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Kim EY, Abides J, Keller CR, Martinez SR, Li W. Tumor Microenvironment Lactate: Is It a Cancer Progression Marker, Immunosuppressant, and Therapeutic Target? Molecules 2025; 30:1763. [PMID: 40333742 PMCID: PMC12029365 DOI: 10.3390/molecules30081763] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/10/2025] [Revised: 04/12/2025] [Accepted: 04/12/2025] [Indexed: 05/09/2025] Open
Abstract
The "Warburg effect" is a term coined a century ago for the preferential use of glycolysis over aerobic respiration in tumor cells for energy production, even under aerobic conditions. Although this is a less efficient mechanism of generating energy from glucose, aerobic glycolysis, in addition to the canonical anaerobic glycolysis, is an effective means of lactate production. The abundant waste product, lactate, yielded by the dual glycolysis in a tumor, has been discovered to be a major biomolecule that drives cancer progression. Lactate is a metabolic energy source that, via cell membrane lactate transporters, shuttles in and out of cancer cells as well as cancer cell-associated stromal cells and immune cells within the tumor microenvironment (TME). Additionally, lactate serves as a pH tuner, signaling ligand and transducer, epigenetic and gene transcription regulator, TME modifier, immune suppressor, chemoresistance modulator, and prognostic marker. With such broad functionalities, the production-consumption-reproduction of TME lactate fuels tumor growth and dissemination. Here, we elaborate on the lactate sources that contribute to the pool of lactate in the TME, the functions of TME lactate, the influence of the TME lactate on immune cell function and local tissue immunity, and anticancer therapeutic approaches adopting lactate manipulations and their efficacies. By scrutinizing these properties of the TME lactate and others that have been well addressed in the field, it is expected that a better weighing of the influence of the TME lactate on cancer development, progression, prognosis, and therapeutic efficacy can be achieved.
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Affiliation(s)
- Eugene Y. Kim
- Department of Translational Medicine and Physiology, Elson S. Floyd College of Medicine, Washington State University, Spokane, WA 99202, USA; (E.Y.K.); (J.A.); (C.R.K.)
| | - Joyce Abides
- Department of Translational Medicine and Physiology, Elson S. Floyd College of Medicine, Washington State University, Spokane, WA 99202, USA; (E.Y.K.); (J.A.); (C.R.K.)
- Doctor of Medicine Program, Elson S. Floyd College of Medicine, Washington State University, Spokane, WA 99202, USA
| | - Chandler R. Keller
- Department of Translational Medicine and Physiology, Elson S. Floyd College of Medicine, Washington State University, Spokane, WA 99202, USA; (E.Y.K.); (J.A.); (C.R.K.)
| | - Steve R. Martinez
- Department of Medical Education and Clinical Sciences, Elson S. Floyd College of Medicine, Washington State University, Spokane, WA 99202, USA
- Providence Regional Cancer Partnership, Providence Regional Medical Center, Everett, WA 98201, USA
| | - Weimin Li
- Department of Translational Medicine and Physiology, Elson S. Floyd College of Medicine, Washington State University, Spokane, WA 99202, USA; (E.Y.K.); (J.A.); (C.R.K.)
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Xuan Q, Huang L, Gu W, Ling C. Twenty years of research on exercise-induced fatigue: A bibliometric analysis of hotspots, bursts, and research trends. Medicine (Baltimore) 2025; 104:e41895. [PMID: 40128028 PMCID: PMC11936639 DOI: 10.1097/md.0000000000041895] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/11/2024] [Accepted: 02/28/2025] [Indexed: 03/26/2025] Open
Abstract
Data from the Web of Science Core Collection (2004-2023) on "exercise-induced fatigue" were analyzed using bibliometric tools to explore research trends across countries, institutions, authors, journals, and keywords. The analysis was limited to "Article" and "Review" literature types. Among 4531 publications, the United States contributed the most articles (1005), followed by England (559) and China (516). The most influential institution was Universidade de São Paulo, while the most productive was Institut National de la Santé et de la Recherche Médicale with 103 papers. The European Journal of Applied Physiology ranked as the top journal with 233 articles. Millet Guillaume Y. emerged as the most prolific author, and Amann Markus was the most cited. Recent keyword trends showed a surge in terms like "physical activity" and "aerobic exercise," while "fatigue" and "exercise" remained dominant. Notable findings were observed in oncology, engineering, and multidisciplinary studies, indicating potential research trends. Oxidative stress was identified as the most commonly mentioned mechanism in exercise-induced fatigue studies. This bibliometric analysis highlights current research trends and gaps, suggesting that future studies should focus on understanding the mechanisms of exercise-induced fatigue, developing objective measurement criteria, and exploring strategies for its alleviation.
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Affiliation(s)
- Qiwen Xuan
- School of Traditional Chinese Medicine, Naval Medical University, Shanghai, China
| | - Lele Huang
- Department of Sports Medicine, Peking University Third Hospital, Institute of Sports Medicine of Peking University, Beijing, China
| | - Wei Gu
- School of Traditional Chinese Medicine, Naval Medical University, Shanghai, China
| | - Changquan Ling
- School of Traditional Chinese Medicine, Naval Medical University, Shanghai, China
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Chen Y, Xiao D, Li X. Lactylation and Central Nervous System Diseases. Brain Sci 2025; 15:294. [PMID: 40149815 PMCID: PMC11940311 DOI: 10.3390/brainsci15030294] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/22/2025] [Revised: 03/01/2025] [Accepted: 03/10/2025] [Indexed: 03/29/2025] Open
Abstract
As the final product of glycolysis, lactate serves as an energy substrate, metabolite, and signaling molecule in various diseases and mediates lactylation, an epigenetic modification that occurs under both physiological and pathological conditions. Lactylation is a crucial mechanism by which lactate exerts its functions, participating in vital biological activities such as glycolysis-related cellular functions, macrophage polarization, and nervous system regulation. Lactylation links metabolic regulation to central nervous system (CNS) diseases, such as traumatic brain injury, Alzheimer's disease, acute ischemic stroke, and schizophrenia, revealing the diverse functions of lactylation in the CNS. In the future, further exploration of lactylation-associated enzymes and proteins is needed to develop specific lactylation inhibitors or activators, which could provide new tools and strategies for the treatment of CNS diseases.
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Affiliation(s)
- Ye Chen
- Department of Emergency Medicine, West China Second University Hospital, Sichuan University, Chengdu 610041, China; (Y.C.); (D.X.)
- Key Laboratory of Birth Defects and Related Diseases of Women and Children, Sichuan University, Ministry of Education, Chengdu 610041, China
| | - Dongqiong Xiao
- Department of Emergency Medicine, West China Second University Hospital, Sichuan University, Chengdu 610041, China; (Y.C.); (D.X.)
- Key Laboratory of Birth Defects and Related Diseases of Women and Children, Sichuan University, Ministry of Education, Chengdu 610041, China
| | - Xihong Li
- Department of Emergency Medicine, West China Second University Hospital, Sichuan University, Chengdu 610041, China; (Y.C.); (D.X.)
- Key Laboratory of Birth Defects and Related Diseases of Women and Children, Sichuan University, Ministry of Education, Chengdu 610041, China
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Sun Y, He J, Bao L, Shi X, Wang J, Li Q. Harnessing exercise to combat chronic diseases: the role of Drp1-Mediated mitochondrial fission. Front Cell Dev Biol 2025; 13:1481756. [PMID: 40078364 PMCID: PMC11897009 DOI: 10.3389/fcell.2025.1481756] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/16/2024] [Accepted: 02/06/2025] [Indexed: 03/14/2025] Open
Abstract
Enhanced Drp1 activity mediates excessive mitochondrial fission, contributing to the onset and progression of various chronic diseases, including neurodegenerative, cardiovascular, and metabolic disorders. Studies indicate that exercise mitigates mitochondrial dysfunction by modulating Drp1-related signaling targets, thereby inhibiting Drp1 activity and reducing excessive mitochondrial fission. This, in turn, enhances mitochondrial function and cellular metabolism. This review synthesizes the current understanding of Drp1 structure and activation mechanisms, and analyzes the effects of exercise interventions on Drp1-mediated mitochondrial fission in different disease models to improve common chronic conditions. This research deepens our insight into the specific mechanisms of Drp1-induced excessive mitochondrial fission in chronic disease pathogenesis, offering new theoretical support and practical guidance for exercise as a non-pharmacological intervention strategy.
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Affiliation(s)
- Yingxin Sun
- School of Exercise and Health Sciences, Tianjin University of Sport, Tianjin, China
| | - Junchen He
- Department of Dermatology, Tianjin Academy of Traditional Chinese Medicine Affiliated Hospital, Tianjin, China
- Department of Dermatology, Tianjin lnstitute of lntegrative Dermatology, Tianjin, China
| | - Lei Bao
- School of Exercise and Health Sciences, Tianjin University of Sport, Tianjin, China
| | - Xiaoming Shi
- School of Exercise and Health Sciences, Tianjin University of Sport, Tianjin, China
| | - Jinghong Wang
- School of Exercise and Health Sciences, Tianjin University of Sport, Tianjin, China
| | - Qingwen Li
- School of Exercise and Health Sciences, Tianjin University of Sport, Tianjin, China
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Velmurugan GV, Vekaria HJ, Patel SP, Sullivan PG, Hubbard WB. Astrocytic mitochondrial transfer to brain endothelial cells and pericytes in vivo increases with aging. J Cereb Blood Flow Metab 2024:271678X241306054. [PMID: 39668588 PMCID: PMC11638933 DOI: 10.1177/0271678x241306054] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/06/2024] [Revised: 11/01/2024] [Accepted: 11/22/2024] [Indexed: 12/14/2024]
Abstract
Intercellular mitochondrial transfer (IMT) is an intriguing biological phenomenon where mitochondria are transferred between different cells and notably, cell types. IMT is physiological, occurring in normal conditions, but also is utilized to deliver healthy mitochondria to cells in distress. Transferred mitochondria can be integrated to improve cellular metabolism, and mitochondrial function. Research on the mitochondrial transfer axis between astrocytes and brain capillaries in vivo is limited by the cellular heterogeneity of the neurovascular unit. To this end, we developed an inducible mouse model that expresses mitochondrial Dendra2 only in astrocytes and then isolated brain capillaries to remove all intact astrocytes. This method allows the visualization of in vivo astrocyte- endothelial cell (EC) and astrocyte-pericyte IMT. We demonstrate evidence of astrocyte-EC and astrocyte-pericyte mitochondrial transfer within brain capillaries. We also show that healthy aging enhances mitochondrial transfer from astrocytes to brain capillaries, revealing a potential link between brain aging and cellular mitochondrial dynamics. Finally, we observe that astrocyte-derived extracellular vesicles transfer mitochondria to brain microvascular endothelial cells, showing the potential route of in vivo IMT. These results represent a breakthrough in our understanding of IMT in the brain and a new target in brain aging and neurovascular metabolism.
