Glycogen metabolism in Sertoli cells sustains germ cell survival through lactate shuttling [RNA_maleGPI]
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ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE293017 | GEO | 2026/05/20
REPOSITORIES: GEO
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Project description:Sertoli cells accumulate glycogen within a specific developmental window, peaking at embryonic day (E) 12.5 and rapidly depleting by E13.5. Using immunofluorescence and single-nuclei RNA-seq, we identified the regulatory mechanisms underlying this transient glycogen storage. Glycogen accumulation correlates with elevated PPP1R3C expression, while its degradation coincides with increased glycogen phosphorylase (PYGB) levels. Functional assays revealed that glycogen metabolism is not required for Sertoli cell differentiation but is essential for germ cell survival. Pharmacological inhibition of glycogen breakdown resulted in germ cell loss, which could not be rescued by exogenous lactate or glucose, highlighting a critical metabolic dependency. Glycogen-derived lactate is transported via the MCT4/MCT1 shuttle from Sertoli cells to germ cells, supporting their survival. These findings establish glycogen metabolism as a key determinant of germ cell viability, emphasizing a metabolic coupling between Sertoli and germ cells during testis development with implications for reproductive health.
2026-04-13 | GSE293016 | GEO
Project description:Glycogen metabolism in Sertoli cells sustains germ cell survival through lactate shuttling
| PRJNA1242356 | ENA
Project description:Many cancers rely on glycolytic metabolism to fuel rapid proliferation. This has spurred interest in designing drugs that target tumor glycolysis such as AZD3965, a small molecule inhibitor of Monocarboxylate Transporter 1 (MCT1) currently undergoing Phase I evaluation for cancer treatment. Since MCT1 mediates proton-linked transport of monocarboxylates such as lactate and pyruvate across the plasma membrane (Halestrap and Meredith, 2004), AZD3965 is thought to block tumor growth through disruption of lactate transport and glycolysis. Here we show that MCT1 inhibition impairs proliferation of glycolytic breast cancer cells that express MCT4 via disruption of pyruvate rather than lactate export. We found that MCT1 expression is elevated in glycolytic breast tumors and cell lines as well as in malignant breast and lung tissues. High MCT1 expression predicts poor prognosis in breast and lung cancer patients. Stable knockdown and AZD3965-mediated inhibition of MCT1 promote oxidative metabolism. Acute inhibition of MCT1 reduces pyruvate export rate but does not consistently alter lactate transport or glycolytic flux in breast cancer cells that also express MCT4. Despite the lack of glycolysis impairment, MCT1 loss-of-function decreases breast cancer cell proliferation and blocks growth of mammary fat pad xenograft tumors. Our data suggest that MCT1 expression is elevated in glycolytic cancers to promote pyruvate export, which when inhibited enhances oxidative metabolism and reduces proliferation. This study presents an alternative molecular consequence of MCT1 inhibitors that further supports their use as anti-cancer therapeutics. Since MCT1 levels are elevated in glycolytic and malignant breast tumors, we hypothesized that MCT1 may contribute to the Warburg effect metabolic phenotype. To test this hypothesis, we generated whole genome microarray data from breast cancer cell lines either a) expressing a short hairpin (sh)RNA-mediated stable knockdown of MCT1; or b) treated for 24 hours with an MCT1 inhibitor (AZD3965). Scramble shRNA or DMSO were used as controls, and all conditions were analzed in triplicate. The cell lines used â HS578T, SUM149PT, and SUM159PT â are among the most glycolytic in a panel of 31 breast cancer cell lines.
