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Long-term potentiation (LTP) impairment has been reported in many studies of autistic models. The aim of the present study was to investigate the effects of interval training (IT) and continuous training (CT) exercises on LTP in the hippocampal dentate gyrus (DG) neurons of valproic acid (VPA) rat model of autism. To induce an autism-like model, pregnant rats were injected 500 mg/kg NaVPA (intraperitoneal) on the embryonic day 12.5. IT and CT aerobic exercises started on postnatal day 56 in the offspring. Four weeks after IT and/or CT exercises, the offspring were urethane-anesthetized and placed into a stereotaxic apparatus for surgery, electrode implantation, and field potential recording. In the DG region, excitatory post synaptic potentials (EPSP) slope and population spike (PS) amplitude were measured. Sex differences in LTP were evident for control rats but not for VPA-exposed offspring. LTP was significantly smaller in VPA-exposed male offspring compared with control male rats. In contrast to males, there was no difference between VPA-exposed female offspring and control female rats. Interestingly, we observed a sex difference in the response to exercise between VPA-exposed male and female offspring. CT exercise training (but not IT) increased LTP in VPA-exposed male offspring. Both IT and CT exercise trainings had no effect on intact LTP in VPA-exposed female offspring. Our work suggests that there may be differences in the benefits of exercise interventions based on sex, and CT exercise training could be more beneficial for LTP improvements., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 International Brain Research Organization (IBRO). Published by Elsevier Inc. All rights reserved.)

Microglia activation-induced neuroinflammation is a risk factor for cognitive dysfunction in the hippocampus during the early stages of neurodegenerative diseases. Exercise is an intrinsic remedy that plays a crucial role in enhancing the survival of neurons and reducing neuroinflammation in the brain. Among these theories, alterations in intracellular signaling pathways associated with neuronal growth and inflammation have been emphasized. Based on these observations and recent evidence demonstrating the beneficial effects of exercise on suppressing brain inflammation in the elderly, we examined cellular signaling pathways in the hippocampal formation of D-galactose-induced accelerated aging mice that underwent 8 weeks of treadmill exercise. To accomplish this, we utilized immunohistochemistry and Western blotting to detect the expression of hippocampal proteins, and qPCR to detect the expression of mRNA. We found that aerobic exercise significantly promoted the survival of hippocampal neurons, inhibited microglia activation, and decreased the expression of inflammatory cytokines TNF-α, IL-1α, IL-1β, and chemokines CXCL-1, CXCR-2 in D-galactose model mice. Furthermore, exercise contributed to decreasing the microglia activation marker Iba1-positive cell count and average optical density and increasing the number of NeuN-immunopositive cells. Exercise also reduced RIPK1 and MAP3K5 expression in the hippocampus. Surprisingly, aerobic exercise significantly decreased the expression ratios of p-p65/p65, p-IκBα/IκBα, and p-JNK/JNK. Therefore, we hypothesized that exercise has an anti-inflammatory effect on the hippocampus of mice in the D-galactose-induced aging model. This effect may be attributed to the ability of aerobic exercise to down-regulate the RIPK1-mediated NF-κB and JNK pathways., Competing Interests: Declaration of competing Interest The authors declare no conflict of interest., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Purpose: The present study aimed to investigate the effects of endurance training (ET) in combination with MitoQ supplementation on antioxidant indices and the expression of sesterin-2 (SESN2) as an anti-aging factor and AMPK as an energy sensor in aged male Wistar rats., Methods: Twenty-eight aged Wistar rats (410 ± 15 g, 22 ± 1.5 months old) were randomly divided into four groups (n = 7): Control, ET (eight weeks endurance training on the treadmill), MitoQ (250 μ/L in drinking water), and ET + MitoQ. We measured the protein and gene expression of SESN2 and AMPK in the heart tissue by western blotting and real-time PCR, respectively. In addition, antioxidant indices, superoxide dismutase (SOD), and glutathione peroxidase (GPx) activity, and oxidant malondialdehyde (MDA) concentration in the cardiac tissue and serum were measured., Results: SESN2 and AMPK protein expression significantly increased in the MitoQ group compared to the control group (P = 0.002, P = 0.0003). MDA content in tissue and serum remained unchanged in all groups (P > 0.05). MitoQ supplementation significantly increased SOD and GPx enzyme activity in serum and cardiac tissue (P = 0.001)., Conclusion: Overall, ET and MitoQ alone and in combination have anti-aging effects and improve the expression of AMPK and SESN2. Additionally, ET and MitoQ lead to improved antioxidant capacity in aged rats by ameliorating the activity of antioxidant enzymes., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Neurodegenerative diseases (NDDs) are a class of neurological disorders marked by the progressive loss of neurons that afflict millions of people worldwide. These illnesses affect brain connection, impairing memory, cognition, behavior, sensory perception, and motor function. Alzheimer's, Parkinson's, and Huntington's diseases are examples of common NDDs, which frequently include the buildup of misfolded proteins. Cognitive-behavioral impairments are early markers of neurodevelopmental disorders, emphasizing the importance of early detection and intervention. Neurotrophins such as brain-derived neurotrophic factor (BDNF) are critical for neuron survival and synaptic plasticity, which is required for learning and memory. NDDs have been associated with decreased BDNF levels. Physical exercise, a non-pharmacological intervention, benefits brain health by increasing BDNF levels, lowering cognitive deficits, and slowing brain degradation. Exercise advantages include increased well-being, reduced depression, improved cognitive skills, and neuroprotection by lowering amyloid accumulation, oxidative stress, and neuroinflammation. This study examines the effects of physical exercise on cognitive-behavioral deficits and BDNF levels in the limbic system impacted by neurodegeneration. The findings highlight the necessity of including exercise into NDD treatment to improve brain structure, function, and total BDNF levels. As research advances, exercise is becoming increasingly acknowledged as an important technique for treating cognitive decline and neurodegenerative disorders., Competing Interests: Conflict of interest The authors of this work declare that they have no conflicts of interest., (Copyright © 2024. Published by Elsevier Inc.)

