Creatine supplementation with exercise reduces α-synuclein oligomerization and necroptosis in Parkinson's disease mouse model
Copyright © 2024 Elsevier Inc. All rights reserved..
Parkinson's disease (PD) is an incurable neurological disorder that causes typical motor deficits. In this study, we investigated the effects of creatine supplementation and exercise in the subacute 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) mouse model of PD. We found that 2% creatine supplementation and/or exercise intervention for 4 weeks elicited neurobehavioral recovery and neuroprotective effects regarding dopaminergic cell loss in MPTP-treated mice; this effect implies functional preservation of dopaminergic cells in the substantia nigra, as reflected by tyrosine hydroxylase expression recovery. Creatine and exercise reduced necroptotic activity in dopaminergic cells by lowering mixed lineage kinase domain-like protein (MLKL) modification to active phenotypes (phosphorylation at Ser345 and oligomerization) and phosphorylated receptor-interacting protein kinase 1 (RIPK1) (Ser166-p) and RIPK3 (Ser232-p) levels. In addition, creatine and exercise reduced the MPTP-induced increase in pathogenic α-synuclein forms, such as Ser129 phosphorylation and oligomerization. Furthermore, creatine and exercise had anti-inflammatory and antioxidative effects in MPTP mice, as evidenced by a decrease in microglia activation, NF-κB-dependent pro-inflammatory molecule expression, and increase in antioxidant enzyme expression. These phenotypic changes were associated with the exercise/creatine-induced AMP-activated protein kinase (AMPK)/nuclear factor erythroid 2-related factor 2 (Nrf2) and sirtuin 3 (SIRT3)/forkhead box O3 (FoxO3a) signaling pathways. In all experiments, combining creatine with exercise resulted in considerable improvement over either treatment alone. Consequently, these findings suggest that creatine supplementation with exercise has anti-inflammatory, antioxidative, and anti-α-synucleinopathy effects, thereby reducing necroptotic cell death in a PD mouse model.
| Medienart: |
E-Artikel |
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| Erscheinungsjahr: |
2024 |
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| Erschienen: |
2024 |
| Enthalten in: |
Zur Gesamtaufnahme - volume:126 |
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| Enthalten in: |
The Journal of nutritional biochemistry - 126(2024) vom: 01. März, Seite 109586 |
| Sprache: |
Englisch |
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| Beteiligte Personen: |
Leem, Yea-Hyun [VerfasserIn] |
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| Links: |
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| Anmerkungen: |
Date Completed 15.03.2024 Date Revised 15.03.2024 published: Print-Electronic Citation Status MEDLINE |
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| doi: |
10.1016/j.jnutbio.2024.109586 |
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| Förderinstitution / Projekttitel: |
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| 245 | 1 | 0 | |a Creatine supplementation with exercise reduces α-synuclein oligomerization and necroptosis in Parkinson's disease mouse model |
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| 520 | |a Parkinson's disease (PD) is an incurable neurological disorder that causes typical motor deficits. In this study, we investigated the effects of creatine supplementation and exercise in the subacute 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) mouse model of PD. We found that 2% creatine supplementation and/or exercise intervention for 4 weeks elicited neurobehavioral recovery and neuroprotective effects regarding dopaminergic cell loss in MPTP-treated mice; this effect implies functional preservation of dopaminergic cells in the substantia nigra, as reflected by tyrosine hydroxylase expression recovery. Creatine and exercise reduced necroptotic activity in dopaminergic cells by lowering mixed lineage kinase domain-like protein (MLKL) modification to active phenotypes (phosphorylation at Ser345 and oligomerization) and phosphorylated receptor-interacting protein kinase 1 (RIPK1) (Ser166-p) and RIPK3 (Ser232-p) levels. In addition, creatine and exercise reduced the MPTP-induced increase in pathogenic α-synuclein forms, such as Ser129 phosphorylation and oligomerization. Furthermore, creatine and exercise had anti-inflammatory and antioxidative effects in MPTP mice, as evidenced by a decrease in microglia activation, NF-κB-dependent pro-inflammatory molecule expression, and increase in antioxidant enzyme expression. These phenotypic changes were associated with the exercise/creatine-induced AMP-activated protein kinase (AMPK)/nuclear factor erythroid 2-related factor 2 (Nrf2) and sirtuin 3 (SIRT3)/forkhead box O3 (FoxO3a) signaling pathways. In all experiments, combining creatine with exercise resulted in considerable improvement over either treatment alone. Consequently, these findings suggest that creatine supplementation with exercise has anti-inflammatory, antioxidative, and anti-α-synucleinopathy effects, thereby reducing necroptotic cell death in a PD mouse model | ||
| 650 | 4 | |a Journal Article | |
| 650 | 4 | |a Parkinson's disease | |
| 650 | 4 | |a creatine | |
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| 700 | 1 | |a Park, Jung-Eun |e verfasserin |4 aut | |
| 700 | 1 | |a Kim, Do-Yeon |e verfasserin |4 aut | |
| 700 | 1 | |a Kim, Hee-Sun |e verfasserin |4 aut | |
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