Light-intensity exercise improves memory dysfunction with the restoration of hippocampal MCT2 and miRNAs in type 2 diabetic mice

Shima, Takeru; Kawabata‐Iwakawa, Reika; Onishi, Hayate; Jesmin, Subrina; Yoshikawa, Tomonori

doi:10.1007/s11011-022-01117-y

Cited by 8 publications

(13 citation statements)

References 53 publications

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“…Some studies indicate that ob/ob mice may develop memory deficits between 13 and 23 weeks of age [ 66 , 67 , 68 , 69 ]. Therefore, we chose to study mice between 15 and 18 weeks of age to fall within this time frame.…”

Section: Methodsmentioning

confidence: 99%

The Brain Metabolome Is Modified by Obesity in a Sex-Dependent Manner

Norman,

Milenkovic,

Nuthikattu

et al. 2024

IJMS

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Obesity is linked to cognitive decline and metabolic dysregulation in the brain, yet the role of sex is relatively unexplored. We sought to explore the effects of obesity and sex on the brain metabolome. In male and female ob/ob and wild-type mice, we assessed whole brain untargeted metabolomics by liquid chromatography–mass spectrometry, behavior by open field test, and cognitive function by Y-maze and Morris water maze. The metabolic profiles of ob/ob and wild-type mice differed in both sexes. There were more obesity-altered brain metabolites in males than females. Thirty-nine metabolites were unique to males, 15 were unique to females, and five were common to both sexes. Two of the common metabolites were involved in nicotinamide adenine dinucleotide homeostasis. A key feature of the metabolites identified in males was an increase in free fatty acids. In females, a unique feature was the presence of the neuro-modulatory metabolites 2-linoleoyl glycerol and taurine. The behavioral effects of obesity were only seen in females. These results demonstrate that most impacts of obesity on the brain metabolomic profile are sex-specific. Our work has implications for understanding the role of obesity in brain metabolism and the differential contribution of obesity to cognitive decline in males and females.

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Section: Methodsmentioning

confidence: 99%

The Brain Metabolome Is Modified by Obesity in a Sex-Dependent Manner

Norman,

Milenkovic,

Nuthikattu

et al. 2024

IJMS

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“…Mice in the exercise group underwent a running habituation phase on a forced exercise wheel bed for 30 min/day, five days/week (a total of five sessions over six days) at speeds ranging from 3.0 to 7.0 m/min for C57BL/6 mice and from 3.0 to 5.0 m/min for ob/ob mice, spanning one week. Subsequently, they engaged in light-intensity exercise sessions (C57BL/6 mice, 7.0 m/min; ob/ob mice, 5.0 m/min) on the same equipment for 30 min/day, five days/week over three weeks [11,43,44]. The exercise intensity for each strain was established based on their ventilatory threshold [44].…”

Section: Exercise Trainingmentioning

confidence: 99%

“…Therefore, elucidating the mechanisms underlying the effects of exercise on the hippocampus in T2DM holds the potential to develop a therapeutic approach targeting the hippocampus in T2DM, a crucial endeavor for the preservation of human well-being. Downregulation of lactate transport through monocarboxylate transporter 2 (MCT2) into neurons is assumed to be a potential etiological mechanism underlying T2DM-induced memory dysfunction [8][9][10][11]. Lactate is a crucial energy substrate for neurons, derived from blood circulation and astrocytes through glycolysis and glycogenolysis pathways [12][13][14][15].…”

Section: Introductionmentioning

confidence: 99%

“…Previous studies have demonstrated that hindering lactate supply and downregulating MCT2 expression and function within the hippocampus result in impairments in learning and memory [16,[19][20][21][22]. Significantly, rodents with T2DM exhibit reduced expression levels of MCT2 in their hippocampi, without notable differences in MCT1 or MCT4 expressions compared to control rodents [8][9][10][11]. Research has shown that a light-intensity exercise intervention improves hippocampal memory dysfunction and enhances MCT2 expression in rodent models of T2DM [11,23].…”

Section: Introductionmentioning

confidence: 99%

“…Significantly, rodents with T2DM exhibit reduced expression levels of MCT2 in their hippocampi, without notable differences in MCT1 or MCT4 expressions compared to control rodents [8][9][10][11]. Research has shown that a light-intensity exercise intervention improves hippocampal memory dysfunction and enhances MCT2 expression in rodent models of T2DM [11,23]. Consequently, the compromised transport of lactate through MCT2 likely plays a pivotal role in the hippocampal complications associated with memory dysfunction in T2DM, shedding light on the potential therapeutic effects of exercise.…”