Autism spectrum disorder (ASD) is a prevalent neurodevelopmental disorder characterized by repetitive behaviors and altered communication abilities. Exercise is a low-cost intervention that could improve cognitive function and improve brain plasticity mechanisms. Here, the valproic acid (VPA) model was utilized to induce ASD-like phenotypes in rodents. Animals were exercised on a treadmill and performance was evaluated on a cognitive flexibility task. Biomarkers related to exercise and plasticity regulation were quantified from the prefrontal cortex, hippocampus, and skeletal muscle. Exercised VPA animals had higher levels of hippocampal BDNF compared to sedentary VPA animals and upregulated antioxidant enzyme expression in skeletal muscle. Cognitive improvements were demonstrated in both sexes, but in different domains of cognitive flexibility. This research demonstrates the benefits of exercise and provides evidence that molecular responses to exercise occur in both the central nervous system and in the periphery. These results suggest that improving regulation of BDNF via exercise, even at low intensity, could provide better synaptic regulation and cognitive benefits for individuals with ASD., Competing Interests: Declaration of competing interest No conflicts of interest., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Obesity continues to rise in prevalence and financial burden despite strong evidence linking it to an increased risk of developing several chronic diseases. Dopamine response and receptor density are shown to decrease under conditions of obesity. However, it is unclear if this could be a potential mechanism for treatment without drugs that have a potential for abuse. Therefore, the aim of this study was to investigate whether moderate-intensity exercise could reduce body weight gain and the associated decreases in dopamine signaling observed with high-fat diet-induced adiposity. We hypothesized that exercise would attenuate body weight gain and diet-induced inflammation in high-fat (HF)-fed mice, resulting in dopamine signaling (release and reuptake rate) comparable to sedentary, low-fat (LF)-fed counterparts. This hypothesis was tested using a mouse model of diet-induced obesity (DIO) and fast-scan cyclic voltammetry to measure evoked dopamine release and reuptake rates. Although the exercise protocol employed in this study was not sufficient to prevent significant body weight gain, there was an enhancement of dopamine signaling observed in female mice fed a HF diet that underwent treadmill running. Additionally, aerobic treadmill exercise enhanced the sensitivity to amphetamine (AMPH) in this same group of exercised, HF-fed females. The estrous cycle might influence the ability of exercise to enhance dopamine signaling in females, an effect not observed in male groups. Further research into females by estrous cycle phase, in addition to determining the optimal intensity and duration of aerobic exercise, are logical next steps., (Copyright © 2024 IBRO. Published by Elsevier Inc. All rights reserved.)

Objective: This study aimed to investigate the impact of lifelong exercise, including both moderate-intensity continuous training and high-intensity interval training, on blood lipid levels and mental behaviour in naturally ageing mice to identify effective exercise strategies for ageing-related health issues., Methods: Six-week-old male BALB/c mice were randomly assigned to one of four groups: young control (YC), natural ageing control (OC), lifelong moderate-intensity continuous exercise (EM), and lifelong high-intensity interval exercise (EH) groups. The EM group was trained at a speed corresponding to 70 % of the maximum running speed, while the EH group was trained at a running speed alternating between 50 % of the maximum running speed, 70 % of the maximum running speed, and 90 % of the maximum running speed. All exercise sessions were conducted three times per week, with each session lasting 50 min. Behavioural tests and blood sample collection were conducted at 72 weeks of age., Results: Ageing in mice led to changes in muscle and fat mass. Both the EM and EH groups showed greater muscle mass and lower fat mass than did the OC group. Ageing was associated with elevated anxiety (fewer open arm entries, time spent in the central region) and depression (lower sucrose preference) indicators. However, these changes were reversed in both exercise groups, with no differences between the two exercise groups. Blood lipid levels, including total cholesterol (TC), total triglycerides (TGs), low-density lipoprotein (LDL), and free fatty acid (FFA) levels, were greater in the OC group than in the YC group. Additionally, the OC group exhibited lower high-density lipoprotein (HDL) levels. However, both the EM and EH groups exhibited improved lipid profiles compared to those of the YC group., Conclusion: Lifelong exercise, whether moderate-intensity continuous or high-intensity interval training, can preserve body health during ageing, prevent anxiety and depression, and maintain stable blood lipid levels. Both exercise types are equally effective, suggesting that exercise intensity may not be the critical factor underlying these beneficial adaptations., Competing Interests: Declaration of competing interest The authors certify that they have no affiliations with or financial involvement in any organization or entity with a direct financial interest in the subject matter or materials discussed in the article. The authors and their immediate family have not received any financial payments or other benefits from any commercial entity related to the subject of this article., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Skeletal muscle aging in rats is a reduction in skeletal muscle mass caused by a decrease in the number or volume of skeletal muscle myofibers. Apoptosis has been recognized to play a key role in accelerating the process of skeletal muscle aging in rats. The thioredoxin (Trx) system is a widely expressed oxidoreductase system that controls the cellular reduction/oxidation state and has both potent anti-free radical damage and important pro-growth and apoptosis inhibitory functions. Previous studies have shown that exercise delays skeletal muscle aging. However, it is unclear whether exercise attenuates skeletal muscle aging via the Trx system. Therefore, the present study used the Trx system as an entry point to explore the effect of aerobic exercise to improve skeletal muscle aging in rats and its possible mechanisms, and to provide a theoretical basis for exercise to delay skeletal muscle aging in rats. It was shown that aerobic exercise in senescent rats resulted in increased gastrocnemius index, decreased body weight, increased endurance, decreased skeletal muscle cell apoptosis, increased activity and protein expression of the Trx system, and decreased expression of p38 and ASK1. Based on these findings, we conclude that 10 weeks of aerobic exercise may enhance the anti-apoptotic effect of Trx by up-regulating Trx and Trx reductase (TR) protein expression, which in turn increases Trx activity in rat skeletal muscle, and ultimately alleviates apoptosis in senescent skeletal muscle cells., Competing Interests: Declaration of competing interest The authors declare no conflicts of interest in relation to this study., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