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Affiliation(s)
- Gopal V Velmurugan
- Spinal Cord and Brain Injury Research Center, University of Kentucky, Lexington, KY, USA
- Department of Neuroscience, University of Kentucky, Lexington, KY, USA
| | - Hemendra J Vekaria
- Spinal Cord and Brain Injury Research Center, University of Kentucky, Lexington, KY, USA
- Department of Neuroscience, University of Kentucky, Lexington, KY, USA
- Lexington Veterans’ Affairs Healthcare System, Lexington, KY, USA
| | - Samir P Patel
- Spinal Cord and Brain Injury Research Center, University of Kentucky, Lexington, KY, USA
- Lexington Veterans’ Affairs Healthcare System, Lexington, KY, USA
| | - Patrick G Sullivan
- Spinal Cord and Brain Injury Research Center, University of Kentucky, Lexington, KY, USA
- Department of Neuroscience, University of Kentucky, Lexington, KY, USA
- Lexington Veterans’ Affairs Healthcare System, Lexington, KY, USA
| | - W Brad Hubbard
- Spinal Cord and Brain Injury Research Center, University of Kentucky, Lexington, KY, USA
- Lexington Veterans’ Affairs Healthcare System, Lexington, KY, USA
- Department of Physiology, University of Kentucky, Lexington, KY, USA
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Wang MY, Zhou Y, Li WL, Zhu LQ, Liu D. Friend or foe: Lactate in neurodegenerative diseases. Ageing Res Rev 2024; 101:102452. [PMID: 39127445 DOI: 10.1016/j.arr.2024.102452] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/18/2024] [Accepted: 08/07/2024] [Indexed: 08/12/2024]
Abstract
Lactate, a byproduct of glycolysis, was considered as a metabolic waste until identified by studies on the Warburg effect. Increasing evidence elucidates that lactate functions as energy fuel, signaling molecule, and donor for protein lactylation. Altered lactate utilization is a common metabolic feature of the onset and progression of neurodegenerative diseases, such as Alzheimer's disease, multiple sclerosis, amyotrophic lateral sclerosis, Parkinson's disease and Huntington's disease. This review offers an overview of lactate metabolism from the perspective of production, transportation and clearance, and the role of lactate in neurodegenerative progression, as well as a summary of protein lactylation and the signaling function of lactate in neurodegenerative diseases. Besides, this review delves into the dual roles of changed lactate metabolism during neurodegeneration and explores prospective therapeutic methods targeting lactate. We propose that elucidating the correlation between lactate and neurodegeneration is pivotal for exploring innovative therapeutic interventions for neurodegenerative diseases.
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Affiliation(s)
- Ming-Yu Wang
- Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China
| | - Yang Zhou
- Department of Pathophysiology, School of Basic Medicine, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei 430030, China
| | - Wen-Lian Li
- Department of Pathophysiology, School of Basic Medicine, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei 430030, China
| | - Ling-Qiang Zhu
- Department of Pathophysiology, School of Basic Medicine, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei 430030, China.
| | - Dan Liu
- Department of Medical Genetics, School of Basic Medicine, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei 430030, China.
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Liu S, Zhou S. Lactate: A New Target for Brain Disorders. Neuroscience 2024; 552:100-111. [PMID: 38936457 DOI: 10.1016/j.neuroscience.2024.06.023] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/18/2024] [Revised: 06/19/2024] [Accepted: 06/22/2024] [Indexed: 06/29/2024]
Abstract
Lactate in the brain is produced endogenously and exogenously. The primary functional cells that produce lactate in the brain are astrocytes. Astrocytes release lactate to act on neurons, thereby affecting neuronal function, through a process known as the astrocyte-neuron shuttle. Lactate affects microglial function as well and inhibits microglia-mediated neuroinflammation. Lactate also provides energy, acts as a signaling molecule, and promotes neurogenesis. This article summarizes the role of lactate in cells, animals, and humans. Lactate is a protective molecule against stress in healthy organisms and in the early stages of brain disorders. Thus, lactate may be a potential therapeutic target for brain disorders. Further research on the role of lactate in microglia may have great prospects. This article provides a new perspective and research direction for the study of lacate in brain disorders.
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Affiliation(s)
- Shunfeng Liu
- College of Pharmacy, Guilin Medical University, Guilin 541199, China; Guangxi Key Laboratory of Brain and Cognitive Neuroscience, Guilin Medical University, Guilin 541199, China; Department of Physiology, School of Basic Medicine, Qingdao University, Qingdao 266071, China.
| | - Shouhong Zhou
- Guangxi Key Laboratory of Brain and Cognitive Neuroscience, Guilin Medical University, Guilin 541199, China; Basic Medical College, Guilin Medical University, Guilin 541199, China.
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Cai M, Wan J, Cai K, Li S, Du X, Song H, Sun W, Hu J. The mitochondrial quality control system: a new target for exercise therapeutic intervention in the treatment of brain insulin resistance-induced neurodegeneration in obesity. Int J Obes (Lond) 2024; 48:749-763. [PMID: 38379083 DOI: 10.1038/s41366-024-01490-x] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/04/2023] [Revised: 01/30/2024] [Accepted: 02/01/2024] [Indexed: 02/22/2024]
Abstract
Obesity is a major global health concern because of its strong association with metabolic and neurodegenerative diseases such as diabetes, dementia, and Alzheimer's disease. Unfortunately, brain insulin resistance in obesity is likely to lead to neuroplasticity deficits. Since the evidence shows that insulin resistance in brain regions abundant in insulin receptors significantly alters mitochondrial efficiency and function, strategies targeting the mitochondrial quality control system may be of therapeutic and practical value in obesity-induced cognitive decline. Exercise is considered as a powerful stimulant of mitochondria that improves insulin sensitivity and enhances neuroplasticity. It has great potential as a non-pharmacological intervention against the onset and progression of obesity associated neurodegeneration. Here, we integrate the current knowledge of the mechanisms of neurodegenration in obesity and focus on brain insulin resistance to explain the relationship between the impairment of neuronal plasticity and mitochondrial dysfunction. This knowledge was synthesised to explore the exercise paradigm as a feasible intervention for obese neurodegenration in terms of improving brain insulin signals and regulating the mitochondrial quality control system.
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Affiliation(s)
- Ming Cai
- Jinshan District Central Hospital affiliated to Shanghai University of Medicine & Health Sciences, Shanghai, 201599, China
| | - Jian Wan
- Department of Emergency and Critical Care Medicine, Shanghai Pudong New Area People's Hospital, Shanghai, 201299, China
| | - Keren Cai
- College of Rehabilitation Sciences, Shanghai University of Medicine and Health Sciences, Shanghai, 201318, China
| | - Shuyao Li
- College of Rehabilitation Sciences, Shanghai University of Medicine and Health Sciences, Shanghai, 201318, China
| | - Xinlin Du
- College of Rehabilitation Sciences, Shanghai University of Medicine and Health Sciences, Shanghai, 201318, China
| | - Haihan Song
- Central Lab, Shanghai Key Laboratory of Pathogenic Fungi Medical Testing, Shanghai Pudong New Area People's Hospital, Shanghai, 201299, China
| | - Wanju Sun
- Central Lab, Shanghai Key Laboratory of Pathogenic Fungi Medical Testing, Shanghai Pudong New Area People's Hospital, Shanghai, 201299, China.
| | - Jingyun Hu
- Central Lab, Shanghai Key Laboratory of Pathogenic Fungi Medical Testing, Shanghai Pudong New Area People's Hospital, Shanghai, 201299, China.
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Cai M, Li S, Cai K, Du X, Han J, Hu J. Empowering mitochondrial metabolism: Exploring L-lactate supplementation as a promising therapeutic approach for metabolic syndrome. Metabolism 2024; 152:155787. [PMID: 38215964 DOI: 10.1016/j.metabol.2024.155787] [Citation(s) in RCA: 2] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/03/2023] [Revised: 12/08/2023] [Accepted: 01/05/2024] [Indexed: 01/14/2024]
Abstract
Mitochondrial dysfunction plays a critical role in the pathogenesis of metabolic syndrome (MetS), affecting various cell types and organs. In MetS animal models, mitochondria exhibit decreased quality control, characterized by abnormal morphological structure, impaired metabolic activity, reduced energy production, disrupted signaling cascades, and oxidative stress. The aberrant changes in mitochondrial function exacerbate the progression of metabolic syndrome, setting in motion a pernicious cycle. From this perspective, reversing mitochondrial dysfunction is likely to become a novel and powerful approach for treating MetS. Unfortunately, there are currently no effective drugs available in clinical practice to improve mitochondrial function. Recently, L-lactate has garnered significant attention as a valuable metabolite due to its ability to regulate mitochondrial metabolic processes and function. It is highly likely that treating MetS and its related complications can be achieved by correcting mitochondrial homeostasis disorders. In this review, we comprehensively discuss the complex relationship between mitochondrial function and MetS and the involvement of L-lactate in regulating mitochondrial metabolism and associated signaling pathways. Furthermore, it highlights recent findings on the involvement of L-lactate in common pathologies of MetS and explores its potential clinical application and further prospects, thus providing new insights into treatment possibilities for MetS.
