Exercise hormone irisin prevents physical inactivity-induced cognitive decline in mice.

We previously reported that physical inactivity (PI) induces cognitive decline and depressive states, which were ameliorated by regular exercise. However, the mechanism underlying the preventive effect of exercise remains unelucidated. Irisin has recently been identified as an exercise-inducible myokine that improves cognitive impairment. Plasma irisin levels increase during physical exercise; therefore, PI could lead to a decline in cognitive function by reducing plasma irisin. Therefore, this study aimed to examine whether irisin is associated with cognitive decline and mental deterioration altered by PI and exercise. The mice were housed for eight weeks in the PI cage, whose living space was one-sixth that of a standard cage. Simultaneously, the mice were subjected to regular exercise in the presence or absence of an irisin-neutralizing antibody. PI increased the epididymal fat mass without increasing body weight, muscle mass, or plasma corticosterone levels. Additionally, PI induced anxiety, depressive states, and a decline in working memory. In contrast, regular exercise after PI elevated irisin levels in plasma and increased fibronectin type III domain-containing 5 (FNDC5) and peroxisome proliferator-activated receptor gammacoactivator 1α expression in skeletal muscle. Regular exercise also increased hippocampal brain-derived neurotrophic factor (BDNF) expression and BrdU-positive cells, alleviating cognitive decline and mental deterioration induced by PI. The beneficial effects of exercise were compromised by the administration of an irisin-neutralizing antibody. Moreover, plasma irisin level was positively correlated with working memory, hippocampal BDNF levels, and hippocampal cell proliferation. These findings suggest that exercise-inducible irisin is critical for maintaining cognitive function in the PI state.

Regular Low-Intensity Exercise Prevents Cognitive Decline and a Depressive-Like State Induced by Physical Inactivity in Mice: A New Physical Inactivity Experiment Model.

Regular exercise has already been established as a vital strategy for maintaining physical health via experimental results in humans and animals. In addition, numerous human studies have reported that physical inactivity is a primary factor that causes obesity, muscle atrophy, metabolic diseases, and deterioration in cognitive function and mental health. Regardless, an established animal experimental method to examine the effect of physical inactivity on physiological, biochemical, and neuroscientific parameters is yet to be reported. In this study, we made a new housing cage, named as the physical inactivity (PI) cage, to investigate the effect of physical inactivity on cognitive function and depressive-like states in mice and obtained the following experimental results by its use. We first compared the daily physical activity of mice housed in the PI and standard cages using the nano-tag method. The mice's physical activity levels in the PI cage decreased to approximately half of that in the mice housed in the standard cage. Second, we examined whether housing in the PI cage affected plasma corticosterone concentration. The plasma corticosterone concentration did not alter before, 1 week, or 10 weeks after housing. Third, we investigated whether housing in the PI cage for 10 weeks affected cognitive function and depressive behavior. Housing in an inactive state caused a cognitive decline and depressive state in the mice without increasing body weight and plasma corticosterone. Finally, we examined the effect of regular low-intensity exercise on cognitive function and depressive state in the mice housed in the PI cage. Physical inactivity decreased neuronal cell proliferation, blood vessel density, and gene expressions of vascular endothelial growth factors and brain-derived neurotrophic factors in the hippocampus. In addition, regular low-intensity exercise, 30 min of treadmill running at a 5-15 m/min treadmill speed 3 days per week, prevented cognitive decline and the onset of a depressive-like state caused by physical inactivity. These results showed that our novel physical inactivity model, housing the mice in the PI cage, would be an adequate and valuable experimental method for examining the effect of physical inactivity on cognitive function and a depressive-like state.

Exercise-Induced Lactate Release Mediates Mitochondrial Biogenesis in the Hippocampus of Mice via Monocarboxylate Transporters.

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.

Olive leaf extract prevents obesity, cognitive decline, and depression and improves exercise capacity in mice.