The traditional understanding of bone mechanosensation implicates osteocytes, canaliculi, and the lacunocanalicular network in biomechanical adaptation. However, recent findings challenge this notion, as shown in advanced teleost fish where anosteocytic bone lacking osteocytes are nevertheless responsive to mechanical load. To investigate specific molecular mechanisms involved in bone mechanoadaptation in osteocytic and anosteocytic fish bone, we conducted a 5-min single swim-training experiment with zebrafish and ricefish, respectively. Through RNASeq analysis of fish spines, analyzed at various time points following swim training, we uncovered distinct gene expression patterns in osteocytic and anosteocytic fish bones. Notably, osteocytic fish bone exhibited an early response to mechanical load, contrasting to a delayed response observed in anosteocytic fish bones, both within 8 h following stimulation. We identified an increase in osteoblast differentiation in anosteocytic bone following training, while chordoblast activity was delayed. This temporal response suggests a time-dependent adaptation in anosteocytic bone, indicating the presence of intricate feedback networks within bone that lacks osteocytes., Competing Interests: Declaration of competing interest Josephine T. Tauer: None. Tobias Thiele: None. Catherine Julien: None. Lior Ofer: None. Paul Zaslansky: None. Ron Shahar: None. Bettina M. Willie receives support for research studies unrelated to the presented study from Mesentech, Novartis, and Mereo BioPharma., (Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.)

The purpose of this study was to assess, from a behavioral, biochemical, and molecular standpoint, how exercise training affected fibromyalgia (FM) symptoms in a reserpine-induced FM model and to look into the potential involvement of the hippocampal PGC-1α/FNDC5/BDNF pathway in this process. Reserpine (1 mg kg -1 ) was subcutaneously injected once daily for three consecutive days and then the rats were exercised for 21 days. Mechanical allodynia was evaluated 1, 11, and 21 days after the last injection. At the end of the exercise training protocol forced swim, open field and Morris water maze tests were performed to assess depression, locomotion and cognition, respectively. Additionally, biochemical and molecular markers related to the pathogenesis of the FM and cognitive functions were measured. Reserpine exposure was associated with a decrease in locomotion, an increase in depression, an increase in mechanical allodynia, and a decrease in spatial learning and memory (p < 0.05). These behavioral abnormalities were found to be correlated with elevated blood cytokine levels, reduced serotonin levels in the prefrontal cortex, and altered PGC-1α/FNDC5/BDNF pathway in the hippocampus (p < 0.05). Interestingly, exercise training attenuated all the neuropathological changes mentioned above (p < 0.05). These results imply that exercise training restored behavioral, biochemical, and molecular changes against reserpine-induced FM-like symptoms in rats, hence mitigating the behavioral abnormalities linked to pain, depression, and cognitive functioning., (Copyright © 2024 IBRO. Published by Elsevier Inc. All rights reserved.)

In this study we investigated the potential synergistic effects of moderate interval training (MIT) and lithium on spatial learning and memory. Forty-two male Wistar males were classified into six groups including I: Control, II: 10 mg/kg/day IP lithium (Li10), III: MIT, IV: Li10 + MIT, V: 40 mg/kg/day IP lithium (Li40), and VI: Li40 + MIT. Then, the rats underwent Morris Water Maze (MWM) test to assess their spatial memory and learning ability. Brain-derived neurotrophic factor (BDNF) density was measured by enzyme-linked immunosorbent assay (ELISA), and the expression of PGC1 and SIRT3 were assessed via qRT-PCR. The results show that MIT improves both memory and spatial learning; but lithium alone, does not cause this. Additionally, those exposed to a combination of exercise and lithium also had improved spatial learning and memory. Finally, we observed a positive role of BDNF protein, and PGC1 gene on the effects of exercise and lithium., Competing Interests: Declaration of competing interest The authors of this study declare no conflicting interests., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Combining physical and cognitive training has been suggested to promote further benefits on brain and cognition, which could include synergistic improvement of hippocampal neuroplasticity. In this paper, we investigated whether treadmill exercise followed by a working memory training in the water maze increase adult hippocampal neurogenesis to a greater extent than either treatment alone. Our results revealed that ten days of scheduled running enhance cell proliferation/survival in the short-term as well as performance in the water maze. Moreover, exercised mice that received working memory training displayed more surviving dentate granule cells compared to those untreated or subjected to only one of the treatments. According to these findings, we suggest that combining physical and cognitive stimulation yield synergic effects on adult hippocampal neurogenesis by extending the pool of newly-born cells and subsequently favouring their survival. Future research could take advantage from this non-invasive, multimodal approach to achieve substantial and longer-lasting enhancement in adult hippocampal neurogenesis, which might be relevant for improving cognition in healthy or neurologically impaired conditions., Competing Interests: Declaration of Competing Interest The authors declare no conflicts of interest., (Copyright © 2023. Published by Elsevier Inc.)

Physical training is a potent therapeutic approach for improving mitochondrial health through peroxisome proliferator-activated receptor gamma coactivator 1 alpha (PGC-1α) signaling pathways. However, comprehensive information regarding the physical training impact on PGC-1α in the different physiological systems with advancing age is not fully understood. This review sheds light on the frontier-of-knowledge data regarding the chronic effects of exercise on the PGC-1α signaling pathways in rodents and humans. We address the molecular mechanisms involved in the different tissues, clarifying the precise biological action of PGC-1α, restricted to the aged cell type. Distinct exercise protocols (short and long-term) and modalities (aerobic and resistance exercise) increase the transcriptional and translational PGC-1α levels in adipose tissue, brain, heart, liver, and skeletal muscle in animal models, suggesting that this versatile molecule induces pleiotropic responses. However, PGC-1α function in some human tissues (adipose tissue, heart, and brain) remains challenging for further investigations. PGC-1α is not a simple transcriptional coactivator but supports a biochemical environment of mitochondrial dynamics, controlling physiological processes (primary metabolism, tissue remodeling, autophagy, inflammation, and redox balance). Acting as an adaptive mechanism, the long-term effects of PGC-1α following exercise may reflect the energy demand to coordinate multiple organs and contribute to cellular longevity., Competing Interests: Declaration of Competing Interest The authors declare that they have no conflicts of interest., (Copyright © 2023 Elsevier B.V. All rights reserved.)