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Affiliation(s)
- Ming Cai
- College of Rehabilitation Sciences, Shanghai University of Medicine and Health Sciences, Shanghai 201318, PR China; Bio-X Institutes, Shanghai Jiao Tong University, Shanghai, 200240, China
| | - Shuyao Li
- College of Rehabilitation Sciences, Shanghai University of Medicine and Health Sciences, Shanghai 201318, PR China
| | - Keren Cai
- College of Rehabilitation Sciences, Shanghai University of Medicine and Health Sciences, Shanghai 201318, PR China
| | - Xinlin Du
- College of Rehabilitation Sciences, Shanghai University of Medicine and Health Sciences, Shanghai 201318, PR China
| | - Jia Han
- College of Rehabilitation Sciences, Shanghai University of Medicine and Health Sciences, Shanghai 201318, PR China.
| | - Jingyun Hu
- Central Lab, Shanghai Key Laboratory of Pathogenic Fungi Medical Testing, Shanghai Pudong New Area People's Hospital, Shanghai 201299, PR China.
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Krzyściak W, Bystrowska B, Karcz P, Chrzan R, Bryll A, Turek A, Mazur P, Śmierciak N, Szwajca M, Donicz P, Furman K, Pilato F, Kozicz T, Popiela T, Pilecki M. Association of Blood Metabolomics Biomarkers with Brain Metabolites and Patient-Reported Outcomes as a New Approach in Individualized Diagnosis of Schizophrenia. Int J Mol Sci 2024; 25:2294. [PMID: 38396971 PMCID: PMC10888632 DOI: 10.3390/ijms25042294] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/10/2024] [Revised: 02/06/2024] [Accepted: 02/10/2024] [Indexed: 02/25/2024] Open
Abstract
Given its polygenic nature, there is a need for a personalized approach to schizophrenia. The aim of the study was to select laboratory biomarkers from blood, brain imaging, and clinical assessment, with an emphasis on patients' self-report questionnaires. Metabolomics studies of serum samples from 51 patients and 45 healthy volunteers, based on the liquid chromatography-electrospray ionization-mass spectrometry (LC-ESI-MS/MS), led to the identification of 3 biochemical indicators (cortisol, glutamate, lactate) of schizophrenia. These metabolites were sequentially correlated with laboratory tests results, imaging results, and clinical assessment outcomes, including patient self-report outcomes. The hierarchical cluster analysis on the principal components (HCPC) was performed to identify the most homogeneous clinical groups. Significant correlations were noted between blood lactates and 11 clinical and 10 neuroimaging parameters. The increase in lactate and cortisol were significantly associated with a decrease in immunological parameters, especially with the level of reactive lymphocytes. The strongest correlations with the level of blood lactate and cortisol were demonstrated by brain glutamate, N-acetylaspartate and the concentrations of glutamate and glutamine, creatine and phosphocreatine in the prefrontal cortex. Metabolomics studies and the search for associations with brain parameters and self-reported outcomes may provide new diagnostic evidence to specific schizophrenia phenotypes.
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Affiliation(s)
- Wirginia Krzyściak
- Department of Medical Diagnostics, Jagiellonian University Medical College, Faculty of Pharmacy, 30-688 Krakow, Poland;
| | - Beata Bystrowska
- Department of Biochemical Toxicology, Jagiellonian University Medical College, Faculty of Pharmacy, 30-688 Krakow, Poland;
| | - Paulina Karcz
- Department of Electroradiology, Jagiellonian University Medical College, Faculty of Health Sciences, 31-126 Krakow, Poland;
| | - Robert Chrzan
- Department of Radiology, Jagiellonian University Medical College, Faculty of Medicine, 31-503 Krakow, Poland; (R.C.); (A.B.); (T.P.)
| | - Amira Bryll
- Department of Radiology, Jagiellonian University Medical College, Faculty of Medicine, 31-503 Krakow, Poland; (R.C.); (A.B.); (T.P.)
| | - Aleksander Turek
- Department of Child and Adolescent Psychiatry and Psychotherapy, Faculty of Medicine, Jagiellonian University Medical College, 31-501 Krakow, Poland; (A.T.); (N.Ś.); (M.S.); (P.D.); (K.F.); (M.P.)
| | - Paulina Mazur
- Department of Medical Diagnostics, Jagiellonian University Medical College, Faculty of Pharmacy, 30-688 Krakow, Poland;
| | - Natalia Śmierciak
- Department of Child and Adolescent Psychiatry and Psychotherapy, Faculty of Medicine, Jagiellonian University Medical College, 31-501 Krakow, Poland; (A.T.); (N.Ś.); (M.S.); (P.D.); (K.F.); (M.P.)
| | - Marta Szwajca
- Department of Child and Adolescent Psychiatry and Psychotherapy, Faculty of Medicine, Jagiellonian University Medical College, 31-501 Krakow, Poland; (A.T.); (N.Ś.); (M.S.); (P.D.); (K.F.); (M.P.)
| | - Paulina Donicz
- Department of Child and Adolescent Psychiatry and Psychotherapy, Faculty of Medicine, Jagiellonian University Medical College, 31-501 Krakow, Poland; (A.T.); (N.Ś.); (M.S.); (P.D.); (K.F.); (M.P.)
| | - Katarzyna Furman
- Department of Child and Adolescent Psychiatry and Psychotherapy, Faculty of Medicine, Jagiellonian University Medical College, 31-501 Krakow, Poland; (A.T.); (N.Ś.); (M.S.); (P.D.); (K.F.); (M.P.)
| | - Fabio Pilato
- Neurology, Neurophysiology and Neurobiology Unit, Department of Medicine, Università Campus Bio-Medico di Roma, 00128 Rome, Italy;
| | - Tamas Kozicz
- Department of Clinical Genomics, Center for Individualized Medicine, Mayo Clinic, Rochester, MN 55905, USA;
| | - Tadeusz Popiela
- Department of Radiology, Jagiellonian University Medical College, Faculty of Medicine, 31-503 Krakow, Poland; (R.C.); (A.B.); (T.P.)
| | - Maciej Pilecki
- Department of Child and Adolescent Psychiatry and Psychotherapy, Faculty of Medicine, Jagiellonian University Medical College, 31-501 Krakow, Poland; (A.T.); (N.Ś.); (M.S.); (P.D.); (K.F.); (M.P.)
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Khosravi P, Shahidi F, Eskandari A, Khoramipour K. High-intensity interval training reduces Tau and beta-amyloid accumulation by improving lactate-dependent mitophagy in rats with type 2 diabetes. IRANIAN JOURNAL OF BASIC MEDICAL SCIENCES 2024; 27:1430-1439. [PMID: 39386233 PMCID: PMC11459343 DOI: 10.22038/ijbms.2024.77038.16664] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Figures] [Subscribe] [Scholar Register] [Indexed: 10/12/2024]
Abstract
Objectives This study aimed to investigate the effect of 8-week high-intensity interval training (HIIT) on lactate-induced mitophagy in the hippocampus of rats with type 2 diabetes. Materials and Methods 28 Wistar male rats were divided into four groups randomly: (i) control (Co), (ii) exercise (EX), (iii) type 2 diabetes (T2D), and (iv) type 2 diabetes + exercise (T2D + Ex). The rats in the T2D and T2D + Ex groups were fed a high-fat diet for two months, then a single dose of STZ (35 mg/kg) was injected to induce diabetes. The EX and T2D + Ex groups performed 4-10 intervals of treadmill running at 80-100% of Vmax. Serum and hippocampal levels of lactate, as well as hippocampal levels of monocarboxylate transporter2 (MCT2), sirtuin1 (SIRT1), forkhead box protein O (FOXO3), light chain 3 (LC3), PTEN-induced kinase 1 (PINK1), parkin, beta-amyloid (Aβ), hyperphosphorylated tau protein (TAU), Malondialdehyde (MDA), and antioxidant enzymes were measured. One-way ANOVA and Tukey post-hoc tests were used to analyze the data. Results Serum and hippocampal levels of lactate as well as hippocampal levels of MCT2, SIRT1, FOXO3, LC3, PINK1, Parkin, and antioxidant enzymes were higher while hippocampal levels of Aβ, TAU, and MDA were lower in T2D+EX compared to T2D group (P-value<0.05). Conclusion HIIT could improve mitophagy through Lactate-SIRT1-FOXO3-PINK1/Parkin signaling in the hippocampus of rats with T2D reducing the accumulation of Tau and Aβ, which may reduce the risk of memory impairments.
