The long culture duration of patient-derived organoids (PDOs) have severely limited their clinical applications. The aim of this study was to determine the effect of lactate supplementation on the growth, genetic profiles and drug sensitivities of PDOs from hepatopancreatobiliary tumors. LM3, Huh7, Panc02, and RBE cell lines were cultured as organoids in the presence or absence of lactate, and total protein was extracted to measure the expression of α-enolase (ENO1), hypoxia-inducible factor-1α (HIF1α), AKT, and PI3 kinase (PI3K). Thirteen hepatopancreatobiliary tumor specimens were collected during surgical resection and cultured as PDOs with or without l-lactate. Hematoxylin and eosin (H&E) staining and immunohistochemical staining were performed on the original tissues and PDOs to compare their pathological structures, and their genetic profiles were analyzed by whole-exome sequencing (WES). The sensitivity of the PDOs to gemcitabine, 5-fluorouracil, cisplatin, paclitaxel, ivosidenib, infigratinib, and lenvatinib were evaluated in terms of cell viability. Peripheral blood mononuclear cells (PBMCs) were isolated and co-cultured with PDOs to test the sensitivity of PDOs to tislelizumab. The addition of 20 mM lactate significantly promoted the growth of LM3 and Huh 7 organoids by 217% and 36%, respectively, compared to the control group, and the inhibition of lactate transporter decreased their growth. The HIF1α/ENO1/AKT/PI3K pathway was also activated by lactate. The inhibition of enolase also partly decreased the growth of organoids treated with lactate. Furthermore, 20 mM lactate increased the viability of 9 PDOs from 135% to 317% without affecting their pathological features. The genetic similarity, in terms of single nucleotide variations, insertions, and deletions, between original tissues and lactate-treated PDOs ranged from 83.2% to 94.1%, and that between the untreated and lactate-treated PDOs was at least 93.2%. Furthermore, the addition of lactate did not significantly change the dose–response curves of the PDOs to chemotherapeutic drugs, targeted drugs, and immune checkpoint inhibitor, especially for the drugs to which the cells were sensitive. Thus, lactate can be added to the culture medium of PDOs to promote their growth without altering their genetic profiles and drug sensitivities.

Metabolic reprogramming in astrocytes results in neuronal dysfunction in intellectual disability.

Astrocyte aerobic glycolysis provides vital trophic support for central nervous system neurons. However, whether and how astrocytic metabolic dysregulation contributes to neuronal dysfunction in intellectual disability (ID) remain unclear. Here, we demonstrate a causal role for an ID-associated SNX27 mutation (R198W) in cognitive deficits involving reshaping astrocytic metabolism. We generated SNX27R196W (equivalent to human R198W) knock-in mice and found that they displayed deficits in synaptic function and learning behaviors. SNX27R196W resulted in attenuated astrocytic glucose uptake via GLUT1, leading to reduced lactate production and a switch from homeostatic to reactive astrocytes. Importantly, lactate supplementation or a ketogenic diet restored neuronal oxidative phosphorylation and reversed cognitive deficits in SNX27R196W mice. In summary, we illustrate a key role for astrocytic SNX27 in maintaining glucose supply and glycolysis and reveal that altered astrocytic metabolism disrupts the astrocyte-neuron interaction, which contributes to ID. Our work also suggests a feasible strategy for treating ID by restoring astrocytic metabolic function.

Endothelium-derived lactate is required for pericyte function and blood-brain barrier maintenance.

Endothelial cells differ from other cell types responsible for the formation of the vascular wall in their unusual reliance on glycolysis for most energy needs, which results in extensive production of lactate. We find that endothelium-derived lactate is taken up by pericytes, and contributes substantially to pericyte metabolism including energy generation and amino acid biosynthesis. Endothelial-pericyte proximity is required to facilitate the transport of endothelium-derived lactate into pericytes. Inhibition of lactate production in the endothelium by deletion of the glucose transporter-1 (GLUT1) in mice results in loss of pericyte coverage in the retina and brain vasculatures, leading to the blood-brain barrier breakdown and increased permeability. These abnormalities can be largely restored by oral lactate administration. Our studies demonstrate an unexpected link between endothelial and pericyte metabolisms and the role of endothelial lactate production in the maintenance of the blood-brain barrier integrity. In addition, our observations indicate that lactate supplementation could be a useful therapeutic approach for GLUT1 deficiency metabolic syndrome patients.

Abstract P1-06-08: Metabolic diversity determines metastatic fitness of breast cancer brain-tropic cells

Abstract HER2+ breast cancer patients presenting with either synchronous (S-BM), latent residual (Lat) or metachronous (M-BM) brain metastases have poor survival outcomes. However, the basis for disparate metastatic fitness among disseminated tumor cells of similar oncotype within a distal organ remains unknown. Employing isogenic HER2+ breast cancer brain metastasis models, we show metabolic diversity and plasticity within brain-tropic cells determines metastatic fitness. Lactate secreted by aggressive metastatic cells (S-BM and M-BM) or lactate supplementation to mice bearing latent residual disease limits innate immune surveillance and triggers overt metastasis. Attenuating lactate metabolism in S-BM impedes metastasis, while M-BM adapt and survive as latent residual disease. In contrast to S-BM, Lat and M-BM survive in equilibrium with innate immune surveillance, oxidize glutamine and maintain cellular redox homeostasis through the anionic amino acid transporter xCT. Moreover, xCT expression is significantly higher in matched metachronous brain metastatic samples compared to primary tumors from HER2+ breast cancer patients. Genetic or pharmacological blockade of xCT eradicates residual disease and brain metastatic relapse in these preclinical models. Citation Format: Srinivas Malladi. Metabolic diversity determines metastatic fitness of breast cancer brain-tropic cells [abstract]. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr P1-06-08.

