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Purpose Previous studies have suggested that circulating extracellular vesicles (EVs) arise after high intensity exercise and urine could reflect the plasma proteome. Herein, we investigated the characteristic of urinary EVs from healthy young adult males who had completed a maximal effort exercise test. Methods Thirteen healthy men completed a 20 m shuttle run test (20 m SRT). Fresh urine samples were collected at first morning, right after, and 1 h rest after 20 m SRT. Also, blood lactate, heart rate, rating of perceived exertion, and blood pressure were measured before, right after, and 1 h rest after 20 m SRT. Urinary EVs were analyzed using Exoview instrument and microRNAs (miRNAs) sequencing on urinary EVs were performed. Results Urinary EVs increased significantly after exercise and returned to baseline value after 1 h of rest. miRNA sequencing on urinary EV revealed alterations in four miRNAs (1 up and 3 down) and nine miRNAs (2 up and 7 down) in pre- vs. post- and post- vs. post-1 h samples, respectively. Lastly, bioinformatic analysis of urinary EV miRNA suggests that predicted target genes could affect PI3K-Akt, mitogen-activated protein kinase, and insulin pathways by exercise. Conclusions Exercise to voluntary exhaustion increased the number of EVs in urine. Also, miRNAs in urinary EVs were altered after exercise. These findings could indicate the possibility of using the urinary EVs as a novel biomarker of acute exercise-induced fatigue.

Skeletal muscles are made up of various muscle fiber type including slow and fast-twitch fibers. Because each muscle fiber has its own physiological characteristics, the effects of aging and exercise vary depending on the type of muscle fiber. We used bioinformatics screening techniques such as differentially expressed gene analysis, gene ontology analysis and gene set enrichment analysis, to try to understand the genetic differences between muscle fiber types. The experiment and gene expression profiling in this study used the soleus (SOL, slow-twitch muscle) and gastrocnemius (GAS, fast-twitch muscle). According to our findings, fatty acid metabolism is significantly up-regulated in SOL compared to GAS, whereas the glucose metabolism pathway is significantly down-regulated in SOL compared to GAS. Furthermore, apoptosis and myogenesis patterns differ between SOL and GAS. SOL did not show differences in apoptosis due to the aging effect, but apoptosis in GAS was significantly up-regulated with age. Apoptosis in GAS of old groups is significantly reduced after 4 weeks of aerobic exercise, but no such finding was found in SOL. In terms of myogenesis, exercise intervention up-regulated this process in GAS of old groups but not in SOL. Taken together, muscle fiber type significantly interacts with aging and exercise. Despite the importance of the interaction between these factors, large-scale gene expression data has rarely been studied. We hope to contribute to a better understanding of the relationship between muscle fiber type, aging and exercise at the molecular level.

[Purpose] Lactate is a principal energy substrate for the brain during exercise. A single bout of high-intensity interval exercise (HIIE) can increase the blood lactate level, brain lactate uptake, and executive function (EF). However, repeated HIIE can attenuate exercise-induced increases in lactate level and EF. The lactate levels in the brain and blood are reported to be cor related with exercise-enhanced EF. However, research is yet to explain the cause-and-effect relationship between lactate and EF. This study examined whether lactate consumption improves the attenuated exercise-enhanced EF caused by repeated HIIE. [Methods] Eleven healthy men performed two sets of HIIE, and after each set, 30 min were given for rest and examination. In the 2nd set, the subjects consumed experimental beverages containing (n = 6) and not containing (n = 5) lactate. Blood, cardiovascular, and psychological variables were measured, and EF was evaluated by the computerized color-word Stroop test. [Results] The lactate group had a higher EF (P < 0.05) and tended to have a higher blood lactate level (P = 0.082) than the control group in the 2nd set of HIIE. Moreover, blood lactate concentration was correlated with the interference score (i.e., reverse score of EF) (r = -0.394; P < 0.05). [Conclusion] Our results suggest that the attenuated exercise-enhanced EF after repeated HIIE can be im proved through lactate consumption. However, the role of lactate needs to be elucidated in future studies, as it can be used for improving athletes’ performance and also in cognitive decline-related clinical studies.

There has been an increasing awareness of sarcopenia, which is characterized by a concomitant decrease in skeletal muscle mass and quality due to aging. Resistance exercise is considered more effective than aerobic exercise in terms of therapeutic exercise. To confirm the effect of long-term aerobic exercise in preventing sarcopenia, we evaluated the skeletal muscle mass, quality, and angiogenic capacity of super-aged mice that had undergone lifelong spontaneous exercise (LSE) through various experiments. Our findings show that LSE could maintain skeletal muscle mass, quality, and fitness levels in super-aged mice. In addition, ex vivo experiments showed that the angiogenic capacity was maintained at a high level. However, these results were not consistent with the related changes in the expression of genes and/or proteins involved in protein synthesis or angiogenesis. Based on the results of previous studies, it seems certain that the expression at the molecular level does not represent the phenotypes of skeletal muscle and angiogenesis. This is because aging and long-term exercise are variables that can affect both protein synthesis and the expression patterns of angiogenesis-related genes and proteins. Therefore, in aging and exercise-related research, various physical fitness and angiogenesis variables and phenotypes should be analyzed. In conclusion, LSE appears to maintain the potential of angiogenesis and slow the aging process to maintain skeletal muscle mass and quality. Aerobic exercise may thus be effective for the prevention of sarcopenia.