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Affiliation(s)
- Pouria Khosravi
- Department of Sports Physiology, Faculty of Physical Education and Sports Sciences, Shahid Rajaee Teacher Training University, Tehran, Iran
| | - Fereshte Shahidi
- Department of Sports Physiology, Faculty of Physical Education and Sports Sciences, Shahid Rajaee Teacher Training University, Tehran, Iran
| | - Arezoo Eskandari
- Department of Sports Physiology, Faculty of Physical Education and Sports Sciences, Shahid Rajaee Teacher Training University, Tehran, Iran
| | - Kayvan Khoramipour
- i+HeALTH Strategic Research Group, Department of Health Sciences, Miguel de Cervantes European University (UEMC), 47012 Valladolid, Spain
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Shang Q, Bian X, Zhu L, Liu J, Wu M, Lou S. Lactate Mediates High-Intensity Interval Training-Induced Promotion of Hippocampal Mitochondrial Function through the GPR81-ERK1/2 Pathway. Antioxidants (Basel) 2023; 12:2087. [PMID: 38136207 PMCID: PMC10740508 DOI: 10.3390/antiox12122087] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/31/2023] [Revised: 11/27/2023] [Accepted: 12/05/2023] [Indexed: 12/24/2023] Open
Abstract
Mitochondrial biogenesis and fusion are essential for maintaining healthy mitochondria and ATP production. High-intensity interval training (HIIT) can enhance mitochondrial function in mouse hippocampi, but its underlying mechanism is not completely understood. Lactate generated during HIIT may mediate the beneficial effects of HIIT on neuroplasticity by activating the lactate receptor GPR81. Furthermore, growing evidence shows that lactate contributes to mitochondrial function. Given that mitochondrial function is crucial for cerebral physiological processes, the current study aimed to determine the mechanism of HIIT in hippocampal mitochondrial function. In vivo, GPR81 was knocked down in the hippocampi of mice via the injection of adeno-associated virus (AAV) vectors. The GPR81-knockdown mice were subjected to HIIT. The results demonstrated that HIIT increased mitochondria numbers, ATP production, and oxidative phosphorylation (OXPHOS) in the hippocampi of mice. In addition, HIIT induced mitochondrial biogenesis, fusion, synaptic plasticity, and ERK1/2 phosphorylation but not in GPR81-knockdown mice. In vitro, Neuro-2A cells were treated with L-lactate, a GPR81 agonist, and an ERK1/2 inhibitor. The results showed that both L-lactate and the GPR81 agonist increased mitochondrial biogenesis, fusion, ATP levels, OXPHOS, mitochondrial membrane potential, and synaptic plasticity. However, the inhibition of ERK1/2 phosphorylation blunted L-lactate or the GPR81 agonist-induced promotion of mitochondrial function and synaptic plasticity. In conclusion, our findings suggest that lactate mediates HIIT-induced promotion of mitochondrial function through the GPR81-ERK1/2 pathway.
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Affiliation(s)
- Qinghui Shang
- Key Laboratory of Exercise and Health Sciences, Shanghai University of Sport, Ministry of Education, Shanghai 200438, China;
- Key Laboratory of Human Performance, Shanghai University of Sport, Shanghai 200438, China; (X.B.); (M.W.)
| | - Xuepeng Bian
- Key Laboratory of Human Performance, Shanghai University of Sport, Shanghai 200438, China; (X.B.); (M.W.)
| | - Lutao Zhu
- Key Laboratory of Human Performance, Shanghai University of Sport, Shanghai 200438, China; (X.B.); (M.W.)
| | - Jun Liu
- Key Laboratory of Human Performance, Shanghai University of Sport, Shanghai 200438, China; (X.B.); (M.W.)
| | - Min Wu
- Key Laboratory of Human Performance, Shanghai University of Sport, Shanghai 200438, China; (X.B.); (M.W.)
| | - Shujie Lou
- Key Laboratory of Exercise and Health Sciences, Shanghai University of Sport, Ministry of Education, Shanghai 200438, China;
- Key Laboratory of Human Performance, Shanghai University of Sport, Shanghai 200438, China; (X.B.); (M.W.)
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13
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Kolotyeva NA, Gilmiyarova FN, Averchuk AS, Baranich TI, Rozanova NA, Kukla MV, Tregub PP, Salmina AB. Novel Approaches to the Establishment of Local Microenvironment from Resorbable Biomaterials in the Brain In Vitro Models. Int J Mol Sci 2023; 24:14709. [PMID: 37834155 PMCID: PMC10572431 DOI: 10.3390/ijms241914709] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/24/2023] [Revised: 09/19/2023] [Accepted: 09/27/2023] [Indexed: 10/15/2023] Open
Abstract
The development of brain in vitro models requires the application of novel biocompatible materials and biopolymers as scaffolds for controllable and effective cell growth and functioning. The "ideal" brain in vitro model should demonstrate the principal features of brain plasticity like synaptic transmission and remodeling, neurogenesis and angiogenesis, and changes in the metabolism associated with the establishment of new intercellular connections. Therefore, the extracellular scaffolds that are helpful in the establishment and maintenance of local microenvironments supporting brain plasticity mechanisms are of critical importance. In this review, we will focus on some carbohydrate metabolites-lactate, pyruvate, oxaloacetate, malate-that greatly contribute to the regulation of cell-to-cell communications and metabolic plasticity of brain cells and on some resorbable biopolymers that may reproduce the local microenvironment enriched in particular cell metabolites.
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Affiliation(s)
| | - Frida N. Gilmiyarova
- Department of Fundamental and Clinical Biochemistry with Laboratory Diagnostics, Samara State Medical University, 443099 Samara, Russia
| | - Anton S. Averchuk
- Brain Science Institute, Research Center of Neurology, 125367 Moscow, Russia
| | - Tatiana I. Baranich
- Brain Science Institute, Research Center of Neurology, 125367 Moscow, Russia
| | | | - Maria V. Kukla
- Brain Science Institute, Research Center of Neurology, 125367 Moscow, Russia
| | - Pavel P. Tregub
- Brain Science Institute, Research Center of Neurology, 125367 Moscow, Russia
- Department of Pathophysiology, I.M. Sechenov First Moscow State Medical University, 119991 Moscow, Russia
| | - Alla B. Salmina
- Brain Science Institute, Research Center of Neurology, 125367 Moscow, Russia
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14
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Li R, Yang Y, Wang H, Zhang T, Duan F, Wu K, Yang S, Xu K, Jiang X, Sun X. Lactate and Lactylation in the Brain: Current Progress and Perspectives. Cell Mol Neurobiol 2023; 43:2541-2555. [PMID: 36928470 PMCID: PMC11410153 DOI: 10.1007/s10571-023-01335-7] [Citation(s) in RCA: 15] [Impact Index Per Article: 7.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/06/2023] [Accepted: 03/04/2023] [Indexed: 03/18/2023]
Abstract
As the final product of glycolysis, lactate features not only as an energy substrate, a metabolite, and a signaling molecule in a variety of diseases-such as cancer, inflammation, and sepsis-but also as a regulator of protein lactylation; this is a newly proposed epigenetic modification that is considered to be crucial for energy metabolism and signaling in brain tissues under both physiological and pathological conditions. In this review, evidence on lactylation from studies on lactate metabolism and disease has been summarized, revealing the function of lactate and its receptors in the regulation of brain function and summarizing the levels of lactylation expression in various brain diseases. Finally, the function of lactate and lactylation in the brain and the potential mechanisms of intervention in brain diseases are presented and discussed, providing optimal perspectives for future research on the role of lactylation in the brain.
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Affiliation(s)
- Ruobing Li
- Heilongjiang University of Chinese Medicine, 24 Heping Road, Xiangfang District, Harbin, 8615-0040, China
| | - Yi Yang
- Heilongjiang University of Chinese Medicine, 24 Heping Road, Xiangfang District, Harbin, 8615-0040, China
| | - Haoyu Wang
- Heilongjiang University of Chinese Medicine, 24 Heping Road, Xiangfang District, Harbin, 8615-0040, China
- First Affiliated Hospital, Heilongjiang University of Chinese Medicine, 26 Heping Road, Xiangfang District, Harbin, 8615-0040, China
| | - Tingting Zhang
- Heilongjiang University of Chinese Medicine, 24 Heping Road, Xiangfang District, Harbin, 8615-0040, China
| | - Fangfang Duan
- Heilongjiang University of Chinese Medicine, 24 Heping Road, Xiangfang District, Harbin, 8615-0040, China
| | - Kaidi Wu
- Heilongjiang University of Chinese Medicine, 24 Heping Road, Xiangfang District, Harbin, 8615-0040, China
| | - Siyu Yang
- Heilongjiang University of Chinese Medicine, 24 Heping Road, Xiangfang District, Harbin, 8615-0040, China
| | - Ke Xu
- Heilongjiang University of Chinese Medicine, 24 Heping Road, Xiangfang District, Harbin, 8615-0040, China
| | - Xicheng Jiang
- Heilongjiang University of Chinese Medicine, 24 Heping Road, Xiangfang District, Harbin, 8615-0040, China.
| | - Xiaowei Sun
- Heilongjiang University of Chinese Medicine, 24 Heping Road, Xiangfang District, Harbin, 8615-0040, China.
- First Affiliated Hospital, Heilongjiang University of Chinese Medicine, 26 Heping Road, Xiangfang District, Harbin, 8615-0040, China.
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15
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Hwang D, Kim J, Kyun S, Jang I, Kim T, Park HY, Lim K. Exogenous lactate augments exercise-induced improvement in memory but not in hippocampal neurogenesis. Sci Rep 2023; 13:5838. [PMID: 37037890 PMCID: PMC10086059 DOI: 10.1038/s41598-023-33017-1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/15/2022] [Accepted: 04/05/2023] [Indexed: 04/12/2023] Open
Abstract
Adult hippocampal neurogenesis (AHN), the lifelong process of formation of new neurons in the mammalian brain, plays an important role in learning and memory. Exercise is an effective enhancer of AHN; however, the molecular mediators of exercise-induced AHN are unknown. Recently, lactate was considered as an important mediator of exercise-induced AHN. Therefore, we hypothesized that exercise with lactate intake could augment exercise-induced AHN. This study was conducted for 5 weeks with 7-week-old ICR male mice that performed mild-intensity exercise (just below lactate threshold, 55-60%VO2max) with or without oral administration of lactate 5 days/week. Cell proliferation, neuronal differentiation, neurogenesis-relevant factors, reference and retention memory, and spatial working memory were evaluated at the end of the experiment. The results showed that AHN was enhanced by lactate intake, but exercise-induced AHN was not augmented by exercise with lactate intake. Nevertheless, exercise-induced improvement in reference and retention memory was augmented by exercise with lactate intake. And spatial working memory was promoted by the co-treatment, also protein expression of hippocampal FNDC5, BDNF, PGC1α, and MCT2 were elevated by the co-treatment. Therefore, our findings suggest that lactate has a potential to be developed as a novel supplement that improves the positive effects of exercise on the hippocampus and its cognitive function.