Obesity is a risk factor for development of metabolic diseases and cognitive decline; therefore, obesity prevention is of paramount importance. Neuronal mitochondrial dysfunction induced by oxidative stress is an important mechanism underlying cognitive decline. Olive leaf extract contains large amounts of oleanolic acid, a transmembrane G protein-coupled receptor 5 (TGR5) agonist, and oleuropein, an antioxidant. Activation of TGR5 results in enhanced mitochondrial biogenesis, which suggests that olive leaf extract may help prevent cognitive decline through its mitochondrial and antioxidant effects. Therefore, we investigated olive leaf extract's effects on obesity, cognitive decline, depression, and endurance exercise capacity in a mouse model. In physically inactive mice fed a high-fat diet, olive leaf extract administration suppressed increases in fat mass and body weight and prevented cognitive declines, specifically decreased working memory and depressive behaviors. Additionally, olive leaf extract increased endurance exercise capacity under atmospheric and hypoxic conditions. Our study suggests that these promising effects may be related to oleanolic acid's improvement of mitochondrial function and oleuropein's increase of antioxidant capacity.

Drinking hydrogen water enhances endurance and relieves psychometric fatigue: a randomized, double-blind, placebo-controlled study 1.

Acute physical exercise increases reactive oxygen species in skeletal muscle, leading to tissue damage and fatigue. Molecular hydrogen (H2) acts as a therapeutic antioxidant directly or indirectly by inducing antioxidative enzymes. Here, we examined the effects of drinking H2 water (H2-infused water) on psychometric fatigue and endurance capacity in a randomized, double-blind, placebo-controlled fashion. In Experiment 1, all participants drank only placebo water in the first cycle ergometer exercise session, and for comparison they drank either H2 water or placebo water 30 min before exercise in the second examination. In these healthy non-trained participants (n = 99), psychometric fatigue judged by visual analogue scales was significantly decreased in the H2 group after mild exercise. When each group was divided into 2 subgroups, the subgroup with higher visual analogue scale values was more sensitive to the effect of H2. In Experiment 2, trained participants (n = 60) were subjected to moderate exercise by cycle ergometer in a similar way as in Experiment 1, but exercise was performed 10 min after drinking H2 water. Endurance and fatigue were significantly improved in the H2 group as judged by maximal oxygen consumption and Borg's scale, respectively. Taken together, drinking H2 water just before exercise exhibited anti-fatigue and endurance effects.

Acute Supplementation with Molecular Hydrogen Benefits Submaximal Exercise Indices. Randomized, Double-Blinded, Placebo-Controlled Crossover Pilot Study.

BACKGROUND: Clinical studies have reported hydrogen-rich water (HRW) to have therapeutic and ergogenic effects. The aim of this study was to determine the effect of acute supplementation with HRW on exercise performance as measured by VO2, respiratory exchange ratio (RER), heart rate (HR), and respiratory rate (RR). METHODS: Baseline levels of all exercise indices were determined in nineteen (4 female, 23.4 ± 9.1 yr; 15 male, 30.5 ± 6.8 yr) healthy subjects using a graded treadmill exercise test to exhaustion. Each subject was examined two additional times in a randomized double-blinded, placebo-controlled crossover fashion. Subjects received either HRW or placebo, which was consumed the day before and the day of the testing. HRW was delivered using the hydrogen-producing tablets, DrinkHRW (5 mg of H2). All data was analyzed with SPSS using pairwise comparisons with Bonferroni adjustment. RESULTS: HRW supplementation did not influence maximal or minimal indices of exercise performance (VO2, RER, HR and RR) (p < 0.05). However, HRW significantly decreased average exercising RR and HR (p < 0.05). HRW decreased exercising HR during minutes 1-9 of the graded exercise test (121 ± 26 bpm) compared to placebo (126 ± 26 bpm) and baseline (124 ± 27 bpm) (p < 0.001) without substantially influencing VO2. CONCLUSION: Acute supplementation of DrinkHRW tablets may benefit submaximal aerobic exercise performance by lowering exercising HR. Further studies are needed to determine the influence and practical significance of HRW on varying exercise intensities as well as optimal dosing protocols and the effects of chronic use.

Intermittent intense exercise protects against cognitive decline in a similar manner to moderate exercise in chronically stressed mice.