PURPOSE Impaired autophagy, a conserved process for the cellular energy homeostasis by degrading damaged cytosolic constituents, is an important contributor to the pathogenesis of atherosclerosis. The purpose of this study was to determine whether regular aerobic exercise can improve obesity-induced dysregulation of autophagy in mice arterial endothelial cells. METHODS High-fat diet-induced obese mice were subjected to the treadmill running for 10 weeks (15 m/min, 1 hour/day, 6 days/week). Endothelial cells were isolated from aorta by perfusing with QIAzol reagent. The mRNA and protein expressions of autophagy-related genes were investigated by qRT-PCR and western-blot respectively. Statistical analysis was performed by one-way ANOVA. RESULTS Autophagy-related gene expressions in both levels of mRNA and protein were significantly decreased in vascular endothelial cells and arterial vessels of obese mice. However, these phenomena have been partly reversed by the regular treatment of treadmill exercise for 10 weeks. Furthermore, eNOS downregulation induced by the obesity was also improved by the regular aerobic exercise, representing enhanced endothelial function. CONCLUSIONS The current study has shown that the obesity-induced autophagy dysregulation and vascular dysfunction can be partly improved by the regular aerobic exercise in mice vascular endothelial cells.

[Purpose] Recent studies have shown that glucose- 6-phosphate isomerase (GPI)―which is a glycolysis interconversion enzyme―reduces oxidative stress. However, these studies are limited to tumors such as fibrosarcoma, and there are no studies that have examined the effects of exercise on GPI expression in mice skeletal muscle. Furthermore, GPI acts in an autocrine manner thorough its receptor, autocrine motility factor receptor (AMFR); therefore, we investigated expression level changes of secreted GPI from skeletal muscle in in vitro study to examine the potential role of GPI on skeletal muscle. [Methods] First, we performed an in vitro study, to identify the condition that upregulates GPI levels in skeletal muscle cells; we treated C2C12 muscle cells with an exercise-mimicking chemical, AICAR. AICAR treatment upregulated GPI expression level in C2C12 cell and its secretomes. To confirm the direct effect of GPI on skeletal muscle cells, we treated C2C12 cells with GPI recombinant protein. [Results] We found that GPI improved the viability of C2C12 cells. In the in vivo study, the exercise-treated mice group showed upregulated GPI expression in skeletal muscle. Based on the in vitro study results, we speculated that expression level of GPI in skeletal muscle might be associated with muscle function. We analyzed the association between GPI expression level and the grip strength of the all mice group. The mice group’s grip strengths were upregulated after 2 weeks of treadmill exercise, and GPI expression level positively correlated with the grip strength. [Conclusion] These results suggested that the exercise- induced GPI expression in skeletal muscle might have a positive effect on skeletal muscle function.

Accumulation of senescent cells leads to aging related phenotypes in various organs. Sarcopenia is a frequently observed aging-related disease, which is associated with the loss of muscle mass and functional disability. Physical activity represents the most critical treatment method for preventing decreased muscle size, mass and strength. However, the underlying mechanism as to how physical activity provides this beneficial effect on muscle function has not yet been fully understood. In particular, one unresolved question about aging is how the boost in catabolism induced by aerobic exercise affects skeletal muscle atrophy and other senescence phenotypes. Here we show that pre-activation of AMPK with the AMPK activator, AICAR can mitigate the diminished cellular viability of skeletal muscle cells induced by doxorubicin, which accelerates senescence through free radical production. Pre-incubation for 3 h with AICAR decreased doxorubicin-induced phosphorylation of AMPK in a differentiated skeletal muscle cell line. Accordingly, cellular viability of skeletal muscle cells was recovered in the cells pre-treated with AICAR then administered doxorubicin as compared to that of doxorubicin-only treatment. In accordance with the results of cellular experiments, we verified that 4 weeks of treadmill exercise decreased the senescence marker, p16 and p21 in 19-month-old mice compared to sedentary mice. In this study, we provide new evidence that prior activation of AMPK can reduce doxorubicin induced cell senescence phenotypes. The evidence in this paper suggest that aerobic exercise-activated catabolism in the skeletal muscle may prevent cellular senescence, partially through the cell cycle regulation.