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Affiliation(s)
- Deunsol Hwang
- Laboratory of Exercise and Nutrition, Department of Sports Medicine and Science in Graduate School, Konkuk University, Seoul, Republic of Korea
- Physical Activity and Performance Institute (PAPI), Konkuk University, Seoul, Republic of Korea
| | - Jisu Kim
- Laboratory of Exercise and Nutrition, Department of Sports Medicine and Science in Graduate School, Konkuk University, Seoul, Republic of Korea
- Physical Activity and Performance Institute (PAPI), Konkuk University, Seoul, Republic of Korea
| | - Sunghwan Kyun
- Laboratory of Exercise and Nutrition, Department of Sports Medicine and Science in Graduate School, Konkuk University, Seoul, Republic of Korea
- Physical Activity and Performance Institute (PAPI), Konkuk University, Seoul, Republic of Korea
| | - Inkwon Jang
- Laboratory of Exercise and Nutrition, Department of Sports Medicine and Science in Graduate School, Konkuk University, Seoul, Republic of Korea
- Physical Activity and Performance Institute (PAPI), Konkuk University, Seoul, Republic of Korea
| | - Taeho Kim
- Laboratory of Exercise and Nutrition, Department of Sports Medicine and Science in Graduate School, Konkuk University, Seoul, Republic of Korea
- Physical Activity and Performance Institute (PAPI), Konkuk University, Seoul, Republic of Korea
| | - Hun-Young Park
- Laboratory of Exercise and Nutrition, Department of Sports Medicine and Science in Graduate School, Konkuk University, Seoul, Republic of Korea
- Physical Activity and Performance Institute (PAPI), Konkuk University, Seoul, Republic of Korea
| | - Kiwon Lim
- Laboratory of Exercise and Nutrition, Department of Sports Medicine and Science in Graduate School, Konkuk University, Seoul, Republic of Korea.
- Physical Activity and Performance Institute (PAPI), Konkuk University, Seoul, Republic of Korea.
- Department of Physical Education, Konkuk University, Seoul, Republic of Korea.
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16
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Lee S, Choi Y, Jeong E, Park J, Kim J, Tanaka M, Choi J. Physiological significance of elevated levels of lactate by exercise training in the brain and body. J Biosci Bioeng 2023; 135:167-175. [PMID: 36681523 DOI: 10.1016/j.jbiosc.2022.12.001] [Citation(s) in RCA: 16] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/16/2022] [Revised: 11/15/2022] [Accepted: 12/07/2022] [Indexed: 01/21/2023]
Abstract
For the past 200 years, lactate has been regarded as a metabolic waste end product that causes fatigue during exercise. However, lactate production is closely correlated with energy metabolism. The lactate dehydrogenase-catalyzed reaction uses protons to produce lactate, which delays ongoing metabolic acidosis. Of note, lactate production differs depending on exercise intensity and is not limited to muscles. Importantly, controlling physiological effect of lactate may be a solution to alleviating some chronic diseases. Released through exercise, lactate is an important biomarker for fat oxidation in skeletal muscles. During recovery after sustained strenuous exercise, most of the lactate accumulated during exercise is removed by direct oxidation. However, as the muscle respiration rate decreases, lactate becomes a desirable substrate for hepatic glucose synthesis. Furthermore, improvement in brain function by lactate, particularly, through the expression of vascular endothelial growth factor and brain-derived neurotrophic factor, is being increasingly studied. In addition, it is possible to improve stress-related symptoms, such as depression, by regulating the function of hippocampal mitochondria, and with an increasingly aging society, lactate is being investigated as a preventive agent for brain diseases such as Alzheimer's disease. Therefore, the perception that lactate is equivalent to fatigue should no longer exist. This review focuses on the new perception of lactate and how lactate acts extensively in the skeletal muscles, heart, brain, kidney, and liver. Additionally, lactate is now used to confirm exercise performance and should be further studied to assess its impact on exercise training.
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Affiliation(s)
- Sungjun Lee
- School of Integrative Engineering, Chung-Ang University, Seoul 06974, Republic of Korea; Feynman Institute of Technology, Nanomedicine Corporation, Seoul 06974, Republic of Korea
| | - Yonghyun Choi
- School of Integrative Engineering, Chung-Ang University, Seoul 06974, Republic of Korea; Feynman Institute of Technology, Nanomedicine Corporation, Seoul 06974, Republic of Korea
| | - Eunseo Jeong
- School of Integrative Engineering, Chung-Ang University, Seoul 06974, Republic of Korea
| | - Jongjun Park
- School of Integrative Engineering, Chung-Ang University, Seoul 06974, Republic of Korea
| | - Jiwon Kim
- School of Integrative Engineering, Chung-Ang University, Seoul 06974, Republic of Korea; Department of Chemical and Biomolecular Engineering, University of Pennsylvania, Philadelphia, PA 19104, USA
| | - Masayoshi Tanaka
- Department of Chemical Science and Engineering, Tokyo Institute of Technology, 4259 Nagatsuta-cho, Midori-ku, Yokohama-shi, Kanagawa 226-8503, Japan
| | - Jonghoon Choi
- School of Integrative Engineering, Chung-Ang University, Seoul 06974, Republic of Korea; Feynman Institute of Technology, Nanomedicine Corporation, Seoul 06974, Republic of Korea; Department of Chemical and Biomolecular Engineering, University of Pennsylvania, Philadelphia, PA 19104, USA.
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17
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Heo J, Noble EE, Call JA. The role of exerkines on brain mitochondria: a mini-review. J Appl Physiol (1985) 2023; 134:28-35. [PMID: 36417200 PMCID: PMC9799148 DOI: 10.1152/japplphysiol.00565.2022] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/26/2022] [Revised: 11/21/2022] [Accepted: 11/22/2022] [Indexed: 11/24/2022] Open
Abstract
Exercise benefits many organ systems, including having a panacea-like effect on the brain. For example, aerobic exercise improves cognition and attention and reduces the risk of brain-related diseases, such as dementia, stress, and depression. Recent advances suggest that endocrine signaling from peripheral systems, such as skeletal muscle, mediates the effects of exercise on the brain. Consequently, it has been proposed that factors secreted by all organs in response to physical exercise should be more broadly termed the "exerkines." Accumulating findings suggest that exerkines derived from skeletal muscle, liver, and adipose tissues directly impact brain mitochondrial function. Mitochondria play a pivotal role in regulating neuronal energy metabolism, neurotransmission, cell repair, and maintenance in the brain, and therefore exerkines may act via impacting brain mitochondria to improve brain function and disease resistance. Therefore, herein we review studies investigating the impact of muscle-, liver-, and adipose tissue-derived exerkines on brain cognitive and metabolic function via modulating mitochondrial bioenergetics, content, and dynamics under healthy and/or disease conditions.
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Affiliation(s)
- Junwon Heo
- Department of Physiology and Pharmacology, College of Veterinary Medicine, University of Georgia, Athens, Georgia
- Regenerative Bioscience Center, University of Georgia, Athens, Georgia
| | - Emily E Noble
- Department of Nutritional Science, College of Family and Consumer Sciences, University of Georgia, Athens, Georgia
| | - Jarrod A Call
- Department of Physiology and Pharmacology, College of Veterinary Medicine, University of Georgia, Athens, Georgia
- Regenerative Bioscience Center, University of Georgia, Athens, Georgia
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18
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Shima T, Yoshikawa T, Onishi H. Low-Carbohydrate and High-Protein Diet Suppresses Working Memory Function in Healthy Mice. J Nutr Sci Vitaminol (Tokyo) 2022; 68:527-532. [PMID: 36596551 DOI: 10.3177/jnsv.68.527] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/31/2022]
Abstract
Low-carbohydrate and high-protein (LC-HP) diets are acceptable for improving physiological and metabolic parameters. However, the effects of LC-HP diets on the brain are unclear, which depend on glycometabolism for neuronal activity. Since astrocyte-neuron lactate shuttle (ANLS) is an essential pathway for maintaining brain functions, we investigated the changes in hippocampal memory function. In addition, the alteration of lactate transporter constituting ANLS and ANLS-related neurotrophic factors by feeding LC-HP diets was evaluated in healthy mice. C57BL/6 mice were divided into two groups: a group feeding LC-HP diet (24.6% carbohydrate, 57.6% protein, and 17.8% fat as percentages of calories) and a group feeding control diet (58.6% carbohydrate, 24.2% protein, and 17.2% fat as percentages of calories). Here, we found that 4 wk of LC-HP diet feeding suppressed memory function in mice evaluated by Y-maze. Hippocampal mRNA levels of lactate transporters, such as Mct1, Mct4, and Mct2, were unchanged with feeding LC-HP diets; however, LC-HP diets significantly decreased Dcx and Igf-1 receptor mRNA levels in the hippocampus. Bdnf and its related signaling in mice hippocampus exhibited no change by LC-HP diets. Although there was non-influence in the lactate-transport system, LC-HP diets would suppress hippocampal working memory with dysregulation of neuroplasticity. The current data propose the importance of food choices for maintaining hippocampal health.
