Interactions between monthly training volume, frequency and running distance per workout on marathon time.

PURPOSE: This study attempted to clarify the relationships between marathon time and monthly training volume, training frequency and the longest (LRD) or average running distance per workout (ARD), as well as their interactions. METHODS: Male recreational runners (n = 587) participating in the Hokkaido Marathon 2017 completed a questionnaire before the race; of these, 494 finished the race. We assessed age, running career, body height, body weight, body mass index (BMI), monthly training volume, training frequency, the LRD and the ARD. These indicators were each divided into 4 or 5 homogeneous subgroups to determine whether the other indicators in each subgroup predicted marathon time. RESULTS: In the training frequency subgroups, there were significant correlations between monthly training volume, the LRD or the ARD and marathon time, except for the subgroup that trained 2 times per week or less; in this subgroup, the relationship between the ARD and marathon time was not significant. In all monthly training volume subgroups, there were no significant relationships between training frequency, the LRD or the ARD and marathon time. In the ≥ 21 km LRD and ≥ 10 km ARD subgroups, there were significant correlations between monthly training volume and marathon time (all P < 0.01); these correlations were not significant in the 1-20 km LRD and < 10 km ARD subgroups. CONCLUSION: These results indicate that monthly training volume is the most important factor in predicting marathon time and that the influence of monthly training volume is only significant if the running distance per workout exceeded a certain level.

High-intensity Intermittent Training Enhances Spatial Memory and Hippocampal Neurogenesis Associated with BDNF Signaling in Rats.

High-intensity intermittent (or interval) training (HIIT) has started to gain popularity as a time-effective approach to providing beneficial effects to the brain and to peripheral organs. However, it still remains uncertain whether HIIT enhances hippocampal functions in terms of neurogenesis and spatial memory due to unconsidered HIIT protocol for rodents. Here, we established the HIIT regimen for rats with reference to human study. Adult male Wistar rats were assigned randomly to Control, moderate-intensity continuous training (MICT; 20 m/min, 30 min/day, 5 times/week), and HIIT (60 m/min, 10 30-s bouts of exercise, interspaced with 2.5 min of recovery, 5 times/week) groups. The ratios of exercise time and volume between MICT and HIIT were set as 6:1 and 2:1-4:1, respectively. After 4 weeks of training, all-out time in the incremental exercise test was prolonged for exercise training. In skeletal muscle, the plantaris citrate synthase activity significantly increased only in the HIIT group. Simultaneously, both HIIT and MICT led to enhanced spatial memory and adult hippocampal neurogenesis (AHN) as well as enhanced protein levels of hippocampal brain-derived neurotrophic factor (BDNF) signaling. Collectively, we suggest that HIIT could be a time-efficient exercise protocol that enhances hippocampal memory and neurogenesis in rats and is associated with hippocampal BDNF signaling.

Colorimetric detection of oxalate in aqueous solution by a pyrogallol red-based Cu2+ complex.

The pyrogallol red (PR)-based Cu2+ complex was proven to be an effective and selective colorimetric chemosensing ensemble for recognition of oxalate over other anions in a perfect aqueous solution. The addition of oxalate to the PR-Cu2+ complex resulted in a colour change from purple to orange colour due to the regeneration of PR by the chelation of oxalate with Cu2+ , while other anions did not induce any significant colour change. Moreover, it was revealed that no obvious interference was observed during the titrations with oxalate into each other anion. Therefore, the PR-Cu2+ complex can be used as a simple and practical colorimetric chemosensor for detecting oxalate.

Moderate exercise ameliorates dysregulated hippocampal glycometabolism and memory function in a rat model of type 2 diabetes.