It is well known that regular low or mild exercise helps to improve and maintain cognition. On the other hand, ever thought many people prefer high-intensity exercise (e.g., running, swimming, biking, soccer, basketball, etc.) to get rid of stress or improve their health, the previous studies reported that intense exercise either impairs cognition or has no effect on cognitive function. However, we previously showed that intermittent intense exercise prevents stress-induced depressive behavior in mice in a similar manner to moderate exercise. On the basis of this finding, we investigated the effect of intermittent intense exercise on cognitive deficit in chronically stressed mice. A total of forty mice were evenly divided into control, stressed, stressed with moderate exercise, and stressed with intense exercise groups. The stressed mice were chronically exposed a restraint stress (10 h/day, 6 days/week for 7 weeks). The exercised mice were subjected to intermittent intense or endurance moderate running on the treadmill three times a week. Cognition was evaluated using the Morris water maze test and the object recognition test. Chronic stress decreased cognition, and newborn cell survival and blood vessel density in the hippocampus. However, both regular intense and moderate exercise prevented decrease of cognition, improved newborn cell survival and blood vessel density. These findings suggest that intermittent intense exercise may protect against decrease of cognition in a similar manner to moderate exercise and that both exercise-induced protection of decrease of cognition is closely related to newborn cell survival and angiogenesis in the hippocampus.

Acute immobilization stress following contextual fear conditioning reduces fear memory: timing is essential.

BACKGROUND: Histone acetylation is regulated in response to stress and plays an important role in learning and memory. Chronic stress is known to deteriorate cognition, whereas acute stress facilitates memory formation. However, whether acute stress facilitates memory formation when it is applied after fear stimulation is not yet known. Therefore, this study aimed to investigate the effect of acute stress applied after fear training on memory formation, mRNA expression of brain-derived neurotrophic factor (BDNF), epigenetic regulation of BDNF expression, and corticosterone level in mice in vivo. METHODS: Mice were subjected to acute immobilization stress for 30 min at 60 or 90 min after contextual fear conditioning training, and acetylation of histone 3 at lysine 14 (H3K14) and level of corticosterone were measured using western blot analysis and enzyme-linked immunosorbent assay (ELISA), respectively. A freezing behavior test was performed 24 h after training, and mRNA expression of BDNF was measured using real-time polymerase chain reactions. Different groups of mice were used for each test. RESULTS: Freezing behavior significantly decreased with the down-regulation of BDNF mRNA expression caused by acute immobilization stress at 60 min after fear conditioning training owing to the reduction of H3K14 acetylation. However, BDNF mRNA expression and H3K14 acetylation were not reduced in animals subjected to immobilization stress at 90 min after the training. Further, the corticosterone level was significantly high in mice subjected to immobilization stress at 60 min after the training. CONCLUSION: Acute immobilization stress for 30 min at 60 min after fear conditioning training impaired memory formation and reduced BDNF mRNA expression and H3K14 acetylation in the hippocampus of mice owing to the high level of corticosterone.

Oral administration of inosine produces antidepressant-like effects in mice.

Inosine, a breakdown product of adenosine, has recently been shown to exert immunomodulatory and neuroprotective effects. We show here that the oral administration of inosine has antidepressant-like effects in two animal models. Inosine significantly enhanced neurite outgrowth and viability of primary cultured neocortical neurons, which was suppressed by adenosine A1 and A2A receptor agonists. Oral administration of inosine to mice transiently increased its concentration in the brain and enhanced neuronal proliferation in the dentate gyrus, accompanied by phosphorylation of mitogen-activated protein kinase and increase in transcript level of brain-derived neurotrophic factor. In stress models, oral inosine prevented an increase in immobility time in forced swim test after chronically unexpected stress and mitigated a reduction in sucrose preference after chronic social defeat stress. These results indicate that oral administration of inosine has the potential to prevent depressive disorder via adenosine receptors.

Regular moderate or intense exercise prevents depression-like behavior without change of hippocampal tryptophan content in chronically tryptophan-deficient and stressed mice.