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Affiliation(s)
- Takeru Shima
- Department of Health and Physical Education, Cooperative Faculty of Education, Gunma University
| | - Tomonori Yoshikawa
- Department of Health and Physical Education, Cooperative Faculty of Education, Gunma University
| | - Hayate Onishi
- Department of Health and Physical Education, Cooperative Faculty of Education, Gunma University
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19
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Zhao K, Hu Z, Wang T, Tian L, Wang M, Liu R, Zuo C, Jihua W. Acute effects of two different work-to-rest ratio of high-intensity interval training on brain-derived neurotrophic factor in untrained young men. Front Physiol 2022; 13:988773. [PMID: 36160866 PMCID: PMC9490303 DOI: 10.3389/fphys.2022.988773] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/07/2022] [Accepted: 08/11/2022] [Indexed: 11/13/2022] Open
Abstract
Background: Aerobic exercise could produce a positive effect on the brain by releasing brain-derived neurotrophic factor (BDNF). In untrained healthy humans there seems to be a linear correlation between exercise duration and the positive effect of acute aerobic exercise on brain-derived neurotrophic factor levels. Therefore, we performed two different duration of high-intensity interval training protocols (HIIT), both known to improve cardiovascular fitness, to determine whether then have a similar efficacy in affecting brain-derived neurotrophic factor levels.Methods: 12 untrained young males (aged 23.7 ± 1.8 years), participated in a randomized controlled cross-over trial. They underwent two different work-to-rest ratio high-intensity interval training protocols: high-intensity interval training 1 (30 min, 15 intervals of 1 min efforts at 85%–90% VO2max with 1 min of active recovery at 50%–60% VO2max) and HIIT2 (30 min, 10 intervals of 2 min efforts at 85%–90% VO2max with 1 min of active recovery at 50%–60% VO2max). Serum cortisol, brain-derived neurotrophic factor were collected at baseline, immediately following intervention, and 30 min into recovery for measurements using a Sandwich ELISA method, blood lactate was measured by using a portable lactate analyzer.Results: Our results showed that the similar serum brain-derived neurotrophic factor change in both high-intensity interval training protocols, with maximal serum brain-derived neurotrophic factor levels being reached toward the end of intervention. There was no significant change in serum brain-derived neurotrophic factor from baseline after 30 min recovery. We then showed that both high-intensity interval training protocols significantly increase blood lactate and serum cortisol compared with baseline value (high-intensity interval training p < 0.01; high-intensity interval training 2 p < 0.01), with high-intensity interval training 2 reaching higher blood lactate levels than high-intensity interval training 1 (p = 0.027), but no difference was observed in serum cortisol between both protocols. Moreover, changes in serum brain-derived neurotrophic factor did corelate with change in blood lactate (high-intensity interval training 1 r = 0.577, p < 0.05; high-intensity interval training 2 r = 0.635, p < 0.05), but did not correlate with the change in serum cortisol.Conclusions: brain-derived neurotrophic factor levels in untrained young men are significantly increased in response to different work-to-rest ratio of high-intensity interval training protocols, and the magnitude of increase is exercise duration independent. Moreover, the higher blood lactate did not raise circulating brain-derived neurotrophic factor. Therefore, given that prolonged exercise causes higher levels of cortisol. We suggest that the 1:1work-to-rest ratio of high-intensity interval training protocol might represent a preferred intervention for promoting brain health.
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Affiliation(s)
- Kegang Zhao
- School of Physical Education of Shandong Normal University, Jinan, China
- *Correspondence: Kegang Zhao,
| | | | - Tao Wang
- School of Physical Education of Liaocheng University, Jinan, China
| | - Lei Tian
- School of Physical Education of Shandong Normal University, Jinan, China
| | - Maoye Wang
- School of Physical Education of Shandong Normal University, Jinan, China
| | - Ruijiang Liu
- School of Physical Education of Shandong Normal University, Jinan, China
| | - Chongwen Zuo
- Capital Institute of Physical Education and Sports, Beijing, China
| | - Wang Jihua
- Department of Information Science and Engineering of Shandong Normal University, Jinan, China
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20
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Xue X, Liu B, Hu J, Bian X, Lou S. The potential mechanisms of lactate in mediating exercise-enhanced cognitive function: a dual role as an energy supply substrate and a signaling molecule. Nutr Metab (Lond) 2022; 19:52. [PMID: 35907984 PMCID: PMC9338682 DOI: 10.1186/s12986-022-00687-z] [Citation(s) in RCA: 43] [Impact Index Per Article: 14.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/22/2021] [Accepted: 07/18/2022] [Indexed: 11/12/2022] Open
Abstract
Lactate has previously been considered a metabolic waste and is mainly involved in exercise-induced fatigue. However, recent studies have found that lactate may be a mediator of the beneficial effects of exercise on brain health. Lactate plays a dual role as an energy supply substrate and a signaling molecule in this process. On the one hand, astrocytes can uptake circulating glucose or degrade glycogen for glycolysis to produce lactate, which is released into the extracellular space. Neurons can uptake extracellular lactate as an important supplement to their energy metabolism substrates, to meet the demand for large amounts of energy when synaptic activity is enhanced. Thus, synaptic activity and energy transfer show tight metabolic coupling. On the other hand, lactate acts as a signaling molecule to activate downstream signaling transduction pathways by specific receptors, inducing the expression of immediate early genes and cerebral angiogenesis. Moderate to high-intensity exercise not only increases lactate production and accumulation in muscle and blood but also promotes the uptake of skeletal muscle-derived lactate by the brain and enhances aerobic glycolysis to increase brain-derived lactate production. Furthermore, exercise regulates the expression or activity of transporters and enzymes involved in the astrocyte-neuron lactate shuttle to maintain the efficiency of this process; exercise also activates lactate receptor HCAR1, thus affecting brain plasticity. Rethinking the role of lactate in cognitive function and the regulatory effect of exercise is the main focus and highlights of the review. This may enrich the theoretical basis of lactate-related to promote brain health during exercise, and provide new perspectives for promoting a healthy aging strategy.
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Affiliation(s)
- Xiangli Xue
- Key Laboratory of Exercise and Health Sciences of Ministry of Education, Shanghai University of Sport, Shanghai, 200438, China.,Shanghai Frontiers Science Research Base of Exercise and Metabolic Health, Shanghai University of Sport, Shanghai, 200438, China
| | - Beibei Liu
- Key Laboratory of Exercise and Health Sciences of Ministry of Education, Shanghai University of Sport, Shanghai, 200438, China.,Department of Clinical Medicine, Weifang Medical College, Weifang, 261053, Shandong, China
| | - Jingyun Hu
- Key Laboratory of Exercise and Health Sciences of Ministry of Education, Shanghai University of Sport, Shanghai, 200438, China
| | - Xuepeng Bian
- Key Laboratory of Exercise and Health Sciences of Ministry of Education, Shanghai University of Sport, Shanghai, 200438, China
| | - Shujie Lou
- Key Laboratory of Exercise and Health Sciences of Ministry of Education, Shanghai University of Sport, Shanghai, 200438, China. .,Shanghai Frontiers Science Research Base of Exercise and Metabolic Health, Shanghai University of Sport, Shanghai, 200438, China.
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21
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Hortobágyi T, Vetrovsky T, Balbim GM, Sorte Silva NCB, Manca A, Deriu F, Kolmos M, Kruuse C, Liu-Ambrose T, Radák Z, Váczi M, Johansson H, Dos Santos PCR, Franzén E, Granacher U. The impact of aerobic and resistance training intensity on markers of neuroplasticity in health and disease. Ageing Res Rev 2022; 80:101698. [PMID: 35853549 DOI: 10.1016/j.arr.2022.101698] [Citation(s) in RCA: 41] [Impact Index Per Article: 13.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/20/2022] [Revised: 07/14/2022] [Accepted: 07/15/2022] [Indexed: 02/07/2023]
Abstract
OBJECTIVE To determine the effects of low- vs. high-intensity aerobic and resistance training on motor and cognitive function, brain activation, brain structure, and neurochemical markers of neuroplasticity and the association thereof in healthy young and older adults and in patients with multiple sclerosis, Parkinson's disease, and stroke. DESIGN Systematic review and robust variance estimation meta-analysis with meta-regression. DATA SOURCES Systematic search of MEDLINE, Web of Science, and CINAHL databases. RESULTS Fifty studies with 60 intervention arms and 2283 in-analyses participants were included. Due to the low number of studies, the three patient groups were combined and analyzed as a single group. Overall, low- (g=0.19, p = 0.024) and high-intensity exercise (g=0.40, p = 0.001) improved neuroplasticity. Exercise intensity scaled with neuroplasticity only in healthy young adults but not in healthy older adults or patient groups. Exercise-induced improvements in neuroplasticity were associated with changes in motor but not cognitive outcomes. CONCLUSION Exercise intensity is an important variable to dose and individualize the exercise stimulus for healthy young individuals but not necessarily for healthy older adults and neurological patients. This conclusion warrants caution because studies are needed that directly compare the effects of low- vs. high-intensity exercise on neuroplasticity to determine if such changes are mechanistically and incrementally linked to improved cognition and motor function.