AIMS/HYPOTHESIS: Type 2 diabetes is likely to be an independent risk factor for hippocampal-based memory dysfunction, although this complication has yet to be investigated in detail. As dysregulated glycometabolism in peripheral tissues is a key symptom of type 2 diabetes, it is hypothesised that diabetes-mediated memory dysfunction is also caused by hippocampal glycometabolic dysfunction. If so, such dysfunction should also be ameliorated with moderate exercise by normalising hippocampal glycometabolism, since 4 weeks of moderate exercise enhances memory function and local hippocampal glycogen levels in normal animals. METHODS: The hippocampal glycometabolism in OLETF rats (model of human type 2 diabetes) was assessed and, subsequently, the effects of exercise on memory function and hippocampal glycometabolism were investigated. RESULTS: OLETF rats, which have memory dysfunction, exhibited higher levels of glycogen in the hippocampus than did control rats, and breakdown of hippocampal glycogen with a single bout of exercise remained unimpaired. However, OLETF rats expressed lower levels of hippocampal monocarboxylate transporter 2 (MCT2, a transporter for lactate to neurons). Four weeks of moderate exercise improved spatial memory accompanied by further increase in hippocampal glycogen levels and restoration of MCT2 expression independent of neurotrophic factor and clinical symptoms in OLETF rats. CONCLUSIONS/INTERPRETATION: Our findings are the first to describe detailed profiles of glycometabolism in the type 2 diabetic hippocampus and to show that 4 weeks of moderate exercise improves memory dysfunction in type 2 diabetes via amelioration of dysregulated hippocampal glycometabolism. Dysregulated hippocampal lactate-transport-related glycometabolism is a possible aetiology of type-2-diabetes-mediated memory dysfunction.

Mild exercise increases dihydrotestosterone in hippocampus providing evidence for androgenic mediation of neurogenesis.

Mild exercise activates hippocampal neurons through the glutamatergic pathway and also promotes adult hippocampal neurogenesis (AHN). We hypothesized that such exercise could enhance local androgen synthesis and cause AHN because hippocampal steroid synthesis is facilitated by activated neurons via N-methyl-D-aspartate receptors. Here we addressed this question using a mild-intense treadmill running model that has been shown to be a potent AHN stimulator. A mass-spectrometric analysis demonstrated that hippocampal dihydrotestosterone increased significantly, whereas testosterone levels did not increase significantly after 2 wk of treadmill running in both orchidectomized (ORX) and sham castrated (Sham) male rats. Furthermore, analysis of mRNA expression for the two isoforms of 5α-reductases (srd5a1, srd5a2) and for androgen receptor (AR) revealed that both increased in the hippocampus after exercise, even in ORX rats. All rats were injected twice with 5'-bromo-2'deoxyuridine (50 mg/kg body weight, i.p.) on the day before training. Mild exercise significantly increased AHN in both ORX and Sham rats. Moreover, the increase of doublecortin or 5'-bromo-2'deoxyuridine/NeuN-positive cells in ORX rats was blocked by s.c. flutamide, an AR antagonist. It was also found that application of an estrogen receptor antagonist, tamoxifen, did not suppress exercise-induced AHN. These results support the hypothesis that, in male animals, mild exercise enhances hippocampal synthesis of dihydrotestosterone and increases AHN via androgenenic mediation.

Influencing factors and physiological parameters of psychological hurdle and motivation immediately prior to exercise.

BACKGROUND: To obtain the benefits of exercise as physical inactivity becomes a global concern, managing psychological hurdles to exercise implementation is important. This study examined troublesomeness, motivation, and physiological parameters immediately before exhaustive exercise. METHODS: Thirty-one healthy university students (mean age 19.87±2.21 years, 19 female) performed two conditions on separate days: performing push-ups to exhaustion (PE condition) and performing push-ups of the 30% count of the PE condition (P30 condition). Before the push-ups, the participants sat at rest for 5 minutes and were asked about their psychological states; after the first 2 minutes, PE or P30 conditions to be performed that day were disclosed to prepare them psychologically. During the rest, changes in the heart rate variability (HRV), pupil diameter, and front polar area (FPA) neural activity were measured before and after disclosure. RESULTS: Troublesomeness and FPA neural activities were significantly higher in the PE than in the P30 (P<0.001, P=0.04, P=0.01). Correlation analysis revealed correlations between motivation and pupil diameter (P=0.002), and negative correlations between total physical activity (TPA) and negative image of exercise (P=0.01). CONCLUSIONS: FPA activity could reflect the psychological hurdle to exhaustive exercise, pupil diameter could reflect the motivational arousal to exercise, and TPA could modulate the psychological hurdle.

Lifestyle Elements for Improving Mental and Physical Health in Japanese University Students: Subjective Sleep Quality is a Common Key Factor.

This study aimed to reveal the key lifestyle elements that improve physical and mental health in university students by focusing on physical activity, nutrition, and sleep. This cross-sectional study was conducted between October 2021 and December 2021. The participants were 290 first-year students (mean age, 18.63 ± .63 years; age range, 18 to 23; 198 female). The outcomes were daily step counts measured using accelerometers, dietary intake by nutrient category, sleep duration, subjective sleep quality, exercise frequency and duration by exercise type, screen time, depression level, and subjective fatigue by body part. Depression and subjective eye fatigue represent mental and physical health outcomes. Subjective sleep quality predicted depression (ß = -1.22, P < .001) and eye fatigue (ß = -.23, P < .01) in the path analysis. Participants with higher subjective sleep quality performed more frequent aerobic exercise (P < .01), longer session times of physical relaxation exercise (P < .05), and shorter screen time (P < .05). Subjective sleep quality could be a key factor for high mental and physical health. Furthermore, performing aerobic and relaxation exercises and reducing screen time are important for improving the subjective sleep quality.

