The effects of long-term lactate and high-intensity interval training (HIIT) on brain neuroplasticity of aged mice

Abstract

Extensive research has confirmed numerous advantages of exercise for promoting brain health. More recent studies have proposed the potential benefits of lactate, the by-product of exercise, in various aspects of brain function and disorders. However, there remains a gap in understanding the effects of lactate dosage and its impact on aged rodents. The present study first examined the long-term effects of three different doses of lactate intervention (2000 mg/kg, 1000 mg/kg, and 500 mg/kg) and high-intensity interval training (HIIT) on aging mice (20-22 months) as the 1st experiment. Subsequently, in the 2nd experiment, we investigated the long-term effects of 500 mg/kg lactate intervention and HIIT on brain neuroplasticity in aged mice (25-27 months). The results of the 1st experiment demonstrated that both HIIT and different doses of lactate intervention (500 mg/kg and 2000 mg/kg) positively impacted the neuroplasticity biomarker VEGF in the hippocampus of aging mice. Subsequently, the 2nd experiment revealed that long-term HIIT significantly improved the performance of mice in open-field, novel object recognition, and passive avoidance tests. However, lactate intervention did not significantly affect these behavioral tests. Moreover, compared to the control group, both HIIT and lactate intervention positively influenced the angiogenesis signaling pathway (p/t-AKT/ENOS/VEGF), mitochondrial biomarker (SDHA), and metabolic protein (p/t-CREB, p/t-HSL, and LDH) in the hippocampus of aged mice. Notably, only lactate intervention significantly elevated the BDNF (PGC-1α, SIRT1, and BDNF) signaling pathway and metabolic content (lactate and pyruvate). In the end, long-term HIIT and lactate intervention failed to change the protein expression of p/t-MTOR, iNOS, nNOS, HIF-1α, SYNAPSIN, SIRT3, NAMPT, CS, FNDC5 and Pan Lactic aid-Lysine in the hippocampus of aged mice. In summary, the present study proved that long-term HIIT and lactate treatment have positive effects on the brain functions of aged mice, suggesting the potential usage of lactate as a therapeutic strategy in neurodegenerative diseases in the elderly population.

Keywords: Aging; Brain function; Exercise; Hippocampus; Lactate; Lactylation.

Fig. 1

(A) The effect of different doses of lactate interventions on blood lactate levels. (B) The effect of different doses of lactate injections, and exercise on cognition tests performance of aging mice. (C) The effects of lactate and exercise on brain plastic biomarkers of aging mice's hippocampus. Data are presented as means ± SD (n = 4). Western blot data is based on each animal's protein expression. Low-level lactate injection (LL); Medium-level lactate injection (LM); High-level lactate injection (LH). The statistical analysis was performed using one-way analysis of variance (ANOVA) analysis followed by Dunnett's multiple comparisons. Statistical significance was denoted as *p＜0.05. The Original uncropped pictures are provided in the supplementary material.

Fig. 2

(A) Open field test (B) Novel object recognition test (C) Passive avoidance test. Data are presented as means ± SD (n = 7). The statistical analysis was performed using one-way analysis of variance (ANOVA) analysis followed by Dunnett's multiple comparisons. Statistical significance was denoted as *p＜0.05.

Fig. 3

The effect of lactate and HIIT on hippocampus angiogenesis signaling pathway in aged mice. (A) Western blot pictures (B) Statistical analysis. Data are presented as means ± SD (n = 5). The statistical analysis was performed using one-way analysis of variance (ANOVA) analysis followed by Dunnett's multiple comparisons. Statistical significance was denoted as *p＜0.05. The Western blot statistics are calculated by each animal's data, and the highest and lowest in each group are excluded from the statistic to remove extreme data.

Fig. 4

The effect of lactate and HIIT on hippocampus BDNF signaling and mitochondrial biomarkers in aged mice. (A) Western blot pictures (B) Statistical analysis. Data are presented as means ± SD (n = 5). The statistical analysis was performed using one-way analysis of variance (ANOVA) analysis followed by Dunnett's multiple comparisons. Statistical significance was denoted as *p＜0.05. The Western blot statistic is calculated by each animal's data, and the highest and lowest in each group are excluded from the statistic to remove extreme data.

Fig. 5

(A) The effect of chronic lactate and exercise interventions on pyruvate and lactate concentration in the hemisphere of aged mice. (B) The effect of lactate and HIIT on hippocampus metabolism-related signaling in aged mice. Data are presented as means ± SD (n = 5). The statistical analysis was performed using one-way analysis of variance (ANOVA) analysis followed by Dunnett's multiple comparisons. Statistical significance was denoted as *p＜0.05. The Western blot statistic is calculated by each animal's data, and the highest and lowest in each group are excluded from the statistic to remove extreme data.

Fig. 6

The effect of lactate and HIIT on Pan Lactic acid-Lysine protein expression in aged mice. Data are presented as means ± SD (n = 5). The statistical analysis was performed using one-way analysis of variance (ANOVA) analysis followed by Dunnett's multiple comparisons. Statistical significance was denoted as *p＜0.05. The Western blot statistics are calculated by each animal's data, and the highest and lowest in each group are excluded from the statistic to remove extreme data.

Fig. 7

Timeline of the experiment.

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