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Affiliation(s)
- Tibor Hortobágyi
- Center for Human Movement Sciences, University of Groningen Medical Center, Groningen, the Netherlands; Somogy County Kaposi Mór Teaching Hospital, Kaposvár, Hungary; Department of Sport Biology, Institute of Sport Sciences and Physical Education, University of Pécs, Hungary; Division of Training and Movement Sciences, Research Focus Cognition Sciences, University of Potsdam, Potsdam, Germany; Hungarian University of Sports Science, Department of Kinesiology, Budapest, Hungary.
| | - Tomas Vetrovsky
- Faculty of Physical Education and Sport, Charles University, Prague, Czech Republic
| | - Guilherme Moraes Balbim
- Department of Physical Therapy, Faculty of Medicine, University of British Columbia, Vancouver, Canada; Djavad Mowafaghian Centre for Brain Health, University of British Columbia, Vancouver, Canada
| | - Nárlon Cássio Boa Sorte Silva
- Department of Physical Therapy, Faculty of Medicine, University of British Columbia, Vancouver, Canada; Djavad Mowafaghian Centre for Brain Health, University of British Columbia, Vancouver, Canada
| | - Andrea Manca
- Department of Biomedical Sciences, University of Sassari, Sassari, Italy
| | - Franca Deriu
- Department of Biomedical Sciences, University of Sassari, Sassari, Italy; Unit of Endocrinology, Nutritional and Metabolic Disorders, AOU Sassari, Sassari, Italy
| | - Mia Kolmos
- Neurovascular Research Unit, Department of Neurology, Herlev Gentofte Hospital, University of Copenhagen, Copenhagen, Denmark
| | - Christina Kruuse
- Neurovascular Research Unit, Department of Neurology, Herlev Gentofte Hospital, University of Copenhagen, Copenhagen, Denmark
| | - Teresa Liu-Ambrose
- Department of Physical Therapy, Faculty of Medicine, University of British Columbia, Vancouver, Canada; Djavad Mowafaghian Centre for Brain Health, University of British Columbia, Vancouver, Canada
| | - Zsolt Radák
- Research Center of Molecular Exercise Science, Hungarian University of Sport Science, Budapest, Hungary
| | - Márk Váczi
- Department of Sport Biology, Institute of Sport Sciences and Physical Education, University of Pécs, Hungary
| | - Hanna Johansson
- Department of Neurobiology, Care Sciences and Society, Division of Physiotherapy, Karolinska Institutet, Stockholm, Sweden; Women's Health and Allied Health Professionals Theme, Medical Unit Occupational Therapy & Physiotherapy, Karolinska University Hospital, Stockholm, Sweden
| | | | - Erika Franzén
- Department of Neurobiology, Care Sciences and Society, Division of Physiotherapy, Karolinska Institutet, Stockholm, Sweden; Women's Health and Allied Health Professionals Theme, Medical Unit Occupational Therapy & Physiotherapy, Karolinska University Hospital, Stockholm, Sweden
| | - Urs Granacher
- Division of Training and Movement Sciences, Research Focus Cognition Sciences, University of Potsdam, Potsdam, Germany
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22
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Cai M, Wang H, Song H, Yang R, Wang L, Xue X, Sun W, Hu J. Lactate Is Answerable for Brain Function and Treating Brain Diseases: Energy Substrates and Signal Molecule. Front Nutr 2022; 9:800901. [PMID: 35571940 PMCID: PMC9099001 DOI: 10.3389/fnut.2022.800901] [Citation(s) in RCA: 33] [Impact Index Per Article: 11.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/24/2021] [Accepted: 03/18/2022] [Indexed: 11/13/2022] Open
Abstract
Research to date has provided novel insights into lactate's positive role in multiple brain functions and several brain diseases. Although notable controversies and discrepancies remain, the neurobiological role and the metabolic mechanisms of brain lactate have now been described. A theoretical framework on the relevance between lactate and brain function and brain diseases is presented. This review begins with the source and route of lactate formation in the brain and food; goes on to uncover the regulatory effect of lactate on brain function; and progresses to gathering the application and concentration variation of lactate in several brain diseases (diabetic encephalopathy, Alzheimer's disease, stroke, traumatic brain injury, and epilepsy) treatment. Finally, the dual role of lactate in the brain is discussed. This review highlights the biological effect of lactate, especially L-lactate, in brain function and disease studies and amplifies our understanding of past research.
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Affiliation(s)
- Ming Cai
- Department of Rehabilitation Medicine, Shanghai University of Medicine and Health Sciences Affiliated Zhoupu Hospital, Shanghai, China
- Bio-X Institutes, Shanghai Jiao Tong University, Shanghai, China
| | - Hongbiao Wang
- Department of Physical Education, Shanghai University of Medicine and Health Sciences, Shanghai, China
| | - Haihan Song
- Central Lab, Shanghai Pudong New Area People's Hospital, Shanghai, China
| | - Ruoyu Yang
- College of Rehabilitation Sciences, Shanghai University of Medicine and Health Sciences, Shanghai, China
| | - Liyan Wang
- College of Rehabilitation Sciences, Shanghai University of Medicine and Health Sciences, Shanghai, China
| | - Xiangli Xue
- Key Laboratory of Exercise and Health Sciences of Ministry of Education, Shanghai University of Sport, Shanghai, China
| | - Wanju Sun
- Central Lab, Shanghai Pudong New Area People's Hospital, Shanghai, China
- *Correspondence: Wanju Sun
| | - Jingyun Hu
- Central Lab, Shanghai Pudong New Area People's Hospital, Shanghai, China
- Jingyun Hu
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23
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Huuha AM, Norevik CS, Moreira JBN, Kobro-Flatmoen A, Scrimgeour N, Kivipelto M, Van Praag H, Ziaei M, Sando SB, Wisløff U, Tari AR. Can exercise training teach us how to treat Alzheimer's disease? Ageing Res Rev 2022; 75:101559. [PMID: 34999248 DOI: 10.1016/j.arr.2022.101559] [Citation(s) in RCA: 29] [Impact Index Per Article: 9.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/24/2021] [Revised: 12/20/2021] [Accepted: 01/04/2022] [Indexed: 01/02/2023]
Abstract
Alzheimer's disease (AD) is the most common cause of dementia and there is currently no cure. Novel approaches to treat AD and curb the rapidly increasing worldwide prevalence and costs of dementia are needed. Physical inactivity is a significant modifiable risk factor for AD, estimated to contribute to 12.7% of AD cases worldwide. Exercise interventions in humans and animals have shown beneficial effects of exercise on brain plasticity and cognitive functions. In animal studies, exercise also improved AD pathology. The mechanisms underlying these effects of exercise seem to be associated mainly with exercise performance or cardiorespiratory fitness. In addition, exercise-induced molecules of peripheral origin seem to play an important role. Since exercise affects the whole body, there likely is no single therapeutic target that could mimic all the benefits of exercise. However, systemic strategies may be a viable means to convey broad therapeutic effects in AD patients. Here, we review the potential of physical activity and exercise training in AD prevention and treatment, shining light on recently discovered underlying mechanisms and concluding with a view on future development of exercise-free treatment strategies for AD.
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Affiliation(s)
- Aleksi M Huuha
- Cardiac Exercise Research Group (CERG), Department of Circulation and Medical Imaging, Faculty of Medicine and Health Sciences, Norwegian University of Science and Technology, Trondheim, Norway; Department of Neurology and Clinical Neurophysiology, St. Olavs Hospital, Trondheim University Hospital, Trondheim, Norway
| | - Cecilie S Norevik
- Cardiac Exercise Research Group (CERG), Department of Circulation and Medical Imaging, Faculty of Medicine and Health Sciences, Norwegian University of Science and Technology, Trondheim, Norway; Department of Neurology and Clinical Neurophysiology, St. Olavs Hospital, Trondheim University Hospital, Trondheim, Norway
| | - José Bianco N Moreira
- Cardiac Exercise Research Group (CERG), Department of Circulation and Medical Imaging, Faculty of Medicine and Health Sciences, Norwegian University of Science and Technology, Trondheim, Norway
| | - Asgeir Kobro-Flatmoen
- Kavli Institute for Systems Neuroscience, Centre for Neural Computation, and Egil and Pauline Braathen and Fred Kavli Centre for Cortical Microcircuits, Norwegian University of Science and Technology, Trondheim, Norway; K.G. Jebsen Centre for Alzheimer's Disease, Norwegian University of Science and Technology, Trondheim, Norway
| | - Nathan Scrimgeour
- Cardiac Exercise Research Group (CERG), Department of Circulation and Medical Imaging, Faculty of Medicine and Health Sciences, Norwegian University of Science and Technology, Trondheim, Norway
| | - Miia Kivipelto
- Karolinska Institute, Department of Neurobiology, Care Sciences and Society, Division of Clinical Geriatrics, Stockholm, Sweden; Karolinska University Hospital, Theme Aging and Inflammation, Stockholm, Sweden
| | - Henriette Van Praag
- Brain Institute and Charles E. Schmidt College of Medicine, Florida Atlantic University, Jupiter, FL, United States
| | - Maryam Ziaei
- Kavli Institute for Systems Neuroscience, Centre for Neural Computation, and Egil and Pauline Braathen and Fred Kavli Centre for Cortical Microcircuits, Norwegian University of Science and Technology, Trondheim, Norway; Queensland Brain Institute, University of Queensland, Brisbane, Australia
| | - Sigrid Botne Sando
- Department of Neurology and Clinical Neurophysiology, St. Olavs Hospital, Trondheim University Hospital, Trondheim, Norway; Department of Neuromedicine and Movement Science, Faculty of Medicine and Health Sciences, Norwegian University of Science and Technology, Trondheim, Norway
| | - Ulrik Wisløff
- Cardiac Exercise Research Group (CERG), Department of Circulation and Medical Imaging, Faculty of Medicine and Health Sciences, Norwegian University of Science and Technology, Trondheim, Norway; Centre for Research on Exercise, Physical Activity and Health, School of Human Movement and Nutrition Sciences, University of Queensland, St. Lucia, Brisbane, Queensland, Australia
| | - Atefe R Tari
- Cardiac Exercise Research Group (CERG), Department of Circulation and Medical Imaging, Faculty of Medicine and Health Sciences, Norwegian University of Science and Technology, Trondheim, Norway; Department of Neurology and Clinical Neurophysiology, St. Olavs Hospital, Trondheim University Hospital, Trondheim, Norway.