Setting Treadmill Intensity for Rat Aerobic Training Using Lactate and Gas Exchange Thresholds.

PURPOSE: To open up new horizons of translational research, we studied the lactate threshold (LT)-dependent physiological responses and adaptations to exercise in rats, highlighting the importance of intensity-specific studies for optimizing exercise prescriptions. LT is physiologically related to the non-invasive gas exchange threshold (GET), and both thresholds are moderate-heavy-intensity boundary indices in determining an effective intensity of aerobic training in humans. While their practical utility is presumed to extend to rats, the actual existence of GET, the thresholds' relations to maximal oxygen consumption (VO2max), and whether aerobic adaptations by training differ around the LT intensity remain uncertain. METHODS: This study sought to identify the GET using our previously established rat LT-model by combining the use of a metabolic chamber and the V-slope method and to confirm the thresholds' relations to VO2max. We investigated changes in the thresholds and VO2max following 6 weeks of endurance training at below or above LT intensity. RESULTS: GET and LT were significantly correlated, and agreed with high precision, although with a fixed bias. Untrained rats exhibited GET and LT at 56% and 52% of their VO2max, respectively. Endurance training at supra-, but not below-, the LT intensity significantly improved VO2max and both thresholds; however, their %VO2max remained unaltered. CONCLUSIONS: GET in rats is identifiable as a threshold associated with LT using the V-slope method. Further, both thresholds can serve as moderate-heavy-intensity boundary indices for the aerobic training of rats. This study advances our understanding of exercise intensity regulation in rats, thereby contributing to the development of a more nuanced and effective model for exercise prescription, with implications for human health and fitness.

Brain glycogen supercompensation following exhaustive exercise.

Brain glycogen localized in astrocytes, a critical energy source for neurons, decreases during prolonged exhaustive exercise with hypoglycaemia. However, it is uncertain whether exhaustive exercise induces glycogen supercompensation in the brain as in skeletal muscle. To explore this question, we exercised adult male rats to exhaustion at moderate intensity (20 m min(-1)) by treadmill, and quantified glycogen levels in several brain loci and skeletal muscles using a high-power (10 kW) microwave irradiation method as a gold standard. Skeletal muscle glycogen was depleted by 82-90% with exhaustive exercise, and supercompensated by 43-46% at 24 h after exercise. Brain glycogen levels decreased by 50-64% with exhaustive exercise, and supercompensated by 29-63% (whole brain 46%, cortex 60%, hippocampus 33%, hypothalamus 29%, cerebellum 63% and brainstem 49%) at 6 h after exercise. The brain glycogen supercompensation rates after exercise positively correlated with their decrease rates during exercise. We also observed that cortical and hippocampal glycogen supercompensation were sustained until 24 h after exercise (long-lasting supercompensation), and their basal glycogen levels increased with 4 weeks of exercise training (60 min day(-1) at 20 m min(-1)). These results support the hypothesis that, like the effect in skeletal muscles, glycogen supercompensation also occurs in the brain following exhaustive exercise, and the extent of supercompensation is dependent on that of glycogen decrease during exercise across brain regions. However, supercompensation in the brain preceded that of skeletal muscles. Further, the long-lasting supercompensation of the cortex and hippocampus is probably a prerequisite for their training adaptation (increased basal levels), probably to meet the increased energy demands of the brain in exercising animals.

Reduction in paracrine Wnt3 factors during aging causes impaired adult neurogenesis.

The mammalian brain contains neural stem cells (NSCs) that enable continued neurogenesis throughout adulthood. However, NSC function and/or numbers decline with increasing age. Adult hippocampal neurogenesis is unique in that astrocytes secreting Wnt3 promote NSC differentiation in a paracrine manner. Here, we show that both the levels of Wnt3 protein and the number of Wnt3-secreting astrocytes influence the impairment of adult neurogenesis during aging. The age-associated reduction in Wnt3 levels affects the regulation of target genes, such as NeuroD1 and retrotransposon L1, as well as the expression of Dcx, which is located adjacent to the L1 loci. Interestingly, the decline in the extrinsic Wnt3 levels and in the intracellular expression of the target genes with aging was reversible. Exercise was found to significantly increase de novo expression of Wnt3 and thereby rescue impaired neurogenesis in aged animals. Furthermore, the chromatin state of NeuroD1, L1, and the L1 loci near Dcx changed relative to Wnt3 levels in an age- or stimulus-associated manner. These results suggest that the regulation of paracrine factors plays a critical role in hippocampal aging and neurogenesis.

