Exercise metabolism and adaptation in skeletal muscle

Nature Reviews Molecular Cell Biology, Journal Year: 2023, Volume and Issue: 24(9), P. 607 - 632

Published: May 24, 2023

Language: Английский

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ULK1-mediated metabolic reprogramming regulates Vps34 lipid kinase activity by its lactylation

Science Advances, Journal Year: 2023, Volume and Issue: 9(22)

Published: June 2, 2023

Autophagy and glycolysis are highly conserved biological processes involved in both physiological pathological cellular programs, but the interplay between these is poorly understood. Here, we show that glycolytic enzyme lactate dehydrogenase A (LDHA) activated upon UNC-51-like kinase 1 (ULK1) activation under nutrient deprivation. Specifically, ULK1 directly interacts with LDHA, phosphorylates serine-196 when nutrients scarce promotes production. Lactate connects autophagy through Vps34 lactylation (at lysine-356 lysine-781), which mediated by acyltransferase KAT5/TIP60. enhances association of Beclin1, Atg14L, UVRAG, then increases lipid activity. autophagic flux endolysosomal trafficking. skeletal muscle during intense exercise maintains cell homeostasis correlates cancer progress inducing autophagy. Together, our findings describe regulation mechanism integrate glycolysis.

Language: Английский

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Lactate activates the mitochondrial electron transport chain independently of its metabolism

Molecular Cell, Journal Year: 2023, Volume and Issue: 83(21), P. 3904 - 3920.e7

Published: Oct. 24, 2023

Language: Английский

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PDK4-dependent hypercatabolism and lactate production of senescent cells promotes cancer malignancy

Nature Metabolism, Journal Year: 2023, Volume and Issue: 5(11), P. 1887 - 1910

Published: Oct. 30, 2023

Abstract Senescent cells remain metabolically active, but their metabolic landscape and resulting implications underexplored. Here, we report upregulation of pyruvate dehydrogenase kinase 4 (PDK4) upon senescence, particularly in some stromal cell lines. display a PDK4-dependent increase aerobic glycolysis enhanced lactate production maintain mitochondrial respiration redox activity, thus adopting special form reprogramming. Medium from PDK4 + promotes the malignancy recipient cancer vitro, whereas inhibition causes tumor regression vivo. We find that reactive oxygen species via NOX1 to drive senescence-associated secretory phenotype, suppression reduces DNA damage severity restrains phenotype. In preclinical trials, alleviates physical dysfunction prevents age-associated frailty. Together, our study confirms hypercatabolic nature senescent reveals link between cellular production, possibly, age-related pathologies, including not limited cancer.

Language: Английский

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Lactate as a myokine and exerkine: drivers and signals of physiology and metabolism

Journal of Applied Physiology, Journal Year: 2023, Volume and Issue: 134(3), P. 529 - 548

Published: Jan. 12, 2023

No longer viewed as a metabolic waste product and cause of muscle fatigue, contemporary view incorporates the roles lactate in metabolism, sensing signaling normal well pathophysiological conditions. Lactate exists millimolar concentrations muscle, blood, other tissues can rise more than an order magnitude result increased production clearance limitations. exerts its powerful driver-like influence by mass action, redox change, allosteric binding, mechanisms described this article. Depending on condition, such during rest exercise, following carbohydrate nutrition, injury, or pathology, serve myokine exerkine with autocrine-, paracrine-, endocrine-like functions that have important basic translational implications. For instance, is: involved reproductive biology, fueling heart, adaptation, brain executive function, growth development, treatment for inflammatory also works many factors controlling cardiac output pulmonary ventilation exercise. Ironically, be disruptive processes insulin secretion when insertion transporters into pancreatic β-cell membranes is not suppressed, carcinogenesis suppress are inhibited, whereas promote upregulated. areas intermediary mitochondrial biogenesis, neurobiology, gut physiology, appetite regulation, overall health vigor. The various reviewed.NEW & NOTEWORTHY relatively new rapidly changing field. As physiological signal both independently concert signals. operates via covalent binding canonical signaling, lactylation DNA. element feedback loops cardiopulmonary regulation. From conception through aging only exerkine, but it certainly deserves consideration signal.