PURPOSE The purpose of this study was to examine the infancy changes of metabolic gene expression level in mouse gastrocnemius muscle after after 1 hour acute treadmill exercise. METHODS C57BL/6 mouse were randomly divided into control (n=5) and 1 hour acute treadmill exercise intervention group (n=5). After the intervention, we extracted total mRNA from the mouse gastrocnemius following the whole set of genes were analyzed by microarray using Affymetrix GeneChip Clariom_S_Mouse Array. The significantly meaningful differentially expressed genes (DEGs) were extracted and compared with the bioinformatic tools. Further analysis of DEGs were conducted using Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway and gene ontology database. Significant cut-off by Fold change and LPE test were used as statistical test. RESULTS Fifty six upregulated and 65 downregulated DEGs were identified after the 1 hour of treadmill exercise. Nr4a3, Nr4a2, Btg2, Otud1, Sik1, Thbs1, Irs2 were included in the top 10 upregulated genes and Ube2l6, Scd3 were one of the most downregulated genes in the DEGs. In gene ontology analysis, metabolic process (>70 counts), organic substance metabolic process (>70) and cellular metabolic process (>60) were in the top 10 terms in the category of biological process. In the molecular function category, binding and protein binding term had more than 80s and 60s count genes each and they were statistically significant (p≤.001) with located on first and second place. In KEGG pathway enrichment analysis, many DEGs were related to MAPK signaling pathway, AMPK signaling pathway, Metabolic pathway, Protein processing in endoplasmic reticulum and Glycolysis/gluconeogenesis pathway. Also, several DEGs (HK1, HK2, Adh1 etc.) related to metabolism were statistically significant. CONCLUSIONS One hour acute treadmill exercise could sufficiently change some energy metabolism and adaptation related genes in mouse gastrocnemius muscle. In this microarray analysis, Nr4a3, Nr4a2, Btg2, Otud1, Sik1, Thbs1, Irs2, Ube2l6, and Scd3 were newly categorized as DEGs in respect of energy metabolism.

Previous studies have identified that a behavior can occur through the strongest predictor intention, but there is a gap between intention and behavior. Dopamine receptor D2 (DRD2) is known to account for a variance in sporting behaviors in human and animal subjects. However, the relationship between DRD2 and sport participation has been poorly studied, and the limited available reports are inconsistent. The present study was performed to examine the impact of DRD2 on sport participation among Korean university students based on the integrated behavioral model (IBM). Data were collected from enrolled university students in Seoul (N = 45). Participants answered survey questions first, and then they gave investigators their hair to provide DNA information (i.e., the A1 allele of DRD2). DRD2 had a significant effect on sport participation, but only in male students. Male students who carried the A1 allele of DRD2 significantly participated in 105.10 min more sporting activities than male students who did not. Moreover, the effect of intention on sport participation was significantly decreased when considering DRD2. Despite the small sample size, the results of this study could be a preliminary case for a larger study and indicate the direction of future research. Our results suggest that DRD2 may have played an important role as the “actual skill” shown in the IBM.

Although several evidence has suggested the impact of exercise on the prevention of aging phenotypes, few studies have been conducted on the mechanism by which exercise alters the immune-cell profile, thereby improving metabolism in senile obesity. In this study, we confirmed that 4-week treadmill exercise sufficiently improved metabolic function, including increased lean mass and decreased fat mass, in 88-week-old mice. The expression level of the senescence marker p16 in the white adipose tissue (WAT) was decreased after 4-weeks of exercise. Exercise induced changes in the profiles of immune-cell subsets, including natural killer (NK) cells, central memory CD8+ T cells, eosinophils, and neutrophils, in the stromal vascular fraction of WAT. In addition, it has been shown through transcriptome analysis of WAT that exercise can activate pathways involved in the interaction between WAT and immune cells, in particular NK cells, in aged mice. These results suggest that exercise has a profound effect on changes in immune-cell distribution and senescent-cell scavenging in WAT of aged mice, eventually affecting overall energy metabolism toward a more youthful state.

Daily physical exercise is an essential part of life and is required for remaining healthy; it enhances therapeutic efficacy in the elderly and prevents age-related diseases associated with lipid profile alterations, such as cardiovascular disease, diabetes mellitus, and dementia. To more efficiently analyse the lipid profiles and unveil the effect of exercise in aged mice, we optimized our study by examining the effects of using ionization modifiers in the mobile phase and in-source fragmentation of lysophospholipids on the simultaneous analysis of fatty acids (FAs) including hydroxyl fatty acids, glycerophospholipids, sphingolipids, and glycerolipids using nanoflow ultrahigh performance liquid chromatography-electrospray ionization-tandem mass spectrometry. We applied the optimization to investigate the lipidomic plasma alterations in young (7 weeks old) and aged (84 weeks old) mice (C57BL/6) subjected to treadmill exercise. Of the 390 identified lipid species, 159 were quantified to investigate ageing-related lipid species responsive to physical exercise. In particular, circulating lysophosphatidylcholine and lysophosphatidylethanolamine levels showed a significant decrease, and lysophosphatidic acid showed a simultaneous increase with ageing. The saturated FA (16:0 and 18:0) increased with ageing while the unsaturated FA 22:6 decreased. Dihydroxy fatty acid (18:1_2OH) showed an exercise-induced recovery against ageing. It is notable that the levels of five triacylglycerol species significantly increased by as much as threefold with ageing, but their levels largely recovered to those observed in the young mice after exercise. These findings can help understand the influence of ageing on lipid perturbation and the role of physical exercise on lipidomic recovery in response to ageing-associated loss of physical status. Graphical abstract.