Correction: Long-Term Mild, rather than Intense, Exercise Enhances Adult Hippocampal Neurogenesis and Greatly Changes the Transcriptomic Profile of the Hippocampus.

[This corrects the article DOI: 10.1371/journal.pone.0128720.].

Long-Term Mild, rather than Intense, Exercise Enhances Adult Hippocampal Neurogenesis and Greatly Changes the Transcriptomic Profile of the Hippocampus.

Our six-week treadmill running training (forced exercise) model has revealed that mild exercise (ME) with an intensity below the lactate threshold (LT) is sufficient to enhance spatial memory, while intense exercise (IE) above the LT negates such benefits. To help understand the unrevealed neuronal and signaling/molecular mechanisms of the intensity-dependent cognitive change, in this rat model, we here investigated plasma corticosterone concentration as a marker of stress, adult hippocampal neurogenesis (AHN) as a potential contributor to this ME-induced spatial memory, and comprehensively delineated the hippocampal transcriptomic profile using a whole-genome DNA microarray analysis approach through comparison with IE. Results showed that only IE had the higher corticosterone concentration than control, and that the less intense exercise (ME) is better suited to improve AHN, especially in regards to the survival and maturation of newborn neurons. DNA microarray analysis using a 4 × 44 K Agilent chip revealed that ME regulated more genes than did IE (ME: 604 genes, IE: 415 genes), and only 41 genes were modified with both exercise intensities. The identified molecular components did not comprise well-known factors related to exercise-induced AHN, such as brain-derived neurotrophic factor. Rather, network analysis of the data using Ingenuity Pathway Analysis algorithms revealed that the ME-influenced genes were principally related to lipid metabolism, protein synthesis and inflammatory response, which are recognized as associated with AHN. In contrast, IE-influenced genes linked to excessive inflammatory immune response, which is a negative regulator of hippocampal neuroadaptation, were identified. Collectively, these results in a treadmill running model demonstrate that long-term ME, but not of IE, with minimizing running stress, has beneficial effects on increasing AHN, and provides an ME-specific gene inventory containing some potential regulators of this positive regulation. This evidence might serve in further elucidating the mechanism behind ME-induced cognitive gain.

DNA microarray-based analysis of voluntary resistance wheel running reveals novel transcriptome leading robust hippocampal plasticity.

In two separate experiments, voluntary resistance wheel running with 30% of body weight (RWR), rather than wheel running (WR), led to greater enhancements, including adult hippocampal neurogenesis and cognitive functions, in conjunction with hippocampal brain-derived neurotrophic factor (BDNF) signaling (Lee et al., J Appl Physiol, 2012; Neurosci Lett., 2013). Here we aimed to unravel novel molecular factors and gain insight into underlying molecular mechanisms for RWR-enhanced hippocampal functions; a high-throughput whole-genome DNA microarray approach was applied to rats performing voluntary running for 4 weeks. RWR rats showed a significant decrease in average running distances although average work levels increased immensely, by about 11-fold compared to WR, resulting in muscular adaptation for the fast-twitch plantaris muscle. Global transcriptome profiling analysis identified 128 (sedentary × WR) and 169 (sedentary × RWR) up-regulated (>1.5-fold change), and 97 (sedentary × WR) and 468 (sedentary × RWR) down-regulated (<0.75-fold change) genes. Functional categorization using both pathway- or specific-disease-state-focused gene classifications and Ingenuity Pathway Analysis (IPA) revealed expression pattern changes in the major categories of disease and disorders, molecular functions, and physiological system development and function. Genes specifically regulated with RWR include the newly identified factors of NFATc1, AVPR1A, and FGFR4, as well as previously known factors, BDNF and CREB mRNA. Interestingly, RWR down-regulated multiple inflammatory cytokines (IL1B, IL2RA, and TNF) and chemokines (CXCL1, CXCL10, CCL2, and CCR4) with the SYCP3, PRL genes, which are potentially involved in regulating hippocampal neuroplastic changes. These results provide understanding of the voluntary-RWR-related hippocampal transcriptome, which will open a window to the underlying mechanisms of the positive effects of exercise, with therapeutic value for enhancing hippocampal functions.

