Effect of exercise-induced Neutrophil maturation on skeletal muscle repair in vitro.

Neutrophils as first line defender initiate a cascade of healing process immediately after muscle injury. At muscle injury site, neutrophils remove damaged muscle fibers and recruit other immune cells and these functions show in mature neutrophils. In the previous study, physical exercise can mediate neutrophils' functional changes such as phagocytosis and chemotaxis, though there is no research on how exercise-induced neutrophils contribute the muscle regeneration. In this present study, we investigated the maturation of neutrophils after 4 weeks of mouse treadmill exercise and assessed wound healing assay to evaluate whether treatment with exercise-activated neutrophils is effective for skeletal muscle repair in vitro. In the exercise group, significantly higher mRNA levels of maturation markers compared to the sedentary group and exercise-activated neutrophils improved wound healing of mouse muscle cells. To confirm at the human cell level, based on the well-known fact that exercise increases circulating cortisol levels, neutrophil-like cells were treated with dexamethasone (dHL60 + dex) as exercise mimetics. dHL60 + dex had significantly higher mRNA levels of neutrophil maturation marker and improved wound healing of human skeletal muscle cells compared to the control. These findings suggest that exercise affects neutrophil maturation and that exercise-induced neutrophils contribute to skeletal muscle repair in vitro.

The effect of voluntary exercise on light cycle stress-induced metabolic resistance.

PURPOSE: Disruption of circadian genes affects metabolic homeostasis. Regular exercise programs prevent metabolic dysfunction and alter circadian gene expression In this study, we investigated whether exercise affects light stress-induced circadian rhythm derangement and metabolic resistance. METHODS: A circadian rhythm derangement mouse model was designed by extending the light exposure by two hours (14 L/10 D) for three weeks. Nine-weekold male mice were single-caged and divided into four groups: sedentary groups with or without light stress, and voluntary wheel-trained groups with or without light stress. In addition, differentiated myotubes were cultured in the presence of dexamethasone with or without 5-aminoimidazole-4-carboxamide-1-beta-4-ribofuranoside (AICAR). The comprehensive laboratory animal monitoring system was used to analyze the metabolic changes in mice. Moreover, reverse transcription-polymerase chain reaction (RT-PCR) was used to quantify the mRNA expression levels of circadian genes in animal and cell culture models. RESULTS: Three weeks of light stress reduced the running distance and increased the weight of mice. In addition, VO2 consumption and heat production were increased during the night cycle under non-stress conditions but not under stress conditions. PCR analysis revealed that exercise and stress altered the expression levels of circadian genes in the hypothalamus and quadriceps muscles. mRNA expression levels of period circadian regulator 1 were downregulated in the quadriceps muscles of the stressed sedentary group compared to that in muscles of the non-stressed sedentary group. Furthermore, differentiated myotube cells cultured in the presence of dexamethasone, with or without AICAR, showed distinct oscillation patterns at various time points. CONCLUSION: Our study demonstrates that exercise partially prevents metabolic disruption by regulating the circadian gene expression in skeletal muscles.

Distinct effect of exercise modes on mood-related behavior in mice.

Exercise can afford several benefits to combat mood disorders in both rodents and humans. Engagement in various physical activities upregulates levels of neurotrophic factors in several brain regions and improves mental health. However, the type of exercise that regulates mood and the underlying mechanisms in the brain remain elusive. Herein, we performed two distinct types of exercise and RNA sequencing analyses to investigate the effect of exercise on mood-related behaviors and explain the distinct patterns of gene expression. Specifically, resistance exercise exhibited reduced immobility time in the forced swim test when compared with both no exercise and treadmill exercise (in the aerobic training [AT] group). Interestingly, anxiety-like behaviors in the open field and nest-building tests were ameliorated in the AT group when compared with those in the control group; however, this was not observed in the RT group. To elucidate the mechanism underlying these different behavioral changes caused by distinct exercise types, we examined the shift in the gene expression pattern in the hippocampus, a brain region that plays a critical role in regulating mood. We discovered that 38 and 40 genes were altered in the AT and RT groups, respectively, compared with the control group. Both exercises regulated 16 common genes. Compared with the control group, mitogen-activated protein kinase (MAPK) was enriched in the AT group and phosphatidylinositol-3-kinase (PI3K)/AKT and neurotrophin signaling pathways were enriched in the RT group, as determined by bioinformatics pathway analysis. PCR results revealed that Cebpß expression was increased in AT group, and Dcx expression was upregulated in both groups. Our findings indicate that different exercise types may exert substantially distinct effects on mood-like behaviors. Accordingly, appropriate types of exercise can be undertaken based on the mood disorder to be regulated.