Background: Although previous studies suggest that dopamine receptor genes partially affect physical activity-related behaviours, all of these studies were cross-sectional studies that examined the effects of dopamine receptor genes on physical activity-related behaviours at some point in time. Therefore, the nature and extent of this relationship across the lifespan are even more uncertain. Aim: The purpose of this study is to examine the effects of dopamine receptor genes (i.e. DRD2, DRD4 and DRD5) on sport participation trajectories from adolescence to young adulthood. Subjects and methods: This study used the National Longitudinal Study of Adolescent Health data (wave 1–4). Group-based trajectory modelling was used to investigate the effect of dopamine receptor genes on the probability of being in each sport participation trajectory group. Results: A three-group model was the best fitting model for men whereas a two-group model was the best fitting model for women. The more participants possess the A1 allele of the DRD2, the less likely they are to be in the “high-decreasing group” rather than the “low-stable group” in both men and women. In male participants, the more participants carry the A1 allele of the DRD2, the more likely they are to be in the “high-stable group” rather than the “high-decreasing group” (coefficient = 0.206, p Conclusions: These results can contribute to the literature by providing important information on the effects of dopamine receptor genes on sport participation trajectories from adolescence through young adulthood.

Recent research suggests that the brain has capable of remarkable plasticity and physical activity can enhance it. In this editorial letter, we summarize the role of hip­pocampal plasticity in brain functions. Furthermore, we briefly sketched the factors and mechanisms of motion that influence brain plasticity. We conclude that physical activity can be an encouraging intervention for brain restoration through neuronal plasticity. At the same time, we suggest that a mechanistic understanding of the beneficial effects of exercise should be accompa­nied in future studies.

OBJECTIVES: Glycemic control is essential for preventing severe complications in patients with diabetes mellitus. This study investigated the association between grip strength and glycemic control in Korean adults with type 2 diabetes mellitus.METHODS: From the Korea National Health and Nutrition Examination Survey, 2,498 participants aged over 19 years that patients with diabetes mellitus who did not have a history of cardiovascular disease or cancer were selected for analysis. Grip strength was assessed using a handheld dynamometer and was represented as age-specific and sex-specific tertiles. Multivariable logistic regression was performed to calculate the odds ratio (OR) and 95% confidence interval (CI) of glycemic control according to the grip strength tertiles.RESULTS: A significantly lower probability (OR, 0.67; 95% CI, 0.47 to 0.97) for glycemic control was found in the lowest tertile of grip strength compared to the highest tertile. Furthermore, a subgroup analysis by sex only found significant associations between grip strength and glycemic control in males.CONCLUSIONS: Lower grip strength was associated with poor glycemic control in patients with diabetes mellitus, especially in males. However, further studies are needed to confirm the causal relationship between grip strength and glycemic control.

There is increasing evidence that an active lifestyle benefits both body and brain. However, not everyone may be able to exercise due to disease, injury or aging-related frailty. Identification of cellular targets activated by physical activity may lead to the development of new compounds that can, to some extent, mimic systemic and central effects of exercise. This review will focus on factors relevant to energy metabolism in muscle, such as the 5’ adenosine monophosphate-activated protein kinase (AMPK) - sirtuin (SIRT1) - Peroxisome proliferator-activated receptor γ coactivator-1α (PGC-1α) pathway, and the molecules affecting it. In particular, putative exercise-mimetics such as AICAR, metformin, and GW501516 will be discussed. Moreover, plant-derived polyphenols such as resveratrol and (-)epicatechin, with exercise-like effects on the body and brain will be evaluated.

Purpose Exercise has been prescribed to the elderly based on its effect on increasing muscle strength and protein synthesis that prevent sense of balance and/or cognitive functions. However, a few molecular mechanism researches has been conducted on how the vestibular organs, cerebellum, and hippocampus, which are responsible for the deterioration and balance of spatial learning memory due to aging, are affected by exercise. Methods The 9-week old and 84-week old C57Bl/6 were assigned randomly to Young-Control (YC), Young-Exercise (YE), Old-Control (OC) and Old-Exercise (OE) groups for 4 -week treadmill running. A Rotarod test was used to evaluate motor coordination function. Moreover, a high-throughput whole transcript expression RNA array approach was applied to the cerebellum of aged mice to explain the novel molecular mechanism of beneficial effect of exercise. Results As results, the motor coordination function was significantly improved in exercise-aged mice. The RNA sequencing analysis showed that the expression of cerebellar genes was significantly changed by aging rather than exercise. Especially, Cers1 was up-regulated in sedentary aged mice and down-regulated in exercise aged mice. Fumonisin B1, inhibition of Cers1, mitigates neuronal cell death induced by doxorubicin. Conclusion These results provide unraveling specific transcripts and understanding of the exercise-related cerebellum transcriptome in aged mice. Well-designed exercise program might prevent the motor coordination defect in aged model, which development of the exercise protocol for elderly population based on these markers.