Regular exercise has an antidepressant effect in human subjects. Studies using animals have suggested that the antidepressant effect of exercise is attributable to an increase of brain 5-hydroxytryptamine (5-HT); however, the precise mechanism underlying the antidepressant action via exercise is unclear. In contrast, the effect of 5-HT on antidepressant activity has not been clarified, in part because the therapeutic response to antidepressant drugs has a time lag in spite of the rapid increase of brain 5-HT upon administration of these drugs. This study was designed to investigate the contribution of brain 5-HT to the antidepressant effect of exercise. Mice were fed a tryptophan-deficient diet and stressed using chronic unpredictable stress (CUS) for 4 weeks with or without the performance of either moderate or intense exercise on a treadmill 3 days per week. The findings demonstrated that the onset of depression-like behavior is attributable not to chronic reduction of 5-HT but to chronic stress. Regular exercise, whether moderate or intense, prevents depression-like behavior with an improvement of adult hippocampal cell proliferation and survival and without the recovery of 5-HT. Concomitantly, the mice that exercised showed increased hippocampal noradrenaline. Regular exercise prevents the impairment of not long-term memory but short-term memory in a 5-HT-reduced state. Together, these findings suggest that: (1) chronic reduction of brain 5-HT may not contribute to the onset of depression-like behavior; (2) regular exercise, whether moderate or intense, prevents the onset of chronic stress-induced depression-like behavior independent of brain 5-HT and dependent on brain adrenaline; and (3) regular exercise prevents chronic tryptophan reduction-induced impairment of not long-term but short-term memory.

Morinda citrifolia fruit reduces stress-induced impairment of cognitive function accompanied by vasculature improvement in mice.

The purpose of this study was to investigate effects of Morinda citrifolia fruit juice, which is locally called Noni, on stress-induced impairment of cognitive function. Male ICR mice were divided into four groups: Control (C mice), Restraint stress (RS mice), Restraint+Noni (Noni mice), and Restraint+vitamin E (VE mice). The RS, Noni, and VE mice were subjected to 8h of chronic restraint stress (CRS) 6days a week for 6weeks. During this period, the Noni and VE mice were given a diet supplemented with either Noni or vitamin E, respectively. At Week 5, the mice were subjected to the Morris water maze (MWM) test to measure cognitive function. At Week 7, mouse brains were isolated for immunohistochemical analysis with BrdU or CD31 antibody to assess the proliferation of new cells and blood vessel density in the dentate gyrus of the hippocampus. The time taken to reach the platform in the MWM test was shorter in the Noni mice than in the RS mice on Day 16. Malondialdehyde (MDA ) level of the Noni mice was significantly higher than that of the C mice; however no difference was found in MDA levels between the VE and C mice. Blood vessel area was significantly lower in the R and VE mice than in the C mice; no difference was found between the C and Noni mice. These findings suggest that the administration of Noni fruit juice protects brains from stress-induced impairment of cognitive function and that this protective effect may be related to improvement in stress-induced decreases in blood vessel density in the hippocampal dentate gyrus.

Regular voluntary exercise cures stress-induced impairment of cognitive function and cell proliferation accompanied by increases in cerebral IGF-1 and GST activity in mice.

Chronic stress impairs cognitive function and hippocampal neurogenesis. This impairment is attributed to increases in oxidative stress, which result in the accumulation of lipid peroxide. On the other hand, voluntary exercise enhances cognitive function, hippocampal neurogenesis, and antioxidant capacity in normal animals. However, the effects of voluntary exercise on cognitive function, neurogenesis, and antioxidants in stressed mice are unclear. This study was designed to investigate whether voluntary exercise cures stress-induced impairment of cognitive function accompanied by improvement of hippocampal neurogenesis and increases in antioxidant capacity. Stressed mice were exposed to chronic restraint stress (CRS), which consisted of 12h immobilization daily and feeding in a small cage, for 8 weeks. Exercised mice were allowed free access to a running wheel during their exposure to CRS. At the 6th week, cognitive function was examined using the Morris water maze (MWM) test. Daily voluntary exercise restored stress-induced impairment of cognitive function and the hippocampal cell proliferation of newborn cells but not cell survival. Voluntary exercise increased insulin-like growth factor 1 (IGF-1) protein and mRNA expression in the cerebral cortex and liver, respectively. In addition, CRS resulted in a significant increase in the number of 4-hydrosynonenal (4-HNE)-positive cells in the hippocampal dentate gyrus; whereas, voluntary exercise inhibited it and enhanced glutathione s-transferases (GST) activity in the brain. These findings suggest that voluntary exercise attenuated the stress-induced impairment of cognitive function accompanied by improvement of cell proliferation in the dentate gyrus. This exercise-induced improvement was attributed to exercise-induced enhancement of IGF-1 protein and GST activity in the brain.