To investigate whether ovariectomy affects mitochondrial respiratory function, gene expression of the biogenesis markers and mitochondrial dynamics of the vastus lateralis muscle, female Wistar rats divided into ovariectomized (OVX) and intact (INT) groups were kept sedentary (SED) or submitted to resistance training (RT) performed for thirteen weeks on a vertical ladder in which animals climbed with a workload apparatus. RT sessions were performed with four climbs with 65, 85, 95, and 100 % of the rat's previous maximum workload. Mitochondrial Respiratory Function data were obtained by High-resolution respirometry. Gene expression of FIS1, MFN1 and PGC1-α was evaluated by real-time PCR. There was a decrease on oxidative phosphorylation capacity in OVX-SED compared to other groups. Trained groups presented increase on oxidative phosphorylation capacity when compared to sedentary groups. For respiratory control ratio (RCR), OVX-SED presented lower values when compared to INT-SED and to trained groups. Trained groups presented RCR values higher compared to INT-SED. Exercise increased the values of FIS1, MFN1 and PGC1-α expression compared to OVX-SED. Our results demonstrated that in the absence of ovarian hormones, there is a great decrease in oxidative phosphorylation and electron transfer system capacities of sedentary animals. RT was able to increase the expression of genes related to mitochondrial dynamics markers, reversing the condition determined by ovariectomy., Competing Interests: Declaration of competing interest The authors declare that there is no conflict of interest., (Copyright © 2023. Published by Elsevier Inc.)

To determine detrimental effects of estrogen and insulin deficiencies on hippocampus, we examined apoptosis-induced neuronal damage and cholinergic system in ovariectomized and/or diabetic rat hippocampus. Possible neuroprotective effects of treadmill exercise were also investigated. Adult female Wistar rats were randomly divided into four groups (n = 5 rats/group) as follows: control, ovariectomized (Ovx), diabetic (Dia, streptozotocin (STZ) 60 mg/kg; i.p.), and Ovx + Dia groups. Each group was further subdivided into exercise and non-exercise groups. Animals in exercise groups were subjected to treadmill training, while those in non-exercise groups were placed on the stationary treadmill for 4 weeks (5 days/week). Apoptosis-related protein levels (i.e. Bax, Bcl-2, and caspase-3), number of survived neurons, and acetylcholinesterase (AChE) activity in the hippocampus were measured using Western blotting, Cresyl Violet staining, and Ellman assay, respectively. Both ovariectomy and diabetes increased expression of Bax and caspase-3 and decreased expression of Bcl-2 at protein levels. In addition, a significant decrease in the number of survived neurons was observed in both Ovx and Dia groups, while AChE activity was lower only in the Dia group. The Ovx + Dia group showed stronger apoptosis-induced neuropathology and inhibition of AChE activity. Treadmill exercise attenuated apoptosis-induced neuropathology in the Ovx and Dia groups and recovered AChE activity in the Dia group. Neuroprotective effects of treadmill exercise were mediated by inhibition of apoptosis. Moderate exercise protocol had no beneficial anti-apoptotic and neuroprotective effects in ovariectomized-diabetic rats., Competing Interests: Declaration of competing interest The authors declare no conflicts of interest., (Copyright © 2022 IBRO. Published by Elsevier Ltd. All rights reserved.)

The physiological effects of exercise vary as a function of frequency and length. However, research on the duration-dependent effects of exercise has focused primarily on young adults and less is known about the influence of exercise duration in the aged. The current study compared the effects of short-term and long-term running wheel access on hippocampal neurogenesis and neuroimmune markers in aged (19-23 months) male C57BL/6J mice. Aged mice were given 24-hour access to a running wheel for 14 days (short-term) or 51 days (long-term). Groups of non-running aged and young (5 months) mice served as comparison groups to detect age-related differences and effects of exercise. Long-term, but not short-term, exercise increased hippocampal neurogenesis as assessed by number of doublecortin (DCX) positive cells in the granular cell layer. Assessment of cytokines, receptors, and glial-activation markers showed the expected age-related increase compared to young controls. In the aged, exercise as a function of duration regulated select aspects of the neuroimmune profile. For instance, hippocampal expression of interleukin (IL)-10 was increased only following long-term exercise. While in contrast brain levels of IL-6 were reduced by both short- and long-term exercise. Additional findings showed that exercise does not modulate all aspects of age-related neuroinflammation and/or may have differential effects in hippocampal compared to brain samples. Overall, the data indicate that increasing exercise duration produces more robust effects on immune modulation and hippocampal neurogenesis., Competing Interests: Declarations of interest None., (Copyright © 2022 IBRO. Published by Elsevier Ltd. All rights reserved.)