Cessation of voluntary wheel running increases anxiety-like behavior and impairs adult hippocampal neurogenesis in mice.

While increasing evidence demonstrates that physical exercise promotes brain health, little is known on how the reduction of physical activity affects brain function. We investigated whether the cessation of wheel running alters anxiety-like and depression-like behaviors and its impact on adult hippocampal neurogenesis in mice. Male C57BL/6 mice (4 weeks old) were assigned to one of the following groups, and housed until 21 weeks old; (1) no exercise control (noEx), housed in a standard cage; (2) exercise (Ex), housed in a running wheel cage; and (3) exercise-no exercise (Ex-noEx), housed in a running wheel cage for 8 weeks and subsequently in a standard cage. Behavioral evaluations suggested that Ex-noEx mice were more anxious compared to noEx control mice, but no differences were found in depression-like behavior. The number of BrdU-labeled surviving cells in the dentate gyrus was significantly higher in Ex but not in Ex-noEx compared with noEx, indicating that the facilitative effects of exercise on cell survival are reversible. Surprisingly, the ratio of differentiation of BrdU-positive cells to doublecortin-positive immature neurons was significantly lower in Ex-noEx compared to the other groups, suggesting that the cessation of wheel running impairs an important component of hippocampal neurogenesis in mice. These results indicate that hippocampal adaptation to physical inactivity is not simply a return to the conditions present in sedentary mice. As the impaired neurogenesis is predicted to increase a vulnerability to stress-induced mood disorders, the reduction of physical activity may contribute to a greater risk of these disorders.

Voluntary resistance running induces increased hippocampal neurogenesis in rats comparable to load-free running.

Recently, we reported that voluntary resistance wheel running with a resistance of 30% of body weight (RWR), which produces shorter distances but higher work levels, enhances spatial memory associated with hippocampal brain-derived neurotrophic factor (BDNF) signaling compared to wheel running without a load (WR) [17]. We thus hypothesized that RWR promotes adult hippocampal neurogenesis (AHN) as a neuronal substrate underlying this memory improvement. Here we used 10-week-old male Wistar rats divided randomly into sedentary (Sed), WR, and RWR groups. All rats were injected intraperitoneally with the thymidine analogue 5-Bromo-2'-deoxuridine (BrdU) for 3 consecutive days before wheel running. We found that even when the average running distance decreased by about half, the average work levels significantly increased in the RWR group, which caused muscular adaptation (oxidative capacity) for fast-twitch plantaris muscle without causing any negative stress effects. Additionally, immunohistochemistry revealed that the total BrdU-positive cells and newborn mature cells (BrdU/NeuN double-positive) in the dentate gyrus increased in both the WR and RWR groups. These results provide new evidence that RWR has beneficial effects on AHN comparable to WR, even with short running distances.

Voluntary resistance running with short distance enhances spatial memory related to hippocampal BDNF signaling.

Although voluntary running has beneficial effects on hippocampal cognitive functions if done abundantly, it is still uncertain whether resistance running would be the same. For this purpose, voluntary resistance wheel running (RWR) with a load is a suitable model, since it allows increased work levels and resultant muscular adaptation in fast-twitch muscle. Here, we examined whether RWR would have potential effects on hippocampal cognitive functions with enhanced hippocampal brain-derived neurotrophic factor (BDNF), as does wheel running without a load (WR). Ten-week-old male Wistar rats were assigned randomly to sedentary (Sed), WR, and RWR (to a maximum load of 30% of body weight) groups for 4 wk. We found that in RWR, work levels increased with load, but running distance decreased by about half, which elicited muscular adaptation for fast-twitch plantaris muscle without causing any negative stress effects. Both RWR and WR led to improved spatial learning and memory as well as gene expressions of hippocampal BDNF signaling-related molecules. RWR increased hippocampal BDNF, tyrosine-related kinase B (TrkB), and cAMP response element-binding (CREB) protein levels, whereas WR increased only BDNF. With both exercise groups, there were correlations between spatial memory and BDNF protein (r = 0.41), p-CREB protein (r = 0.44), and work levels (r = 0.77). These results suggest that RWR plays a beneficial role in hippocampus-related cognitive functions associated with hippocampal BDNF signaling, even with short distances, and that work levels rather than running distance are more determinant of exercise-induced beneficial effects in wheel running with and without a load.