Oral supplementation with melon superoxide dismutase extract promotes antioxidant defences in the brain and prevents stress-induced impairment of spatial memory.

The purpose of this study was to investigate the effect of antioxidant ingestion on stress-induced impairment of cognitive memory. Male C57BL/6 mice were divided into four groups as follows: (1) control mice (C mice) fed in a normal cage without immobilization; (2) restraint-stressed (RS mice) fed in a small cage; (3) vitamin E mice (VE mice), mice were fed in a small cage with a diet supplemented with vitamin E; (4) GliSODin mice (GS mice) fed in a small cage with a diet supplemented with GliSODin. RS, VE and GS mice were exposed to 12 h of immobilization daily. Five weeks later, spatial learning was measured using the Morris Water Maze (MWM) test. After water maze testing, we performed immunohistochemical analysis using 4-hydroxy-2-noneral (4-HNE) and an anti-Ki67 antibody. 4-HNE is a marker of lipid peroxidation. RS mice showed impaired spatial learning performance and an increased number of 4-HNE-positive cells in the granule cell layer (GCL) of the hippocampal dentate gyrus when compared to C mice. Moreover, RS mice showed a decreased number of Ki67-positive cells in the subgranular zone (SGZ). GS mice showed better spatial learning memory than RS mice. The number of 4-HNE-positive cells in the GCL of GS mice was significantly less than that of RS mice. The number of Ki67-positive cells in the SGZ of GS mice was significantly greater than that of RS mice. These finding suggests that GliSODin prevents stress-induced impairment of cognitive function and maintains neurogenesis in the hippocampus through antioxidant activity.

Consumption of molecular hydrogen prevents the stress-induced impairments in hippocampus-dependent learning tasks during chronic physical restraint in mice.

We have reported that hydrogen (H(2)) acts as an efficient antioxidant by gaseous rapid diffusion. When water saturated with hydrogen (hydrogen water) was placed into the stomach of a rat, hydrogen was detected at several microM level in blood. Because hydrogen gas is unsuitable for continuous consumption, we investigated using mice whether drinking hydrogen water ad libitum, instead of inhaling hydrogen gas, prevents cognitive impairment by reducing oxidative stress. Chronic physical restraint stress to mice enhanced levels of oxidative stress markers, malondialdehyde and 4-hydroxy-2-nonenal, in the brain, and impaired learning and memory, as judged by three different methods: passive avoidance learning, object recognition task, and the Morris water maze. Consumption of hydrogen water ad libitum throughout the whole period suppressed the increase in the oxidative stress markers and prevented cognitive impairment, as judged by all three methods, whereas hydrogen water did not improve cognitive ability when no stress was provided. Neural proliferation in the dentate gyrus of the hippocampus was suppressed by restraint stress, as observed by 5-bromo-2'-deoxyuridine incorporation and Ki-67 immunostaining, proliferation markers. The consumption of hydrogen water ameliorated the reduced proliferation although the mechanistic link between the hydrogen-dependent changes in neurogenesis and cognitive impairments remains unclear. Thus, continuous consumption of hydrogen water reduces oxidative stress in the brain, and prevents the stress-induced decline in learning and memory caused by chronic physical restraint. Hydrogen water may be applicable for preventive use in cognitive or other neuronal disorders.

Oxidative stress stimulates skeletal muscle glucose uptake through a phosphatidylinositol 3-kinase-dependent pathway.