Physical activity has profound effects on neuronal progenitor cell growth, differentiation, and integration, but the mechanism for these effects is still ambiguous. Using a mouse model, we investigated the effects of two weeks of treadmill running on the dynamics of the size distribution and miRNA profiles of serum extracellular derivatives (EDs) using particle-sizing analysis and small RNA sequencing. We found that an increased average diameter of EDs in the running group compared with the sedentary group (p

Background : Autophagy maintains metabolic homeostasis of muscles, and its impairment may cause muscle dysfunction. Exercise can improve muscle dysfunction induced by long-term high-fat diet. This study aimed to explore the association of autophagy with impaired muscle dysfunction in obese conditions and investigate its relationship with exercise-induced muscle function improvement. Methods : Male C57BL/6 mice (n=24) were randomly assigned to four groups: low-fat diet+plain water feeding sedentary (CON) group, low-fat diet+plain water feeding exercise (CON+EX) group, high-fat high-sucrose (HFHS) diet-fed sedentary group, and HFHS diet-fed exercise (HFHS+EX) group, and subjected to a single bout of exhaustive exercise. Results : HFHS diet resulted in shorter hanging time, reduced grip force, and lower exhaustion time and distance, and decreased lean mass per body weight. Moreover, in the soleus, which is chosen as a representative red (oxidative) muscle, LC3II/LC3I ratio, P62, and Bnip3 levels were altered following the HFHS diet, and were negatively correlated with muscle performance parameters; exercise significantly decreased the LC3II/LC3 ratio while P62 increased with HFHS diet. Autophagy-related protein changes were not found in the white (glycolytic) gastrocnemius. Conclusion : The study revealed that 20-week HFHS diet causes a significant increase in body weight and fat mass, along with a decrease in muscle function. Autophagy-related LC3 and P62 protein expression was negatively correlated with muscle function, and they were reduced when a single bout of exercise stimulated the soleus of obese mice. However, no change of autophagy-related proteins was seen in the gastrocnemius.

[Purpose] Despite numerous studies, the mechanisms underlying the effects of exercise on brain function are not yet fully understood. Adult hippocampal neurogenesis is one of the most well-known effects of exercise on the brain, but its physiological roles during exercise are still ambiguous, mostly due to the difference in the structure and composition of each part of the hippocampus. [Methods] In this study, we analyzed exercise-induced changes in gene expression in the subgranular zone (SGZ) and granular cell layer (GCL) of the hippocampus. [Results] Surprisingly, only about 10% of changes were common to both areas. Tollip expression, which is altered in the SGZ and in Engrailed-2 mutant mice following exercise, did not change in the GCL. Tollip levels were not changed in the whole hippocampus after two weeks of treadmill exercise, but immunofluorescence analysis showed that Tollip and Ki-67 co-localize in the hippocampal dentate gyrus . Through siRNA knockdown experiments, we found that levels of DCX and cellular survival rates were decreased in Tollip-deficient Neuro2A cells. [Conclusion] Taken together, these results suggest a role for Tollip in mediating the beneficial effects of exercise, probably affecting cellular health in the SGZ of the hippocampus.

Tight junction protein is representative regulator of gut permeability. Also, it has been noted for controlling inflammatory responses through tight junction. Therefore, in this study, we examined that whether tight junction protein is changed in aged mice, and to further, confirmed the effect of treadmill exercise on the tight junction protein. In in vitro study, doxorubicin that induces cell senescence was treated to Caco2 cells (colon cell) to mimic aging effect. After that, 5-aminoimidazole-4-carboxamide-1-β-D-ribofuranoside (AICAR), exercise mimic chemical that stimulates AMPK level, was also administered to Caco2 cells. In animal study, 2 months and 21 months C57BL/6 J mouse were treated with treadmill exercise for 4 weeks (YE = 5, OE = 5). Then, the tight junction protein expression level was examined by western blot. Also, serum lipopolysaccharide (LPS) and zonulin level were analyzed to identify gut permeability. In vitro studies showed that doxorubicin downregulates tight junction protein expression levels in Caco2 cell, and also AICAR treatment upregulates tight junction protein expression levels. In animal study, 4 weeks treadmill exercise upregulated claudin-1 (p 0.05) and occludin (p 0.01) protein expression level in 21 months old mice. Also, zonula occluden-1 (ZO-1) protein expression level was not significant difference among all mice group. In addition, old mice group had higher level of serum LPS compared to young mice group, but the level was downregulated in both 2 months and 21 months mice group after four weeks of treadmill exercise. Zonulin, which is known as degrading tight junction protein, is not significantly changed by both age and exercise. This study compared that tight junction protein expression level in old mice compared to its level in young mice, and also clarified that the effect of treadmill exercise on tight junction protein in both young and old mice.

Peripheral processes that mediate beneficial effects of exercise on the brain remain sparsely explored. Here, we show that a muscle secretory factor, cathepsin B (CTSB) protein, is important for the cognitive and neurogenic benefits of running. Proteomic analysis revealed elevated levels of CTSB in conditioned medium derived from skeletal muscle cell cultures treated with AMP-kinase agonist AICAR. Consistently, running increased CTSB levels in mouse gastrocnemius muscle and plasma. Furthermore, recombinant CTSB application enhanced expression of brain-derived neurotrophic factor (BDNF) and doublecortin (DCX) in adult hippocampal progenitor cells through a mechanism dependent on the multifunctional protein P11. In vivo, in CTSB knockout (KO) mice, running did not enhance adult hippocampal neurogenesis and spatial memory function. Interestingly, in Rhesus monkeys and humans, treadmill exercise elevated CTSB in plasma. In humans, changes in CTSB levels correlated with fitness and hippocampus-dependent memory function. Our findings suggest CTSB as a mediator of effects of exercise on cognition.