2016-03-08 | E-GEOD-76675 | biostudies-arrayexpress
Project description:Many cancers rely on glycolytic metabolism to fuel rapid proliferation. This has spurred interest in designing drugs that target tumor glycolysis such as AZD3965, a small molecule inhibitor of Monocarboxylate Transporter 1 (MCT1) currently undergoing Phase I evaluation for cancer treatment. Since MCT1 mediates proton-linked transport of monocarboxylates such as lactate and pyruvate across the plasma membrane (Halestrap and Meredith, 2004), AZD3965 is thought to block tumor growth through disruption of lactate transport and glycolysis. Here we show that MCT1 inhibition impairs proliferation of glycolytic breast cancer cells that express MCT4 via disruption of pyruvate rather than lactate export. We found that MCT1 expression is elevated in glycolytic breast tumors and cell lines as well as in malignant breast and lung tissues. High MCT1 expression predicts poor prognosis in breast and lung cancer patients. Stable knockdown and AZD3965-mediated inhibition of MCT1 promote oxidative metabolism. Acute inhibition of MCT1 reduces pyruvate export rate but does not consistently alter lactate transport or glycolytic flux in breast cancer cells that also express MCT4. Despite the lack of glycolysis impairment, MCT1 loss-of-function decreases breast cancer cell proliferation and blocks growth of mammary fat pad xenograft tumors. Our data suggest that MCT1 expression is elevated in glycolytic cancers to promote pyruvate export, which when inhibited enhances oxidative metabolism and reduces proliferation. This study presents an alternative molecular consequence of MCT1 inhibitors that further supports their use as anti-cancer therapeutics.
2016-03-08 | GSE76675 | GEO
Project description:Dysregulated cancer metabolism, driven in part by excessive lactate export through monocarboxylate transporter 1 (MCT1) and 4 (MCT4), generates an acidic tumor microenvironment (TME) that suppresses antitumor immunity and impairs therapy. While direct MCT1 and/or MCT4 inhibitors show promise, clinical translation remains limited by systemic toxicity. In this study, we developed polymer-based lysosome-targeting chimeras (LYTACs) that selectively degrade CD147, the MCT1/4 chaperone, in liver cancer cells, reducing lactate efflux in cancer cells while sparing healthy cells, thereby reprogramming lactate metabolism within the TME. We further engineered polymer-based acid-responsive CD147-targeting LYTACs (PARTACs) to achieve controlled intratumoral release under acidic conditions. Systemic administration of PARTACs significantly suppressed tumor progression in several orthotopic liver cancer models. Moreover, PARTACs sensitized tumors to chemo-, immuno-, and radiotherapy with a favorable safety profile. Collectively, our nano-enabled spatially selective strategy modulates lactate metabolism in vivo, augmenting antitumor immunity and improving standard-of-care cancer therapies efficacy.
2026-05-24 | GSE328342 | GEO
Project description:Glycogen storage, conversion and utilization in astrocytes play important roles in brain energy metabolism. The conversion of glycogen to lactate through glycolysis occurs through the coordinated activities of various enzymes, and inhibition of this process can impair different brain processes including formation of long-lasting memories. To replenish depleted glycogen stores, astrocytes undergo glycogen synthesis, a cellular process that has been shown to require transcription and translation during specific stimulation paradigms. However, the detailed nuclear signaling mechanisms and transcriptional regulation during glycogen synthesis in astrocytes remain to be explored. In this report, we study the molecular details of vasoactive intestinal peptide (VIP)-induced glycogen synthesis in astrocytes. VIP is a potent neuropeptide that triggers glycogenolysis followed by glycogen synthesis in astrocytes. We show evidence that VIP-induced glycogen synthesis requires CREB-mediated transcription that is Protein Kinase C and calcium-dependent but is independent of Protein Kinase A. In parallel to CREB activation, we demonstrate that VIP also triggers nuclear accumulation of the CREB coactivator CRTC2 only in astrocytic nuclei that also requires Protein Kinase C activity. Transcriptome profiles of VIP-induced astrocytes identified robust CREB-dependent transcription of glycogenic genes including the upregulation of Ppp1r3c along with robust repression of Phkg1, the catalytic subunit of phosphorylase kinase. Overall, our data demonstrates the importance of CREB-mediated transcription in astrocytes during stimulus-driven glycogenesis.