Type 2 diabetes is a major factor contributing to cognitive decline and Alzheimer's disease (AD). Treadmill running is considered to be a critical approach for mice and rats to lower blood sugar and improve learning and memory capacity. The growth factor receptor-bound protein 10 (Grb10) has been proposed to inhibit insulin signaling and defective brain insulin signaling resulted in the cognitive deficits in patients with AD. However, the positive roles of treadmill training on diabetic- related impaired cognitive function and their molecular mechanisms remain unclear. Here, to investigate whether there was neuroprotective effects of treadmill training on impaired cognitive function caused by diabetes, the rats were injected intraperitoneally with streptozotocin at a dose of 30 mg/kg to establish diabetic model (DM). We found that higher Grb10, BACE1 and PHF10 protein levels in the hippocampus of DM rats, lower phosphorylation IGF-1Rβ and IRS-1( ser307 ). However, 8 weeks treadmill training effectively reduced abnormal Grb10, enhanced postsynaptic density protein PSD-93, PSD-95, SYN expressions of hippocampus, restored PI3K/Akt/ERK and mTOR/AMPK signaling, thus alleviated spatial learning and memory deficit, compared with DM group. Additionally, treadmill training also increased GLUT4 transportation. Overall, our findings suggest that treadmill intervention improved cognitive impairments caused by diabetes disease partly through modulating Grb10/ PI3K/Akt/ERK as well as mTOR/AMPK signaling., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Purpose: Exercise helps improve mitochondrial function to combat sarcopenia. Certain parts of the mitochondrial respiratory chain complex can form a higher-order structure called "supercomplex" to reduce the production of reactive oxygen species and improve muscle mass. The effect of exercise on the assembly of the mitochondrial supercomplex is still unclear. The aim of this study was to investigate the effects of long-term high-intensity interval training (HIIT) on mitochondrial biogenesis, mitophagy, and mitochondrial supercomplexes (mitoSCs) assembly in aging soleus muscle., Methods: Female Sprague-Dawley rats (n = 36) were randomly divided into four groups: young sedentary (Y-SED, 8 months old, n = 12), old sedentary (O-SED, 26 months old, n = 12), moderate-intensity continuous training (MICT, from 18 to 26 months old, n = 12), and HIIT (from 18 to 26 months old, n = 12). Rats in the MICT and HIIT groups were subjected to an 8-month training program. Real-time fluorescent quantitative polymerase chain reaction was used to measure the expression of the antioxidative factors, inflammatory factors, and mitochondrial fusion- and division-related genes. Western blotting was used to detect the expression of mitochondrial biogenesis and mitophagy markers and AMP-activated protein kinase (AMPK) pathway proteins. Enzyme-linked immunosorbent assays were used to determine serum irisin contents. Blue native polyacrylamide gel electrophoresis was used to assess the formation of mitochondrial supercomplexes., Results: Compared with the Y-SED group, the soleus muscle and mitochondria in the O-SED group showed reduced expression of mitophagy- and mitochondrial biogenesis-related proteins. In the HIIT group, the expression of autophagy-related proteins in the soleus muscle and mitochondria was significantly increased compared with that in the MICT group. Serum irisin and mitochondrial fusion protein levels significantly decreased with age. Superoxide dismutase 2 protein levels and AMPK pathway protein expression were significantly increased in the HIIT group compared with those in the other groups. Additionally, the expression levels of mitoSCs and the mRNA levels of interleukin-15 and optical atrophy 1 increased in the HIIT group compared with that in the MICT group., Conclusion: Compared with MICT, HIIT activated the AMPK pathway to upregulate mitochondrial biogenesis- and mitophagy-related proteins, and promote the assembly and formation of mitoSCs to improve the mitochondrial function of aging soleus muscles., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Background: We evaluated angiogenic responses in the left ventricular muscle and aerobic capacity according to exercise type (aerobic, resistance, combined) in aged rats., Methods: In total, 24 male Sprague-Dawley rats (100 weeks old) were used. To investigate the effect of regular training, the rats were divided into non-exercise (NE), aerobic exercise (AE), resistance exercise (RE), and combined exercise (CE) groups (six rats per group). Regular training tailored to each exercise type was performed for 8 weeks (five times a week, 1 h per day). After 8 weeks of training, aerobic capacity was evaluated by a treadmill running test. Left ventricular muscle tissue was collected and the protein levels of angiogenesis indicators (eNOS, HIF-1α, PGC-1α, VEGF, FLK-1, Ang-1, Ang-2) were analyzed by Western blotting. Capillaries were observed by immunohistochemical staining for CD31., Results: Body weight, heart weight, and heart/body weight ratio showed no difference among the groups. The AE and CE groups showed higher treadmill running capacity than the NE and RE groups. The eNOS, VEGF, HIF-1α, PGC-1α, and Ang-2 protein levels were significantly higher in the AE than NE group. The PGC-1α and FLK-1 protein levels were significantly higher in the RE than NE group. In addition, in the CE group, the eNOS, FLK-1, and PGC-1α protein levels were significantly higher than in the NE group. Expression of CD31 in cardiac tissue was higher in the AE and CE groups than in the other groups., Conclusions: Taken together, the results suggest that regular exercise training, irrespective of exercise type, might improve cardiovascular function by inducing angiogenic responses in the aged myocardium; however, AE may be the most effective., (Copyright © 2021 Elsevier Inc. All rights reserved.)