Exercise has profound benefits for brain function in animals and humans. In rodents, voluntary wheel running increases the production of new neurons and upregulates neurotrophin levels in the hippocampus, as well as improving synaptic plasticity, memory function and mood. The underlying cellular mechanisms, however, remain unresolved. Recent research indicates that peripheral organs such as skeletal muscle, liver and adipose tissue secrete factors during physical activity that may influence neuronal function. Here we used an in vitro cell assay and proteomic analysis to investigate the effects of proteins secreted from skeletal muscle cells on adult hippocampal neural progenitor cell (aNPC) differentiation. We also sought to identify the relevant molecules driving these effects. Specifically, we treated rat L6 skeletal muscle cells with the AMP-kinase (AMPK) agonist 5-aminoimidazole-4-carboxamide-1-β-d-ribofuranoside (AICAR) or vehicle (distilled water). We then collected the conditioned media (CM) and fractionated it using high-performance liquid chromatography (HPLC). Treatment of aNPCs with a specific fraction of the AICAR-CM upregulated expression of doublecortin (DCX) and Tuj1, markers of immature neurons. Proteomic analysis of this fraction identified proteins known to be involved in energy metabolism, cell migration, adhesion and neurogenesis. Culturing differentiating aNPCs in the presence of one of the factors, glycolytic enzyme glucose-6-phosphate isomerase (GPI), or AICAR-CM, increased the proportion of neuronal (Tuj1+) and astrocytic, glial fibrillary acidic protein (GFAP+) cells. Our study provides further evidence that proteins secreted from skeletal muscle cells may serve as a critical communication link to the brain through factors that enhance neural differentiation.

Apolipoprotein a1, which is a major lipoprotein component of high-density lipoprotein (HDL), was reported to decrease plasma glucose in type 2 diabetes. Although recent studies also have shown that apolipoprotein a1 is involved in triglyceride (TG) metabolism, the mechanisms by which apolipoprotein a1 modulates TG levels remain largely unexplored. Here we demonstrated that apolipoprotein a1 increased mitochondrial DNA and mitochondria contents through sustained AMPK activation in myotubes. This resulted in enhanced fatty acid oxidation and attenuation of free fatty acid-induced insulin resistance features in skeletal muscle. The increment of mitochondria was mediated through induction of transcription factors, such as peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC-1α) and nuclear transcription factor 1 (NRF-1). The inhibition of AMPK by a pharmacological agent inhibited the induction of mitochondrial biogenesis. Increase of AMPK phosphorylation by apolipoprotein a1 occurs through activation of upstream kinase LKB1. Finally, we confirmed that scavenger receptor Class B, type 1 (SR-B1) is an important receptor for apolipoprotein a1 in stimulating AMPK pathway and mitochondrial biogenesis. Our study suggests that apolipoprotein a1 can alleviate obesity related metabolic disease by inducing AMPK dependent mitochondrial biogenesis.

Myogenesis, the formation and regeneration of muscular tissue, is a fundamental factor in embryonic development. N-methyl d-aspartate (NMDA) receptor synaptonuclear signaling and neuronal migration factor (Nsmf) mediates NMDA receptor endocytosis in GnRH neuronal cells. NMDA receptor is involved in myoblast differentiation by regulating Ca2 + dependent fusion of myocytes. In this study, we investigated the role of Nsmf in myoblast proliferation and differentiation. Quantitative-PCR, immunoblotting, and immunohistochemistry results showed that the Nsmf expression levels increased during both the differentiation and proliferation of myocytes. Knockdown of Nsmf in myocytes by siRNA did not affect the myocyte differentiation marker myogenin. However, flow cytometry showed that the proliferation rate of the Nsmf-knockdown cells was reduced compared to the control cells. Therefore, our results indicate that Nsmf is a novel myogenic factor that can enhance myoblast proliferation. Furthermore, Nsmf may be an important therapeutic target in diseases associated with aging, muscular dystrophy, or cachexia.

Physical inactivity can lead to obesity and fat accumulation in various tissues. Critical complications of obesity include type II diabetes and nonalcoholic fatty liver disease (NAFLD). Exercise has been reported to have ameliorating effects on obesity and NAFLD. However, the underlying mechanism is not fully understood. We showed that liver expression of macrophage migration inhibitory factor (MIF) was increased after 4 weeks of treadmill exercise. Phosphorylation of AMP-activated protein kinase and acetyl-CoA carboxylase in human hepatocyte cell lines was enhanced after MIF treatment. These responses were accompanied by increases in lipid oxidation. Moreover, inhibition of either AMPK or cluster of differentiation 74 resulted in inhibition of MIF-induced lipid oxidation. Furthermore, the administration of MIF to a human hepatocyte cell line and mice liver reduced liver X receptor agonist-induced lipid accumulation. Taken together, these results indicate that MIF is highly expressed in the liver during physical exercise and may prevent hepatic steatosis by activating the AMPK pathway.