Potential involvement of neutrophils on exercise effects in breast cancer malignancy.

PURPOSE: This review aimed to comprehensively explore and elucidate multifaceted neutrophils in breast cancer, particularly in the context of physical activity. Neutrophils play a critical role in the tumor microenvironment and systemic immune response, despite their short half-life and terminal differentiation. Through a thorough review of research related to changes in immunity in breast cancer during exercise, this review aims to provide comprehensive insights into immunological changes, especially focusing on neutrophils. Recognizing that much of the existing research has predominantly focused on T cells and nature killer (NK) cells, our review seeks to shift the spotlight toward understanding how exercise affects neutrophils, a less-explored but critical immune response component in breast cancer. METHODS: This study involved an extensive review of the literature (from 2000 to 2023) using the PubMed, Science Direct, and Google Scholar databases. The keywords chosen for the searches were "immune cells and exercise," "exercise and breast cancer," "tumor microenvironment and neutrophils," and "neutrophils and exercise and breast cancers." RESULTS: Neutrophils in the tumor microenvironment can exhibit distinct phenotypes and functions. These differences have yielded conflicting results regarding tumor progression. Exercise plays a positive role in breast cancer and alters the immune system. Physical activity can quantitatively and functionally regulate neutrophils under various conditions such as metabolic disruption or senescence. CONCLUSION: This short communication outlines exercise-induced neutrophil diversification and its role in breast cancer progression, both within and systemically within the tumor microenvironment. Exercise may provide benefits through the potential neutrophil involvement in breast cancer.

Effects of lifelong spontaneous exercise on skeletal muscle and angiogenesis in super-aged mice.

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.

Urinary extracellular vesicle as a potential biomarker of exercise-induced fatigue in young adult males.

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.

Muscle fiber type-dependence effect of exercise on genomic networks in aged mice models.

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.

Associations between grip strength and glycemic control in type 2 diabetes mellitus: an analysis of data from the 2014-2019 Korea National Health and Nutrition Examination Survey.

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.

Effects of Voluntary Running Wheel Exercise-Induced Extracellular Vesicles on Anxiety.

Anxiety disorders are the most frequently diagnosed psychological condition, associated with serious comorbidities including excessive fear and interference with daily life. Drugs for anxiety disorders are typically prescribed but the side effects include weight gain, nausea, and sleepiness. Exercise is an effective treatment for anxiety. Exercise induces the release of extracellular vesicles (EVs) into the circulation, which transmit signals between organs. However, the effects of exercise-induced EVs on anxiety remain poorly understood. Here, we isolated EVs from the sera of mice that were sedentary or that voluntarily exercised. We characterized the changes in the miRNA profile of serum EVs after 4 weeks of voluntary exercise. miRNA sequencing showed that 82 miRNAs (46 of which were positive and 36 negative regulators) changed after exercise. We selected genes affected by at least two miRNAs. Of these, 27.27% were associated with neurotrophin signaling (9.09% with each of central nervous system neuronal development, cerebral cortical cell migration, and peripheral neuronal development). We also analyzed behavioral changes in mice with 3 weeks of restraint stress-induced anxiety after injection of 20 µg amounts of EVs from exercised or sedentary mice into the left cerebral ventricle. We found that exercise-derived EVs reduced anxiety (compared to a control group) in a nest-building test but found no between-group differences in the rotarod or open field tests. Exercise-derived EVs enhanced the expression of neuroactive ligand-receptor interaction genes. Thus, exercise-derived EVs may exhibit anti-anxiety effects and may be of therapeutic utility.