It is unknown if consumption of a Western diet (WD; high-fat/sucrose), versus a non-WD (healthy diet), accelerates declines in physical function over the adult lifespan, and whether regular voluntary activity attenuates age- and WD-associated declines in function. Accordingly, we studied 4 cohorts of mice that consumed either normal chow [NC] or WD with or without access (sedentary, Sed) to voluntary wheel running [VWR] beginning at 3 mo of age. We assessed coordination, grip strength and endurance every 6 mo throughout life, and measured skeletal muscle mass and inflammation at 3 pre-determined ages (6-7, 13-14 and 19-20 mo). Age-related declines (% change 3-18 mo) in physical function were accelerated in WD-Sed versus NC-Sed (coordination: +47 ± 5%; grip strength: +18 ± 2%; endurance: +32 ± 5%; all p < 0.05). VWR attenuated declines in physical function within diet group (coordination: -31 ± 3% with WD-VWR; -18 ± 2% with NC-VWR; grip strength: -26 ± 2% with WD-VWR; -24 ± 2% with NC-VWR; endurance: -48 ± 4% with WD-VWR; -23 ± 6% with NC-VWR; all p < 0.05). Skeletal muscle mass loss and pro-inflammatory cytokine abundance were exacerbated by WD throughout life (mass: NC-Sed [-]7-28%, WD-Sed [-]17-40%; inflammation: NC-Sed [+]40-65%, WD-Sed [+]40-84%, all p < 0.05 versus NC-Sed), and attenuated by VWR (mass: NC-VWR, [-]0-10%, WD-VWR [-]0-10%; inflammation: NC-VWR [+]0-30%, WD-VWR [+]0-42%, all p < 0.05 versus diet-matched Sed group). Our results depict the temporal impairment of physical function over the lifespan in mice, acceleration of dysfunction with WD, the protective effects of voluntary exercise, and the potential associations with skeletal muscle mass and inflammation., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Diaphragm muscle blood flow (BF) and vascular conductance (VC) are elevated with chronic heart failure (HF) during exercise. Exercise training (ExT) elicits beneficial respiratory muscle and pulmonary system adaptations in HF. We hypothesized that diaphragm BF and VC would be lower in HF rats following ExT than their sedentary counterparts (Sed). Respiratory muscle BFs and mean arterial pressure were measured via radiolabeled microspheres and carotid artery catheter, respectively, during submaximal treadmill exercise (20 m/min, 5 % grade). During exercise, no differences were present between HF + ExT and HF + Sed in diaphragm BFs (201 ± 36 vs. 227 ± 44 mL/min/100 g) or VCs (both, p > 0.05). HF + ExT compared to HF + Sed had lower intercostal BF (27 ± 3 vs. 41 ± 5 mL/min/100 g) and VC (0.21 ± 0.02 vs. 0.31 ± 0.04 mL/min/mmHg/100 g) during exercise (both, p < 0.05). Further, HF + ExT compared to HF + Sed had lower transversus abdominis BF (20 ± 1 vs. 35 ± 6 mL/min/100 g) and VC (0.14 ± 0.02 vs. 0.27 ± 0.05 mL/min/mmHg/100 g) during exercise (both, p < 0.05). These data suggest that exercise training lowers the intercostal and transversus abdominis BF responses in HF rats during submaximal treadmill exercise., (Copyright © 2021 Elsevier B.V. All rights reserved.)

Background: Oxidation resistance protein 1 (OXR1) is of scientific interest due its role in protecting tissues against oxidative stress, DNA mutations and tumorigenesis, but little is known regarding strategies to increase OXR1 in different tissues. As an improved antioxidant defense may result from a high total amount of physical activity, the present study was designed to determine whether an active lifestyle including aerobic training exercise and spontaneous physical activity (SPA) can increase OXR1. We have built a large cage (LC) that allows animals to move freely, promoting an increase in SPA in comparison to a small cage (SC)., Methods: We examined the effects of aerobic training applied for 8 weeks on SPA and OXR1 of C57BL/6 J mice living in two types of housing (SC and LC). OXR1 protein was studied in hypothalamus, muscle and liver, which were chosen due to their important role in energy and metabolic homeostasis., Results: LC-mice were more active than SC-mice as determined by SPA values. Despite both trained groups exhibiting similar gains in aerobic capacity, only trained mice kept in a large cage (but not for trained mice housed in SC) exhibited high OXR1 in the hypothalamus and liver. Trained mice housed in LC that exhibited an up-regulation of OXR1 also were those who exhibited an energy-expensive metabolism (based on metabolic parameters)., Conclusions: These results suggest that aerobic training associated with a more active lifestyle exerts a protective effect against oxidative damage and may be induced by changes in energy metabolism., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Treadmill exercise has been recognized as an effectively therapeutic strategy for Parkinson's disease (PD). However, its exact molecular mechanism of promoting PD remain unclear. Recently, the NLRP3 inflammasome is considered to play a critical role in the pathogenesis of PD. In this study, we investigated whether NLRP3 inflammasome was involved in treadmill exercise-induced neuroprotection and anti-inflammation effect in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) model of PD. 8-week-old male mice (C57BL/6 strain) were divided into four groups: Control, MPTP, MPTP + EX and EX. MPTP was intraperitoneally injected into mice to establish chronic PD model. The open-field test and pole test were used to assess motor function. The results showed that treadmill exercise significantly alleviated motor dysfunction and dopaminergic neuron degeneration induced by MPTP. In addition, we also found that treadmill exercise suppressed MPTP-triggered microglia activation and the co-localization of NLRP3+/Iba-1+ cells in the substantia nigra. These effects were associated with suppression NLRP3 inflammasome via down-regulation of TLR4/MyD88/NF-κB pathway. Overall, our study demonstrated that treadmill exercise could effectively alleviates neuronal damage via inhibition of NLRP3 inflammasome and microglial activation in MPTP-induced PD mouse model., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Autophagy is a highly regulated intracellular process for the degradation of protein aggregates and damaged organelles. Recently, autophagy has been implicated in Alzheimer's disease (AD) and aging. Autophagy process is regulated by the recruitment and assembly of several autophagy-related genes (Atgs) such as, Atg7 and LC3, as the highly conserved and important markers involved in the regulation of autophagy. We recently reported the reduced LC3-II/LC3-I ratio, down-regulated ATG7, and increased p62 protein levels in hippocampal tissues of aging rats. MicroRNA-130a (miR-130a) plays a crucial role in physiological and pathological processes, but whether miR-130a affects the autophagy of brain is unknown. We aim to explore the regulatory role of miR-130a on the autophagy and cell senescence of SH-SY5Y, as well as LC3-II/LC3-I ratio, and the expression of p62, ATG7, Ac-p53 and p21 during exercise intervention of aging rats. In this study, miR-130a expression was markedly down-regulated in the hippocampal of aged rats companying with up-regulated expression of Ac-p53 and p21 when compared with young rats. In contrast, voluntary wheel running could up-regulate miR-130a expression; decrease the expression of Ac-p53 and p21 in aging rats. Interestingly, exercise reversed the impaired autophagy resulted from aging possibly by activating AMPK signaling. Moreover, overexpression of miR-130a in d-galactose (D-gal)-induced SH-SY5Y cell senescence model attenuated d-gal-induced impaired autophagy and cell senescence, demonstrated by decreased levels of LC3, Ac-p53, p21 and increased p62, suggesting that voluntary wheel running can alleviate brain aging in natural aging rats by up-regulating miR-130a-mediated autophagy., (Copyright © 2021 Elsevier Inc. All rights reserved.)