Dysregulation of O-GlcNAc modification catalyzed by O-GlcNAc transferase (OGT) and O-GlcNAcase (OGA) contributes to the etiology of chronic diseases of aging, including cancer, cardiovascular disease, type 2 diabetes, and Alzheimer's disease. Here we found that natural aging in wild-type mice was marked by a decrease in OGA and OGT protein levels and an increase in O-GlcNAcylation in various tissues. Genetic disruption of OGA resulted in constitutively elevated O-GlcNAcylation in embryos and led to neonatal lethality with developmental delay. Importantly, we observed that serum-stimulated cell cycle entry induced increased O-GlcNAcylation and decreased its level after release from G2/M arrest, indicating that O-GlcNAc cycling by OGT and OGA is required for precise cell cycle control. Constitutively, elevated O-GlcNAcylation by OGA disruption impaired cell proliferation and resulted in mitotic defects with downregulation of mitotic regulators. OGA loss led to mitotic defects including cytokinesis failure and binucleation, increased lagging chromosomes, and micronuclei formation. These findings suggest an important role for O-GlcNAc cycling by OGA in embryonic development and the regulation of the maintenance of genomic stability linked to the aging process.

Depression is associated with elevated kynurenine levels, a tryptophan metabolite generated under stress and inflammatory conditions. Agudelo et al. (2014) now reveal how PGC-1α1 overexpression in muscle mimics anti-depressant effects of exercise by promoting kynurenine aminotransferase expression, likely preventing kynurenine from crossing the blood brain barrier to disrupt neural plasticity.

Accumulating research in rodents and humans indicates that exercise benefits brain function and may prevent or delay onset of neurodegenerative conditions. In particular, exercise modifies the structure and function of the hippocampus, a brain area important for learning and memory. This review addresses the central and peripheral mechanisms underlying the beneficial effects of exercise on the hippocampus. We focus on running-induced changes in adult hippocampal neurogenesis, neural circuitry, neurotrophins, synaptic plasticity, neurotransmitters, and vasculature. The role of peripheral factors in hippocampal plasticity is also highlighted. We discuss recent evidence that systemic factors released from peripheral organs such as muscle (myokines), liver (hepatokines), and adipose tissue (adipokines) during exercise contribute to hippocampal neurotrophin and neurogenesis levels, and memory function. A comprehensive understanding of the body–brain axis is needed to elucidate how exercise improves hippocampal plasticity and cognition.

// Yong Ryoul Yang 1 , Dae Hyun Kim 1 , Young-Kyo Seo 1 , Dohyun Park 2 , Hyun-Jun Jang 1,2 , Soo Youn Choi 1 , Yong Hwa Lee 1 , Gyun Hui Lee 1 , Kazuki Nakajima 3 , Naoyuki Taniguchi 3 , Jung-Min Kim 1 , Eun-Jeong Choi 2 , Hyo Youl Moon 1 , Il Shin Kim 1 , Jang Hyun Choi 1 , Ho Lee 4 , Sung Ho Ryu 2 , Lucio Cocco 5 and Pann-Ghill Suh 1 1 School of Life Sciences, Ulsan National Institute of Science and Technology, Ulsan, Republic of Korea 2 Division of Molecular and Life Science, Pohang University of Science and Technology, Pohang, Kyungbuk, Republic of Korea 3 Disease Glycomics Team, Systems Glycobiology Research Group, RIKENMax Planck Joint Research Center, Global Research Cluster, RIKEN, Hirosawa, Wako, Saitama, Japan 4 Cancer Experimental Resources Branch, National Cancer Center, Goyang-si, Gyeonggi-do, Republic of Korea 5 Cellular Signaling Laboratory, Department of Biomedical and Neuromotor Sciences, University of Bologna, Bologna, Italy Correspondence to: Pann-Ghill Suh, email: // Keywords : O-GlcNAcylation, O-GlcNAcase, colitis, colitis-associated cancer Received : May 06, 2014 Accepted : March 11, 2015 Published : March 30, 2015 Abstract O-GlcNAcylation is a reversible post-translational modification. O-GlcNAc addition and removal is catalyzed by O-GlcNAc transferase (OGT) and O-GlcNAcase (OGA), respectively. More recent evidence indicates that regulation of O-GlcNAcylation is important for inflammatory diseases and tumorigenesis. In this study, we revealed that O-GlcNAcylation was increased in the colonic tissues of dextran sodium sulfate (DSS)-induced colitis and azoxymethane (AOM)/DSS-induced colitis-associated cancer (CAC) animal models. Moreover, the O-GlcNAcylation level was elevated in human CAC tissues compared with matched normal counterparts. To investigate the functional role of O-GlcNAcylation in colitis, we used OGA heterozygote mice, which have an increased level of O-GlcNAcylation. OGA +/- mice have higher susceptibility to DSS-induced colitis than OGA +/+ mice. OGA +/- mice exhibited a higher incidence of colon tumors than OGA +/+ mice. In molecular studies, elevated O-GlcNAc levels were shown to enhance the activation of NF-κB signaling through increasing the binding of RelA/p65 to its target promoters. We also found that Thr-322 and Thr352 in the p65-O-GlcNAcylation sites are critical for p65 promoter binding. These results suggest that the elevated O-GlcNAcylation level in colonic tissues contributes to the development of colitis and CAC by disrupting regulation of NF-κB-dependent transcriptional activity.