Altering calcium and phosphorus supplementation in pregnancy and lactation affects offspring craniofacial morphology in a sex-specific pattern

The effects on offspring craniofacial bone morphology and accretion because of altered maternal exposure to dietary components such as calcium (Ca) and phosphorus (P) are unclear. The objective of this study was to investigate the changes in offspring skull morphology and tissue mineral density (TMD), including sex-specific changes, with exposure to a maternal diet high in Ca-to-P levels during gestation and lactation in mice. Time-mated FVB wild-type mice were fed a normal or experimental diet during gestation until weaning. The experimental diet contained a 3-fold increase in Ca and a 3-fold decrease in P (Ca:P molar ratio, 10.5) compared with normal mouse chow (Ca:P molar ratio, 1.5). The heads of 6-week-old control andexperimental offspring mice were collected and scanned using microcomputed tomography. Three-dimensional geometric morphometric analysis was performed to analyze changes in craniofacial morphology. TMD measurements were also analyzed. We observed subtle changes and no significant differences between offspring control and experimental skulls when we compared all samples. However, when we separated skulls by sex, we discovered significant differences in craniofacial morphology and TMD. Experimental female offspring possessed skulls that were smaller, narrower transversely, taller vertically, and decreased in TMD. Experimental male offspring possessed skulls that were larger, wider transversely, shorter vertically, and increased in TMD. Maternal exposure to diet and increased Ca:P molar ratio during gestation and lactation led to significant, sex-specific morphologic and TMD changes in 6-week-old mouse skulls.

Lactate Activates Germline and Cleavage Embryo Genes in Mouse Embryonic Stem Cells.

Lactate was recently found to mediate histone lysine lactylation and facilitate polarization of M1 macrophages, indicating its role in metabolic regulation of gene expression. During somatic cell reprogramming, lactate promotes histone lactylation of pluripotency genes and improves reprogramming efficiency. However, the function of lactate in cell fate control in embryonic stem cells (ESCs) remains elusive. In this study, we revealed that lactate supplementation activated germline genes in mouse ESCs. Lactate also induced global upregulation of cleavage embryo genes, such as members of the Zscan4 gene family. Further exploration demonstrated that lactate stimulated H3K18 lactylation accumulation on germline and cleavage embryo genes, which in turn promoted transcriptional elongation. Our findings indicated that lactate supplementation expanded the transcriptional network in mouse ESCs.

Lactate Enhances Mouse ES Cell Differentiation Toward XEN Cells In Vitro

Metabolism plays a crucial role for cell survival and function; however, recent evidence has implicated it in regulating embryonic development. In the embryo, the inner cell mass undergoes orchestrated cellular divisions resulting in the formation of pluripotent epiblast stem cells and primitive endoderm cells. However, both lineages can be captured in vitro as embryonic stem (ES) cells and extraembryonic endoderm (XEN) cells. Concomitantly, changes in the metabolic profile occurs during development, and are well documented in the embryonic lineages. However, a comprehensive multi-omic analysis of these features in XEN cells remains lacking. We observed that mouse XEN cells exhibited high sensitivity to glycolytic inhibition in addition to maintaining elevated intra- and extracellular lactate levels in vitro. Extraembryonic endoderm cells maintain high lactate levels by increased LDHA activity, and re-routing pyruvate away from the mitochondria resulting in reduced mitochondrial activity due to disruptions in electron transport chain stoichiometry. Importantly, exogenous lactate supplementation or promoting intracellular lactate accumulation enhances XEN differentiation in vitro. These results highlight how lactate contributes to XEN differentiation in vitro and may serve to enhance reprogramming efficiency of cells used for regenerative medicine.

Effects of Calcium Lactate on the Development of Chicken Embryos in a Shell-less Culture System up to Day Seventeen of Incubation.

This study examined the effects of calcium lactate on the development of chicken embryos in a shell-less culture system (cSLCS) up to the seventeenth day of incubation. In the presence of calcium lactate, a significant reduction in embryo viability was observed during the first week of incubation in cSLCS. On day 17 of embryo development, no significant difference was observed in the blood plasma calcium concentration or tibia bone density between cSLCS and intact control embryos, whereas the tibia length was significantly shorter in cSLCS embryos than in the intact control. These results suggest that calcium lactate supplementation in cSLCS supports bone formation in developing chicken embryos, but has adverse effects on the viability of embryos, particularly during the first week of embryo development.

Metabolic diversity within breast cancer brain-tropic cells determines metastatic fitness

HER2+ breast cancer patients are presented with either synchronous (S-BM), latent (Lat), or metachronous (M-BM) brain metastases. However, the basis for disparate metastatic fitness among disseminated tumor cells of similar oncotype within a distal organ remains unknown. Here, employing brain metastatic models, we show that metabolic diversity and plasticity within brain-tropic cells determine metastatic fitness. Lactate secreted by aggressive metastatic cells or lactate supplementation to mice bearing Lat cells limits innate immunosurveillance and triggers overt metastasis. Attenuating lactate metabolism in S-BM impedes metastasis, while M-BM adapt and survive as residual disease. In contrast to S-BM, Lat and M-BM survive in equilibrium with innate immunosurveillance, oxidize glutamine, and maintain cellular redox homeostasis through the anionic amino acid transporter xCT. Moreover, xCT expression is significantly higher in matched M-BM brain metastatic samples compared to primary tumors from HER2+ breast cancer patients. Inhibiting xCT function attenuates residual disease and recurrence in these preclinical models.