We sought to investigate whether RVLM iNOS activity and oxidative profile may participate in the reduction of sympathetic responsiveness in swimming trained normotensive rats. Sedentary (S) and swimming trained (T) Wistar male rats chronically instrumented with an arterial catheter and guide cannula into the RVLM were submitted to continuous pressure and heart rate (HR) recordings and determination of autonomic control (power spectral analysis) before and after unilateral RVLM iNOS inhibition (aminoguanidine, 250 pmol/100 nL). Other S and T rats received local l-glutamate microinjection (5 nmol/100 nL). In separate S and T groups not submitted to brainstem cannulation, fresh bilateral RVLM punchs were collected for iNOS gene expression (qPCR); reduced glutathione and lipid peroxidation quantification (spectrophotometry); iron-reducing antioxidant (FRAP) and 2,2'-azino-bis (3-ethylbenzothiazoline-6-sulphonic acid) radical cation (ABTS˙ + ) scavenger assays. iNOS gene expression was confirmed in fixed RVLM slices (immunofluorescence). T rats exhibited resting bradycardia, lower sympathovagal balance, reduced RVLM iNOS gene/protein expression and higher antioxidant capacity. Decreased iNOS expression was positively correlated with reduced HR. Pressor and tachycardic response to l-Glutamate were smaller in T rats. Aminoguanidine microinjection reduced sympathetic activity in S rats but did not change it in T rats expressing reduced RVLM iNOS content. Our data indicate that iNOS, expressed in the RVLM of normotensive male rats, has tonic effects on sympathetic activity and that swimming training is an efficient tool to reduce iNOS expression and augment the antioxidant defense, thus reducing glutamatergic responsiveness and sympathetic drive to cardiovascular effectors., (Copyright © 2021 Elsevier Inc. All rights reserved.)

We investigated the effects of chronic (∼7 weeks) treatment with the angiotensin converting enzyme (ACE) inhibitor Captopril in rats with heart failure with reduced ejection fraction (HF-rEF) on brain blood flow (BF; radiolabeled microspheres) at rest and during submaximal exercise. We hypothesized that middle cerebral, posterior cerebral, and cerebellar BF during submaximal exercise (20 m/min, 5% incline) would be reduced in rats with HF-rEF (n = 10) compared to healthy (SHAM, n = 10) controls and HF-rEF rats chronically treated with Captopril (HF-rEF + Cap., n = 20). During submaximal exercise middle cerebral (HF-rEF + Cap.: 274 ± 12; HF-rEF: 234 ± 23; SHAM: 248 ± 24 ml/min/100 g) and cerebellar (HF-rEF + Cap.: 222 ± 14; HF-rEF: 243 ± 22; SHAM: 214 ± 23 ml/min/100 g) BF increased from rest in all groups with no difference among groups (P > 0.24). Posterior cerebral BF increased from rest in all groups but was lower than SHAM (394 ± 46 ml/min/100 g; P = 0.03) in HF-rEF (298 ± 19 ml/min/100 g) but not HF-rEF + Cap. (356 ± 18 ml/min/100 g; P = 0.14), supporting the concept that ACE inhibition in HF-rEF elevates brain BF increases, at least to the posterior cerebral region, during moderate intensity exercise/physical activity., (Published by Elsevier B.V.)

Recent studies have discovered a strong link between physical exercise and the prevention of neuro-degenerative symptoms, especially in elderly subjects, nonetheless, the exact underlying mechanism remains unclear. In this study, we hypothesized that aerobic exercise training may have a protective effect on myelin sheath in aged mice by regulating the ROCK signal pathway, which is considered as a crucial mechanism for decreasing apoptosis and promoting regeneration. Briefly, C57/BL aged mice underwent an exercise training (5 days/week, lasting 6 weeks). Memory and cognitive impairment were examined using Novel object recognition (NOR) test and Morris water maze test (MWM). Demyelination was explored using Luxol fast blue staining and transmission electron microscopy in the corpus callosum (CC), and the expression of ROCK and apoptotic protein were analyzed via western blot. We demonstrated the impairment of memory and cognitive and the decrease of myelin sheath thickness in aged mice. In addition, severe demyelination was observed in aged mice, accompanied with increased expression of RhoA, ROCK, ATF3, and Caspase 3, and reduced expression of MBP, Olig2, and NG2. Aerobic exercise training improved behavioral functions, increased the expression of MBP and myelin sheath thickness, reduced apoptosis and promoted myelination. To sum up, our data indicate that aerobic exercise training protects demyelination from aging-related white matter injury, which is associated with the up-regulation of ROCK signal pathway., (Copyright © 2020. Published by Elsevier Inc.)

The behavioral changes, including spatial learning and memory impairment as well as depressive- and anxiety-like behaviors in an animal model of asthma were demonstrated previously. On the other hand, there is increasing evidence that the anti-inflammatory actions of exercise are related to their neuroprotective properties against different insults in the brain. This study was aimed to explore the effects of moderate treadmill exercise on cognitive deficits and possible anti-inflammatory mechanisms in ovalbumin (OVA)-sensitized rats. The exercise groups were trained to run on the treadmill 30 min/day with an intensity of 12 m/min, 5 days/week for 4 weeks. Animals in the OVA groups were sensitized by two intraperitoneal (i.p.) injections of OVA (10 μg/injection) and challenged with OVA by inhalation during the treadmill running exercise period. Passive avoidance (PA) memory, levels of interleukin (IL)-10 and tumor necrosis factor (TNF)-α in the hippocampus, total and differential white blood cell (WBC) count in the blood as well as pathological changes of the lung were then evaluated. OVA-sensitization was resulted in cognitive deficits in the PA task, along with increased total and differential WBC in blood and TNF-α in the hippocampus. However, exercise ameliorated these changes and increased the IL-10 level in the hippocampus, suggesting that moderate treadmill exercise can improve memory impairment in OVA-sensitized rats due to its anti-inflammatory properties., (Copyright © 2020. Published by Elsevier Inc.)