2024-04-30 | GSE243500 | GEO
Project description:Enchondromas are common bone tumors composed of chondrocytes originating from growth plate cells, which can progress to malignant chondrosarcoma. Mutations in the genes encoding isocitrate dehydrogenase (IDH1 and IDH2) are identified in a large proportion of these tumors. IDH enzymes convert isocitrate to alpha-ketoglutarate (α-KG), an essential component of the citric acid cycle. The mutant IDH enzymes produce 2-hydroxyglutarate (2-HG), which has epigenetic effects important in tumor initiation. Tumor maintenance and growth rely on additional factors as well. Prior work shows that intracellular cholesterol and glycogen are upregulated in mutant IDH chondrocytes. Here, we show that Protein Phosphatase 1 Regulatory Subunit 3C (PPP1R3C, previously termed Protein Targeting to Glycogen or PTG) is upregulated in chondrocytes harboring a mutant IDH. PPP1R3C expression correlates with the level of intracellular cholesterol biosynthesis and can be regulated by Sterol Regulatory Element-Binding Proteins (SREBPs), which are transcriptional regulators of enzymes involved in sterol biosynthesis. We found that PPP1R3C regulates glycolysis and glycolytic capacity in chondrocytes. Depletion of PPP1R3C in mouse chondrocytes in vivo suppresses the enchondroma phenotype. The growth plate phenotype associated with the inhibition of cholesterol biosynthesis is partially rescued by PPP1R3C overexpression. Taken together, our data show that PPP1R3C integrates the effects of cholesterol metabolism and isocitrate dehydrogenase on growth plate and neoplastic chondrocyte metabolism by regulating intracellular glycogen levels.
2025-04-02 | GSE270026 | GEO
Project description:Enchondromas are common bone tumors composed of chondrocytes originating from growth plate cells, which can progress to malignant chondrosarcoma. Mutations in the genes encoding isocitrate dehydrogenase (IDH1 and IDH2) are identified in a large proportion of these tumors. IDH enzymes convert isocitrate to alpha-ketoglutarate (α-KG), an essential component of the citric acid cycle. The mutant IDH enzymes produce 2-hydroxyglutarate (2-HG), which has epigenetic effects important in tumor initiation. Tumor maintenance and growth rely on additional factors as well. Prior work shows that intracellular cholesterol and glycogen are upregulated in mutant IDH chondrocytes. Here, we show that Protein Phosphatase 1 Regulatory Subunit 3C (PPP1R3C, previously termed Protein Targeting to Glycogen or PTG) is upregulated in chondrocytes harboring a mutant IDH. PPP1R3C expression correlates with the level of intracellular cholesterol biosynthesis and can be regulated by Sterol Regulatory Element-Binding Proteins (SREBPs), which are transcriptional regulators of enzymes involved in sterol biosynthesis. We found that PPP1R3C regulates glycolysis and glycolytic capacity in chondrocytes. Depletion of PPP1R3C in mouse chondrocytes in vivo suppresses the enchondroma phenotype. The growth plate phenotype associated with the inhibition of cholesterol biosynthesis is partially rescued by PPP1R3C overexpression. Taken together, our data show that PPP1R3C integrates the effects of cholesterol metabolism and isocitrate dehydrogenase on growth plate and neoplastic chondrocyte metabolism by regulating intracellular glycogen levels.
2025-04-02 | GSE286965 | GEO
Project description: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 functionrelated 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 to 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.
2023-10-01 | GSE242294 | GEO
Project description:Lactate metabolism and signaling intricately intertwine in the context of cancer and immunity. Basigin, working alongside monocarboxylate transporters MCT1 and MCT4, orchestrates the movement of lactate across cell membranes. Despite promising potential in treating aggressive tumors, the impact of basigin antibodies on these interactions remains unclear. Our research sheds light on this complex interplay: basigin positively modulates MCT activity. A basigin antibody transforms basigin into a negative regulator of MCTs. The antibody suppresses lactate transport and enhances anti-tumor immunity in vitro and in vivo. Furthermore, antibody alters metabolic profiles in PDOs-NSCLCs and T cells. Cryo-EM structure analysis and molecular dynamics simulations unveil that MCT1’s turnover rate is influenced by the flexibility of basigin’s Ig2 domain. By restricting Ig2 flexibility, antibody reduces MCT1 turnover. These findings underscore the promise of basigin antibodies in tumor combat by influencing metabolism and immunity and the value of shared ancillary subunits in targeting heteromeric transporters.
2025-05-14 | GSE268751 | GEO