Effects of Aerobic Exercise Training on Systemic Biomarkers and Cognition in Late Middle-Aged Adults at Risk for Alzheimer's Disease.

Increasing evidence indicates that physical activity and exercise training may delay or prevent the onset of Alzheimer's disease (AD). However, systemic biomarkers that can measure exercise effects on brain function and that link to relevant metabolic responses are lacking. To begin to address this issue, we utilized blood samples of 23 asymptomatic late middle-aged adults, with familial and genetic risk for AD (mean age 65 years old, 50% female) who underwent 26 weeks of supervised treadmill training. Systemic biomarkers implicated in learning and memory, including the myokine Cathepsin B (CTSB), brain-derived neurotrophic factor (BDNF), and klotho, as well as metabolomics were evaluated. Here we show that aerobic exercise training increases plasma CTSB and that changes in CTSB, but not BDNF or klotho, correlate with cognitive performance. BDNF levels decreased with exercise training. Klotho levels were unchanged by training, but closely associated with change in VO2peak. Metabolomic analysis revealed increased levels of polyunsaturated free fatty acids (PUFAs), reductions in ceramides, sphingo- and phospholipids, as well as changes in gut microbiome metabolites and redox homeostasis, with exercise. Multiple metabolites (~30%) correlated with changes in BDNF, but not CSTB or klotho. The positive association between CTSB and cognition, and the modulation of lipid metabolites implicated in dementia, support the beneficial effects of exercise training on brain function. Overall, our analyses indicate metabolic regulation of exercise-induced plasma BDNF changes and provide evidence that CTSB is a marker of cognitive changes in late middle-aged adults at risk for dementia.

The Role of Dopamine Receptor D2 in Bridging the Intention-Behavior Gap in Sport Participation.

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.

Exercise reduces metabolic burden while altering the immune system in aged mice.

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.

Exercise-induced recovery of plasma lipids perturbed by ageing with nanoflow UHPLC-ESI-MS/MS.

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.

Effects of treadmill exercise on the regulation of tight junction proteins in aged mice.

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-ß-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.

Neural maturation enhanced by exercise-induced extracellular derivatives.

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 < 0.05), and 16 miRNAs were significantly altered (p < 0.05) in the running group. Furthermore, functional annotation analysis of differentially expressed miRNA-predicted target genes showed that many of these target genes are involved in the PI3K-Akt pathway. Exercise-induced serum EDs increased Neuro2A cell viability and Akt phosphorylation. We also found that expression levels of neuronal maturation markers such as Microtubule-Associated Protein 2 (MAP2ab) and Neuronal nuclei (NeuN) were increased (p < 0.05, respectively), and that inhibition of the PI3K-Akt pathway by LY294002 pre-treatment ameliorated their expression in Neuro2A cells. Finally, the administration of exercise-induced EDs for 3 days increased the Histone 3 phosphorylation and ß-III tubulin expression in Ink/Arf null neural stem cells and progenitors (NSPCs) under each proliferation and differentiation condition. These results suggest that exercise-induced circulating EDs may mediate neuronal maturation during exercise.

Lactate consumption mediates repeated high-intensity interval exercise-enhanced executive function in adult males.

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 correlated 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 exerciseenhanced 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 improved 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.

Exercise-induced changes of gene expression in the cerebellum of aged mice.

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.

Effect of a Single Bout of Exercise on Autophagy Regulation in Skeletal Muscle of High-Fat High-Sucrose Diet-Fed Mice.

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.

Potential role of exercise-induced glucose-6-phosphate isomerase in skeletal muscle function.

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.

Exercise-induced AMPK activation is involved in delay of skeletal muscle senescence.

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.