Section: Introductionmentioning

confidence: 99%

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Muscle-derived miR-200a-3p through light-intensity exercise may contribute to improve memory dysfunction in type 2 diabetic mice

Shima,

Onishi,

Terashima

2024

Preprint

Self Cite

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Background: Memory dysfunction associated with type 2 diabetes mellitus (T2DM) poses a considerable threat to overall well-being. Engaging in light-intensity exercise has been shown to exert favorable effects on hippocampal function and molecular profiles, including Mct2 mRNA and miR-200a-3p. Nonetheless, a comprehensive understanding of the mechanisms underlying the positive impact of light-intensity exercise remains elusive. Here, we assessed the influence of exosomal miR-200a-3p secretion from gastrocnemius muscles in T2DM mice undergoing light-intensity exercise intervention, focusing on its potential to ameliorate memory dysfunction. Basic procedures: We initially assessed the effects of light-intensity exercise (7.0 m/min for healthy mice, 5.0 m/min for ob/ob mice, 30 min/day, five days/week, over a four-week period) on memory function, hippocampal mRNA associated with memory function, and the secretion of exosomal miR-200a-3p from their gastrocnemius muscle. Subsequently, the impact of a daily intraperitoneal injection of the miR-200a-3p mimic over a four-week duration was investigated, focusing on its influence on hippocampal dysregulation in ob/ob mice. Main findings: The light-intensity exercise intervention increased gastrocnemius muscle-derived and plasma exosomal miR-200a-3p levels in ob/ob mice, concomitant with improved memory dysfunction. Intriguingly, the daily intraperitoneal injection of mmu-miR-200a-3p mimic also demonstrated an ameliorative effect on memory function in ob/ob mice. Notably, both the exercise intervention and miR-200a-3p mimic treatment induced downregulation in hippocampal Keap1 mRNA and upregulation in mRNA of Hsp90aa1 and Mct2 in ob/ob mice. Principal conclusions: The current results imply that the augmentation of exosomal miR-200a-3p derived from the gastrocnemius muscle contributes to the amelioration of memory dysfunction in T2DM undergoing light-intensity exercise. Additionally, it is proposed that miR-200a-3p emulates the effects of light-intensity exercise, suggesting a potential therapeutic pathway for addressing hippocampal complications in the context of T2DM.

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Possible Involvement of Hippocampal miR‐539‐3p/Lrp6/Igf1r Axis for Diminished Working Memory in Mice Fed a Low‐Carbohydrate and High‐Protein Diet

Shima,

Onishi,

Terashima

2024

Molecular Nutrition Food Res

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A low‐carbohydrate and high‐protein (LC‐HP) diet demonstrates favorable impacts on metabolic parameters, albeit it leads to a decline in hippocampal function with the decreased expression of hippocampal insulin‐like growth factor‐1 receptor (IGF‐1R) among healthy mice. However, the precise mechanisms underlying this phenomenon remain unexplored. Eight‐week‐old male C57BL/6 mice were divided into the LC‐HP diet‐fed group (25.1% carbohydrate, 57.2% protein, and 17.7% fat as percentages of calories; n = 10) and the control diet‐fed group (58.9% carbohydrate, 24.0% protein, and 17.1% fat; n = 10). After 4 weeks, all mice underwent the Y‐maze test, followed by analyses of hippocampal mRNA and miRNA expressions. We revealed that feeding the LC‐HP diet suppressed working memory function and hippocampal Igf1r mRNA levels in mice. Sequencing of hippocampal miRNA demonstrated 17 upregulated and 27 downregulated miRNAs in the LC‐HP diet‐fed mice. Notably, we found decreased hippocampal mRNA levels of low‐density lipoprotein receptor‐related protein 6 (Lrp6), a gene modulated by miR‐539‐3p, in mice fed the LC‐HP diet. Furthermore, a significant positive correlation was observed between Lrp6 and Igf1r mRNA levels in the hippocampus. These findings suggest that LC‐HP diets may suppress hippocampal function via the miR‐539‐3p/Lrp6/Igf1r axis.

show abstract

Light-intensity exercise improves memory dysfunction with the restoration of hippocampal MCT2 and miRNAs in type 2 diabetic mice

Cited by 8 publications

References 53 publications

The Brain Metabolome Is Modified by Obesity in a Sex-Dependent Manner

The Brain Metabolome Is Modified by Obesity in a Sex-Dependent Manner

Muscle-derived miR-200a-3p through light-intensity exercise may contribute to improve memory dysfunction in type 2 diabetic mice

Possible Involvement of Hippocampal miR‐539‐3p/Lrp6/Igf1r Axis for Diminished Working Memory in Mice Fed a Low‐Carbohydrate and High‐Protein Diet

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