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24
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Li X, He Q, Zhao N, Chen X, Li T, Cheng B. High intensity interval training ameliorates cognitive impairment in T2DM mice possibly by improving PI3K/Akt/mTOR Signaling-regulated autophagy in the hippocampus. Brain Res 2021; 1773:147703. [PMID: 34743961 DOI: 10.1016/j.brainres.2021.147703] [Citation(s) in RCA: 13] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/14/2020] [Revised: 10/11/2021] [Accepted: 10/22/2021] [Indexed: 10/19/2022]
Abstract
Exercise can improve cognitive impairment in type 2 diabetes mellitus (T2DM). However, the underlying mechanisms are not clear, and the optimal exercise modes for cognitive benefits are controversial. The aim of this study was to investigate the effects of high-intensity interval training (HIIT) and moderate-intensity interval training (MICT) on cognitive function and the PI3K/Akt/mTOR pathway as well as autophagy in T2DM mice. The results showed that 8 weeks of HIIT and MICT intervention could improve the spatial learning and memory ability of T2DM mice, as determined by the Morris water maze (MWM) test. Both HIIT and MICT similarly improved autophagy, as evidenced by increased Beclin1 and LC3 II/I ratios and decreased p62. Meanwhile, HIIT and MICT inhibited excessive activation of the PI3K/Akt/mTOR pathway in the hippocampus. HIIT induced a larger reduction in mTOR activity than MICT. This study suggests that both HIIT and MICT can alleviate cognitive decline induced by T2DM, improve autophagy in the hippocampus, and downregulate the excessive activation of the PI3K/Akt/mTOR signaling pathway, with similar effects.
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Affiliation(s)
- Xuejiao Li
- School of Physical Education of Shandong University, Jinan, China
| | - Qiang He
- School of Physical Education of Shandong University, Jinan, China
| | - Na Zhao
- Key Laboratory of Adolescent Health Assessment and Exercise Intervention of Ministry of Education, East China Normal University, Shanghai, China
| | - Xianghe Chen
- College of Physical Education, Yangzhou University, Yangzhou, China
| | - Tuojian Li
- School of Physical Education of Shandong University, Jinan, China
| | - Bin Cheng
- School of Physical Education of Shandong University, Jinan, China.
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25
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Park J, Kim J, Mikami T. Exercise-Induced Lactate Release Mediates Mitochondrial Biogenesis in the Hippocampus of Mice via Monocarboxylate Transporters. Front Physiol 2021; 12:736905. [PMID: 34603087 PMCID: PMC8481603 DOI: 10.3389/fphys.2021.736905] [Citation(s) in RCA: 34] [Impact Index Per Article: 8.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/06/2021] [Accepted: 08/17/2021] [Indexed: 12/25/2022] Open
Abstract
Regular exercise training induces mitochondrial biogenesis in the brain via activation of peroxisome proliferator-activated receptor gamma-coactivator 1α (PGC-1α). However, it remains unclear whether a single bout of exercise would increase mitochondrial biogenesis in the brain. Therefore, we first investigated whether mitochondrial biogenesis in the hippocampus is affected by a single bout of exercise in mice. A single bout of high-intensity exercise, but not low- or moderate-intensity, increased hippocampal PGC-1α mRNA and mitochondrial DNA (mtDNA) copy number at 12 and 48h. These results depended on exercise intensity, and blood lactate levels observed immediately after exercise. As lactate induces mitochondrial biogenesis in the brain, we examined the effects of acute lactate administration on blood and hippocampal extracellular lactate concentration by in vivo microdialysis. Intraperitoneal (I.P.) lactate injection increased hippocampal extracellular lactate concentration to the same as blood lactate level, promoting PGC-1α mRNA expression in the hippocampus. However, this was suppressed by administering UK5099, a lactate transporter inhibitor, before lactate injection. I.P. UK5099 administration did not affect running performance and blood lactate concentration immediately after exercise but attenuated exercise-induced hippocampal PGC-1α mRNA and mtDNA copy number. In addition, hippocampal monocarboxylate transporters (MCT)1, MCT2, and brain-derived neurotrophic factor (BDNF) mRNA expression, except MCT4, also increased after high-intensity exercise, which was abolished by UK5099 administration. Further, injection of 1,4-dideoxy-1,4-imino-D-arabinitol (glycogen phosphorylase inhibitor) into the hippocampus before high-intensity exercise suppressed glycogen consumption during exercise, but hippocampal lactate, PGC-1α, MCT1, and MCT2 mRNA concentrations were not altered after exercise. These results indicate that the increased blood lactate released from skeletal muscle may induce hippocampal mitochondrial biogenesis and BDNF expression by inducing MCT expression in mice, especially during short-term high-intensity exercise. Thus, a single bout of exercise above the lactate threshold could provide an effective strategy for increasing mitochondrial biogenesis in the hippocampus.
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Affiliation(s)
- Jonghyuk Park
- Department of Anatomy and Neurobiology, Graduate School of Medicine, Nippon Medical School, Tokyo, Japan
| | - Jimmy Kim
- Department of Anatomy and Neurobiology, Graduate School of Medicine, Nippon Medical School, Tokyo, Japan
| | - Toshio Mikami
- Department of Health and Sports Science, Nippon Medical School, Tokyo, Japan
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26
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Huang Z, Zhang Y, Zhou R, Yang L, Pan H. Lactate as Potential Mediators for Exercise-Induced Positive Effects on Neuroplasticity and Cerebrovascular Plasticity. Front Physiol 2021; 12:656455. [PMID: 34290615 PMCID: PMC8287254 DOI: 10.3389/fphys.2021.656455] [Citation(s) in RCA: 18] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/20/2021] [Accepted: 06/09/2021] [Indexed: 01/22/2023] Open
Abstract
The accumulated evidence from animal and human studies supports that exercise is beneficial to physical health. Exercise can upregulate various neurotrophic factors, activate neuroplasticity, and play a positive role in improving and enhancing cerebrovascular function. Due to its economy, convenience, and ability to prevent or ameliorate various aging-related diseases, exercise, a healthy lifestyle, is increasingly popularized by people. However, the mechanism by which exercise performs this function and how it is transmitted from muscles to the brain remains incompletely understood. Here, we review the beneficial effects of exercise with different intensities on the brain with a focus on the positive effects of lactate on neuroplasticity and cerebrovascular plasticity. Based on these recent studies, we propose that lactate, a waste previously misunderstood as a by-product of glycolysis in the past, may be a key signal molecule that regulates the beneficial adaptation of the brain caused by exercise. Importantly, we speculate that a central protective mechanism may underlie the cognitive benefits induced by exercise.
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Affiliation(s)
| | | | | | - Luodan Yang
- Cognitive and Sports Neuroscience Laboratory, National Demonstration Center for Experimental Sports Science Education, College of Physical Education and Sports Science, South China Normal University, Guangzhou, China
| | - Hongying Pan
- Cognitive and Sports Neuroscience Laboratory, National Demonstration Center for Experimental Sports Science Education, College of Physical Education and Sports Science, South China Normal University, Guangzhou, China
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27
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Dimmek DJ, Korallus C, Buyny S, Christoph G, Lichtinghagen R, Jacobs R, Nugraha B. Brain-Derived Neurotrophic Factor and Immune Cells in Osteoarthritis, Chronic Low Back Pain, and Chronic Widespread Pain Patients: Association with Anxiety and Depression. MEDICINA (KAUNAS, LITHUANIA) 2021; 57:327. [PMID: 33915758 PMCID: PMC8065931 DOI: 10.3390/medicina57040327] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 02/19/2021] [Revised: 03/17/2021] [Accepted: 03/25/2021] [Indexed: 01/09/2023]
Abstract
Background and Objectives: Musculoskeletal dysfunction can induce several types of chronic pain syndromes. It is of particular interest to elucidate the pathomechanism of different forms of chronic pain. It is possible that patients who have developed chronic widespread pain (CWP) may endure different pathomechanisms as compared to those who suffer from local pain (osteoarthritis, OA) and regional pain (chronic low back pain, cLBP), especially with regard to pain regulation and its related biomediators. The aim of this study was to determine the differences in pathomechanisms among these patients by measuring pain-related biomediators, particularly brain-derived neurotrophic factor (BDNF). Additionally, subpopulations of immune cells were determined in parallel. Materials and Methods: Patients and healthy subjects (HSs) were recruited (age and gender-matched). BDNF was measured from serum samples of patients and HSs and the data of body composition parameters were recorded. Additionally, both patients and HSs were asked to fill in questionnaires related to pain intensity, anxiety, and depression. Results: Our results highlight that the levels of both free and total BDNF are significantly lower in pain patients compared to HSs, with p values of 0.041 and 0.024, respectively. The number of CD3- CD56bright natural killer (NK) cells shows significant differences between the groups. Comparing all chronic pain patients with HSs reveals a significantly lower number of CD4+ CD8+ T cells (p = 0.031), CD3- CD56bright NK cells (p = 0.049) and CD20+ CD3- cells (p = 0.007). Conclusions: To conclude, it seems that a general conformity between the pathomechanisms of different chronic pain diseases exists, although there are unique findings only in specific chronic pain patients.
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Affiliation(s)
- Dominique Josephine Dimmek
- Department of Rehabilitation Medicine, Hannover Medical School, Carl-Neuberg-Str.1, 30625 Hannover, Germany; (D.J.D.); (C.K.); (G.C.)
| | - Christoph Korallus
- Department of Rehabilitation Medicine, Hannover Medical School, Carl-Neuberg-Str.1, 30625 Hannover, Germany; (D.J.D.); (C.K.); (G.C.)
| | - Sabine Buyny
- Department of Rheumatology and Clinical Immunology, Hannover Medical School, Carl-Neuberg-Str.1, 30625 Hannover, Germany; (S.B.); (R.J.)
| | - Gutenbrunner Christoph
- Department of Rehabilitation Medicine, Hannover Medical School, Carl-Neuberg-Str.1, 30625 Hannover, Germany; (D.J.D.); (C.K.); (G.C.)
| | - Ralf Lichtinghagen
- Institute of Clinical Chemistry, Hannover Medical School, Carl-Neuberg-Str.1, 30625 Hannover, Germany;
| | - Roland Jacobs
- Department of Rheumatology and Clinical Immunology, Hannover Medical School, Carl-Neuberg-Str.1, 30625 Hannover, Germany; (S.B.); (R.J.)
| | - Boya Nugraha
- Department of Rehabilitation Medicine, Hannover Medical School, Carl-Neuberg-Str.1, 30625 Hannover, Germany; (D.J.D.); (C.K.); (G.C.)
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