We determined the acute effects of oxidative stress on glucose uptake and intracellular signaling in skeletal muscle by incubating muscles with reactive oxygen species (ROS). Xanthine oxidase (XO) is a superoxide-generating enzyme that increases ROS. Exposure of isolated rat extensor digitorum longus (EDL) muscles to Hx/XO (Hx/XO) for 20 min resulted in a dose-dependent increase in glucose uptake. To determine whether the mechanism leading to Hx/XO-stimulated glucose uptake is associated with the production of H2O2, EDL muscles from rats were preincubated with the H2O2 scavenger catalase or the superoxide scavenger superoxide dismutase (SOD) prior to incubation with Hx/XO. Catalase treatment, but not SOD, completely inhibited the increase in Hx/XO-stimulated 2-deoxyglucose (2-DG) uptake, suggesting that H2O2 is an intermediary leading to Hx/XO-stimulated glucose uptake with incubation. Direct H2O2 also resulted in a dose-dependent increase in 2-DG uptake in isolated EDL muscles, and the maximal increase was threefold over basal levels at a concentration of 600 micromol/l H2O2. H2O2-stimulated 2-DG uptake was completely inhibited by the phosphatidylinositol 3-kinase (PI3K) inhibitor wortmannin, but not the nitric oxide inhibitor NG-monomethyl-l-arginine. H2O2 stimulated the phosphorylation of Akt Ser473 (7-fold) and Thr308 (2-fold) in isolated EDL muscles. H2O2 at 600 micromol/l had no effect on ATP concentrations and did not increase the activities of either the alpha1 or alpha2 catalytic isoforms of AMP-activated protein kinase. These results demonstrate that acute exposure of muscle to ROS is a potent stimulator of skeletal muscle glucose uptake and that this occurs through a PI3K-dependent mechanism.

Intense exercise induces the degradation of adenine nucleotide and purine nucleotide synthesis via de novo pathway in the rat liver.

The purpose of this study was to investigate the influence of intense exercise on the metabolism of adenine nucleotides in the liver. In the first experiment, to determine the degradation of adenine nucleotides, hepatic adenine nucleotides of rats were labeled by an intraperitoneal administration of 15N-labeled adenine the day before treadmill running to exhaustion. In the second experiment, to determine the de novo synthesis of purine nucleotides after intense exercise, 14C-glycine was intraperitoneally administered to rats performing intense running on a treadmill. In the first experiment, hepatic levels of ATP and total adenine nucleotides showed a reduction immediately after exercise. In contrast, hepatic levels of AMP, adenosine, hypoxanthine and uric acid showed an increase immediately after exercise. The hepatic 15N level continued to decline during the recovery period after exercise. Urinary excretion of 15N-urate was 40% higher in the exercised rats than in the control rats. In the second experiment, the radioactivity of 14C detected in the fraction of hepatic urate and allantoin was approximately 300% higher in the exercised rats than in the control rats. 14C-radioactivity that excreted into urine as urate and allantoin was approximately 200% higher in the exercised rats. Intense exercise led to the degradation of hepatic adenine nucleotides, which were not utilized for the re-synthesis of nucleotide and further degraded to hypoxanthine or uric acid. Intense exercise induced the synthesis of purine nucleotides in the liver via a de novo pathway and these synthesized nucleotides were also degraded to nucleosides and excreted into urine.

Endurance exercise training inhibits activity of plasma GOT and liver caspase-3 of mice [correction of rats] exposed to stress by induction of heat shock protein 70.

A single bout of exercise increases production of heat shock protein 70 (HSP70), which protects cells against various stresses. In this study, we investigated whether endurance exercise training enhances liver level of HSP70 and, if so, whether HSP70 contributes to hepatic protection against stress in vivo. Mice of an exercise-training group performed 60 min of treadmill running 5 days/wk for 4 wk. The resting level of liver HSP70 was 4.5 times higher in the trained than in sedentary mice. After 4 wk of exercise training, both groups of mice were exposed to the following stresses: 1) heat stress, 2) cold stress, 3) oxidative stress, 4) ethanol stress, and 5) exercise stress by compelling the mice to run on a treadmill until exhausted. After exposure to the stresses, the liver was immediately isolated. Elevation of liver HSP70 in the trained mice was evident, whereas no elevation was found in the sedentary mice. On exposure to heat, diethyldithiocarbamate and ethanol, activities of glutanic oxalacetic transaminase in plasma, and liver caspase-3, a key enzyme of apoptotic processing, were elevated in the sedentary mice but not in the trained mice. These results suggest that exercise training enhanced the resting level of liver HSP70 and hepatic protection against various stresses, at least partly attributing to the suppression of caspase-3 activity by the increase in HSP70.