Language: Английский

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Noninvasive Imaging of Tumor Glycolysis and Chemotherapeutic Resistance via De Novo Design of Molecular Afterglow Scaffold

Journal of the American Chemical Society, Journal Year: 2023, Volume and Issue: 145(44), P. 24386 - 24400

Published: Oct. 26, 2023

Chemotherapeutic resistance poses a significant challenge in cancer treatment, resulting the reduced efficacy of standard chemotherapeutic agents. Abnormal metabolism, particularly increased anaerobic glycolysis, has been identified as major contributing factor to resistance. To address this issue, noninvasive imaging techniques capable visualizing tumor glycolysis are crucial. However, currently available methods (such PET, MRI, and fluorescence) possess limitations terms sensitivity, safety, dynamic capability, autofluorescence. Here, we present de novo design unique afterglow molecular scaffold based on hemicyanine rhodamine dyes, which holds promise for low-background optical imaging. In contrast previous designs, exhibits responsive "OFF-ON" signals through spirocyclization, thus enabling simultaneous control photodynamic effects luminescence efficacy. This leads larger range, broader detection higher signal enhancement ratio, sensitivity. Furthermore, integration multiple functionalities simplifies probe design, eliminates need spectral overlap, enhances reliability. Moreover, have expanded applications by developing various probes different targets. Notably, developed water-soluble pH-responsive nanoprobe living mice. monitors glycolytic inhibitors or oxidative phosphorylation providing valuable tool evaluating cell sensitivity these inhibitors. Therefore, new presents promising approach understanding monitoring resistance, guiding precision medicine future.

Language: Английский

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Artificial intelligence in drug development

Nature Medicine, Journal Year: 2025, Volume and Issue: 31(1), P. 45 - 59

Published: Jan. 1, 2025

Language: Английский

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Lactylated Apolipoprotein C‐II Induces Immunotherapy Resistance by Promoting Extracellular Lipolysis

Advanced Science, Journal Year: 2024, Volume and Issue: 11(38)

Published: July 9, 2024

Abstract Mortality rates due to lung cancer are high worldwide. Although PD‐1 and PD‐L1 immune checkpoint inhibitors boost the survival of patients with non‐small‐cell (NSCLC), resistance often arises. The Warburg Effect, which causes lactate build‐up potential lysine‐lactylation (Kla), links dysfunction tumor metabolism. role non‐histone Kla in microenvironment immunotherapy remains be clarified. Here, global lactylome profiling metabolomic analyses samples from NSCLC is conducted. By combining multi‐omics analysis vitro vivo validation, that intracellular promotes extracellular lipolysis through lactyl‐APOC2 revealed. Mechanistically, enhances APOC2 lactylation at K70, stabilizing it resulting FFA release, regulatory T cell accumulation, resistance, metastasis. Moreover, anti‐APOC2 K70‐lac antibody sensitized anti‐PD‐1 therapy developed. This findings highlight anti lactyl‐APOC2‐K70 approach as a new combination for sensitizing immunotherapeutic responses.

Language: Английский

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Lactate and lactylation in cancer

Signal Transduction and Targeted Therapy, Journal Year: 2025, Volume and Issue: 10(1)

Published: Feb. 11, 2025

Abstract Accumulated evidence has implicated the diverse and substantial influence of lactate on cellular differentiation fate regulation in physiological pathological settings, particularly intricate conditions such as cancer. Specifically, been demonstrated to be pivotal molding tumor microenvironment (TME) through its effects different cell populations. Within cells, impacts signaling pathways, augments shuttle process, boosts resistance oxidative stress, contributes lactylation. In various populations, interplay between immune cells governs processes differentiation, response, surveillance, treatment effectiveness. Furthermore, communication stromal/endothelial supports basal membrane (BM) remodeling, epithelial-mesenchymal transitions (EMT), metabolic reprogramming, angiogenesis, drug resistance. Focusing production transport, specifically dehydrogenase (LDH) monocarboxylate transporters (MCT), shown promise Inhibitors targeting LDH MCT act both suppressors enhancers immunotherapy, leading a synergistic therapeutic effect when combined with immunotherapy. The review underscores importance progression provides valuable perspectives potential approaches that target vulnerability metabolism, highlighting Heel Achilles for cancer treatment.

Language: Английский

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Energy metabolism in health and diseases

Signal Transduction and Targeted Therapy, Journal Year: 2025, Volume and Issue: 10(1)

Published: Feb. 18, 2025

Language: Английский

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