Exercise improves cognitive dysfunction and neuroinflammation in mice through Histone H3 lactylation in microglia

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Abstract

Background

Exercise is postulated to be a promising non-pharmacological intervention for the improvement of neurodegenerative disease pathology. However, the mechanism of beneficial effects of exercise on the brain remains to be further explored. In this study, we investigated the effect of an exercise-induced metabolite, lactate, on the microglia phenotype and its association with learning and memory.

Results

Microglia were hyperactivated in the brains of AlCl ₃/D-gal-treated mice, which was associated with cognitive decline. Running exercise ameliorated the hyperactivation and increased the anti-inflammatory/reparative phenotype of microglia and improved cognition. Mice were injected intraperitoneally with sodium lactate (NaLA) had similar beneficial effects as that of exercise training. Exogenous NaLA addition to cultured BV2 cells promoted their transition from a pro-inflammatory to a reparative phenotype.

Conclusion

The elevated lactate acted as an “accelerator” of the endogenous “lactate timer” in microglia promoting this transition of microglia polarization balance through lactylation. These findings demonstrate that exercise-induced lactate accelerates the phenotypic transition of microglia, which plays a key role in reducing neuroinflammation and improving cognitive function.

Supplementary Information

The online version contains supplementary material available at 10.1186/s12979-023-00390-4.

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Most cited references 89

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Ageing as a risk factor for neurodegenerative disease

Yujun Hou, Xiuli Dan, Mansi Babbar … (2019)

Ageing is the primary risk factor for most neurodegenerative diseases, including Alzheimer disease (AD) and Parkinson disease (PD). One in ten individuals aged ≥65 years has AD and its prevalence continues to increase with increasing age. Few or no effective treatments are available for ageing-related neurodegenerative diseases, which tend to progress in an irreversible manner and are associated with large socioeconomic and personal costs. This Review discusses the pathogenesis of AD, PD and other neurodegenerative diseases, and describes their associations with the nine biological hallmarks of ageing: genomic instability, telomere attrition, epigenetic alterations, loss of proteostasis, mitochondrial dysfunction, cellular senescence, deregulated nutrient sensing, stem cell exhaustion and altered intercellular communication. The central biological mechanisms of ageing and their potential as targets of novel therapies for neurodegenerative diseases are also discussed, with potential therapies including NAD+ precursors, mitophagy inducers and inhibitors of cellular senescence.

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Alzheimer's disease: the amyloid cascade hypothesis

Christopher J. Hardy, Larry G. Higgins (1992)

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Metabolic regulation of gene expression by histone lactylation

Di Zhang, Zhanyun Tang, He Huang … (2019)

The Warburg effect, originally describing augmented lactogenesis in cancer, is associated with diverse cellular processes such as angiogenesis, hypoxia, macrophage polarization, and T-cell activation. This phenomenon is intimately linked with multiple diseases including neoplasia, sepsis, and autoimmune diseases 1,2 . Lactate, a compound generated during Warburg effect, is widely known as an energy source and metabolic byproduct. However, its non-metabolic functions in physiology and disease remain unknown. Here we report lactate-derived histone lysine lactylation as a new epigenetic modification and demonstrate that histone lactylation directly stimulates gene transcription from chromatin. In total, we identify 28 lactylation sites on core histones in human and mouse cells. Hypoxia and bacterial challenges induce production of lactate through glycolysis that in turn serves as precursor for stimulating histone lactylation. Using bacterially exposed M1 macrophages as a model system, we demonstrate that histone lactylation has different temporal dynamics from acetylation. In the late phase of M1 macrophage polarization, elevated histone lactylation induces homeostatic genes involved in wound healing including arginase 1. Collectively, our results suggest the presence of an endogenous “lactate clock” in bacterially challenged M1 macrophages that turns on gene expression to promote homeostasis. Histone lactylation thus represents a new avenue for understanding the functions of lactate and its role in diverse pathophysiological conditions, including infection and cancer.

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Author and article information

Contributors

Ming Zhang: zhangming99@jlu.edu.cn

Li Chen: chenl@jlu.edu.cn

Journal

Journal ID (nlm-ta): Immun Ageing

Journal ID (iso-abbrev): Immun Ageing

Title: Immunity & Ageing : I & A

Publisher: BioMed Central (London )

ISSN (Electronic): 1742-4933

Publication date (Electronic): 17 November 2023

Publication date PMC-release: 17 November 2023

Publication date Collection: 2023

Volume: 20

Electronic Location Identifier: 63

Affiliations

[1 ]Key Laboratory of Pathobiology, Ministry of Education, College of Basic Medical Sciences, Jilin University, ( https://ror.org/00js3aw79) Changchun, 130021 China

[2 ]Department of Pharmacology, College of Basic Medical Sciences, Jilin University, ( https://ror.org/00js3aw79) 126 Xin Min Street, Changchun, 130021 Jilin China

[3 ]School of Pharmaceutical Sciences, Jilin University, ( https://ror.org/00js3aw79) Changchun, 130021 China

[4 ]GRID grid.452829.0, ISNI 0000000417660726, The Second Hospital of Jilin University, ; Changchun, 130041 China

[5 ]South China Institute of Collaborative Innovation, ( https://ror.org/04jnpk588) Dongguan, 523808 China

[6 ]GRID grid.21613.37, ISNI 0000 0004 1936 9609, Departments of Pharmacology and Therapeutics, Biochemistry and Medical Genetics, Center for Research and Treatment of Atherosclerosis, , DREAM Children’s Hospital Research Institute of Manitoba, University of Manitoba, ; Winnipeg, MB R3E0T6 Canada

Article

Publisher ID: 390

DOI: 10.1186/s12979-023-00390-4

PMC ID: 10655345

PubMed ID: 37978517

SO-VID: 7848b4cb-b822-433f-ac03-1d4b310f8ebd

License:

Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/. The Creative Commons Public Domain Dedication waiver ( http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated in a credit line to the data.

History

Date received : 8 May 2023

Date accepted : 7 November 2023

Custom metadata

ScienceOpen disciplines: Immunology

Keywords: exercise,lactate,lactylation,microglia,neuroinflammation,alzheimers disease

Data availability:

ScienceOpen disciplines: Immunology

Keywords: exercise, lactate, lactylation, microglia, neuroinflammation, alzheimers disease

Exercise improves cognitive dysfunction and neuroinflammation in mice through Histone H3 lactylation in microglia

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Abstract

Background

Results

Conclusion

Supplementary Information

Related collections

Alternative approaches to Alzheimer's Disease

Most cited references 89

Ageing as a risk factor for neurodegenerative disease

Alzheimer's disease: the amyloid cascade hypothesis

Metabolic regulation of gene expression by histone lactylation

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