AMP-activated protein kinase has been described as a key signaling protein that can regulate energy homeostasis. Here, we aimed to characterize novel AMP-activated kinase (AMPK)-activating compounds that have a much lower effective concentration than metformin. As a result, emodin, a natural anthraquinone derivative, was shown to stimulate AMPK activity in skeletal muscle and liver cells. Emodin enhanced GLUT4 translocation and [14C]glucose uptake into the myotube in an AMPK-dependent manner. Also, emodin inhibited glucose production by suppressing the expression of key gluconeogenic genes, such as phosphoenolpyruvate carboxykinase and glucose-6-phosphatase, in hepatocytes. Furthermore, we found that emodin can activate AMPK by inhibiting mitochondrial respiratory complex I activity, leading to increased reactive oxygen species and Ca2+/calmodulin-dependent protein kinase kinase activity. Finally, we confirmed that a single dose administration of emodin significantly decreased the fasting plasma glucose levels and improved glucose tolerance in C57Bl/6J mice. Increased insulin sensitivity was also confirmed after daily injection of emodin for 8 days using an insulin tolerance test and insulin-stimulated PI3K phosphorylation in wild type and high fat diet-induced diabetic mouse models. Our study suggests that emodin regulates glucose homeostasis in vivo by AMPK activation and that this may represent a novel therapeutic principle in the treatment of type 2 diabetic models. Background: AMPK activation improves glucose tolerance and insulin sensitivity. Results: Emodin increases glucose uptake in skeletal muscle and lowers blood glucose levels via AMPK activation. Conclusion: Administration of emodin leads to increased glucose tolerance and insulin sensitivity in vivo. Significance: Our results highlight the potential value of emodin as a drug for the treatment of diabetes.

Voluntary exercise is known to have an antidepressant effect. However, the underlying mechanism for this antidepressant action of exercise remains unclear, and little progress has been made in identifying genes that are directly involved. We have identified macrophage migration inhibitory factor (MIF) by analyzing existing mRNA microarray data and confirmed the augmented expression of selected genes under two experimental conditions: voluntary exercise and electroconvulsive seizure. A proinflammatory cytokine, MIF is expressed in the central nervous system and involved in innate and adaptive immune responses. A recent study reported that MIF is involved in antidepressant-induced hippocampal neurogenesis, but the mechanism remains elusive. In our data, tryptophan hydroxylase 2 ( Tph2 ) and brain-derived neurotrophic factor ( Bdnf ) expression were induced after MIF treatment in vitro, as well as during both exercise and electroconvulsive seizure in vivo. This increment of Tph2 was accompanied by increases in the levels of total serotonin in vitro. Moreover, the MIF receptor CD74 and the ERK1/2 pathway mediate the MIF-induced Tph2 and Bdnf gene expression as well as serotonin content. Experiments in Mif −/− mice revealed depression-like behaviors and a blunted antidepressant effect of exercise, as reflected by changes in Tph2 and Bdnf expression in the forced swim test. In addition, administration of recombinant MIF protein produced antidepressant-like behavior in rats in the forced swim test. Taken together, these results suggest a role of MIF in mediating the antidepressant action of exercise, probably by enhancing serotonin neurotransmission and neurotrophic factor-induced neurogenesis in the brain.

For a long time, athletes have used androgenic anabolic steroids (AASs) in an inappropriate and veiled manner with the aim of improving exercise performance or for cosmetic purposes. Abuse of AASs triggers adverse effects such as hepatocarcinogenesis, heart attacks, and aggressive behavior. However, AAS-induced toxicity is not completely understood at the molecular level. In the present study, we showed, by performing a dioxin response element (DRE)-luciferase reporter gene assay, that tetrahydrogestrinone (THG), a popular and potent androgen receptor agonist, has dioxin-like effects. In addition, we showed that THG increased cytochrome P-450 1A1 (CYP1A1) mRNA and protein levels, and enzyme activity. The gene encoding CYP1A1 is involved in phase 1 xenobiotic metabolism and a target gene of the aryl hydrocarbon receptor (AhR). Using the AhR antagonist CH-223191, we also examined whether the effects of THG on DRE activation depended on AhR. Our results suggest that synthetic anabolic steroids may have dioxin-like side effects that can disturb endocrine systems and may cause other side effects including cancer through AhR.

Dysregulation of O-GlcNAc modification catalyzed by O-GlcNAc transferase (OGT) and O-GlcNAcase (OGA) contributes to the etiology of chronic diseases of aging, including cancer, cardiovascular disease, type 2 diabetes, and Alzheimer's disease. Here we found that natural aging in wild-type mice was marked by a decrease in OGA and OGT protein levels and an increase in O-GlcNAcylation in various tissues. Genetic disruption of OGA resulted in constitutively elevated O-GlcNAcylation in embryos and led to neonatal lethality with developmental delay. Importantly, we observed that serum-stimulated cell cycle entry induced increased O-GlcNAcylation and decreased its level after release from G2/M arrest, indicating that O-GlcNAc cycling by OGT and OGA is required for precise cell cycle control. Constitutively, elevated O-GlcNAcylation by OGA disruption impaired cell proliferation and resulted in mitotic defects with downregulation of mitotic regulators. OGA loss led to mitotic defects including cytokinesis failure and binucleation, increased lagging chromosomes, and micronuclei formation. These findings suggest an important role for O-GlcNAc cycling by OGA in embryonic development and the regulation of the maintenance of genomic stability linked to the aging process.