Although previous studies showed that exercise can improve cognitive dysfunction in type 2 diabetes (T2DM), the underlying mechanism remains unclear. Sirtuin 1 (SIRT1) has been shown to play a role in regulating inflammatory responses in the brain and increasing BDNF expression. This study investigated the effects of treadmill exercise on the hippocampal inflammatory response and BDNF expression in a T2DM mice model. We also tested whether these effects are SIRT1-dependent. In this study, C57BL/ 6 mice were used to construct T2DM model by a high-fat diet and STZ injection. We found that treadmill exercise for 8 weeks can significantly improve the cognitive dysfunction, alleviate activation of proinflammatory microglia M1 (Iba1 labeling) in the hippocampus of T2DM mice, and reduce the levels of proinflammatory factors IL-1β, IL-6, TNF-α, increase the expression levels of anti-inflammatory factors IL-10, TGF-β1, and promote the release of BDNF. We also found that exercise activate the signaling pathway of SIRT1/ NF-κB and SIRT1/ PGC-1α/ FNDC5/ BDNF. After the application of nicotinamide (NAM, SIRT1 inhibitor), the positive effects of exercise were remarkably suppressed. Our results showed that long-term moderate intensity treadmill exercise can alleviate inflammatory response in the hippocampus and increase BDNF expression in T2DM mice by activating SIRT1., (Copyright © 2020 Elsevier Inc. All rights reserved.)

The involvement of brainstem noradrenergic system in thermoregulation during exercise was evaluated by assessing the neuronal activation of A1, A2, locus coeruleus (LC) during exercise. Male Wistar rats weighing 280-330 g were used in the present study. Ninety minutes after exercise bout until fatigue, animals were anaesthesiated and brain removed and processed immunohistochemically for Fos protein and tyrosine hydroxylase in A1, A2 and LC and for Fos in POA subregions. Core and tail temperature were recorded during all running period by telemetry system. Heat storage rate (HSR, cal.min -1 ), maximum tail vasoconstriction (°C) and vasodilatation threshold (°C) were calculated and correlated with Fos expression in all nuclei studied. Fos expression in LC correlated inversely with maximum tail skin vasoconstriction (r = -0.787, p < 0.03) and HSR (r = -0.834, p < 0.02) and positively to time to fatigue (r = 0.862, p < 0.01). A1 nucleus showed an inverse correlation with tail skin vasodilatation threshold (r = -0.861, p < 0.01). Fos expression in LC correlated inversely with Fos expression in the median (MnPO, r = -0.909, p < 0.01) and medial preoptic nucleus (MPOM, r = -0.942, p < 0.05). Our results bring further evidences that noradrenergic neurons from LC and A1 nuclei are involved in cutaneous heat loss mechanisms during exercise. LC nucleus probably modulates the sympathetic tonus of tail artery and integrates the central network LC / POA that could represent an important circuitry of temperature regulation during exercise. Also, noradrenergic neurons from A1 nucleus could be involved in cutaneous heat loss during exercise by modulating of vasodilatation threshold., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Various sleep disorders have deleterious effects on mental and cognitive performance. Exercise, as an alternative therapeutic strategy, exerts beneficial impacts on human health. In the present study, we aimed to evaluate the effects of 4 weeks treadmill exercise (4W-TE) on anxiety-like behavior and cognitive performance in mice exposed to 2 months REM sleep deprivation (2M-SD) (20 h per day). Behavioral performance of mice in elevated plus maze test (EPM), open field test (OFT), Y maze test (YM) and Morris water maze test (MWM) was recorded and analyzed 28 h after the last day of sleep deprivation. After behavioral tests, various neurotransmitters including norepinephrine (NE), dopamine (DA), serotonin (5-HT) and γ-aminobutyric acid (GABA) in mouse hippocampus were quantified using high performance liquid chromatography. The hippocampal levels of insulin-like growth factor-1 (IGF-1) and brain derived neurotrophic factor (BDNF) were further detected using ELISA. Behavioral data indicated that 2M-SD exposure induced anxiety-like behaviors and cognitive impairment, as evidenced by the decreased open-arm entries in EPM, reduced central area travels in OFT, declined spontaneous alteration in YM and prolonged escaping latency in MWM. In addition, 2M-SD exposure increased NE and DA, decreased 5-HT and GABA, and reduced IGF-1 and BDNF levels in mouse hippocampus. Interestingly, all these behavioral, neurochemical and neurobiological changes can be ameliorated by 4W-TE training. In summary, these findings confirm the beneficial impacts of exercise on health and provide further experimental evidence for future application of exercise as an alternative therapy against the mental and cognitive problems in patients with sleep disorders., (Copyright © 2020 Elsevier Inc. All rights reserved.)

We investigated the effect of type 2 diabetes mellitus (T2DM) on respiratory muscle blood flow (BF) during exercise. Using the Goto-Kakizaki (GK) rat model of T2DM, we hypothesized that diaphragm, intercostal and transverse abdominis BFs (radiolabeled microspheres) would be higher in male GK rats (n = 10) compared to healthy male Wistar controls (CON; n = 8) during submaximal exercise (20 m/min, 10 % grade). Blood glucose was significantly higher in GK (246 ± 29 mg/dL) compared to CON (103 ± 4 mg/dL; P < 0.01). Respiratory muscle BFs were not different at rest (P> 0.50). From rest to submaximal exercise, respiratory muscle BFs increased in both groups to all muscles (P < 0.01). During submaximal exercise GK rats had higher diaphragm BFs (GK: 189 ± 13; CON: 138 ± 14 mL/min/100 g, P < 0.01), and vascular conductance (GK: 1.4 ± 0.1; CON: 1.0 ± 0.1 mL/min/mmHg/100 g; P < 0.01) compared to CON. There were no differences in intercostal or transverse abdominis BF or VC during exercise (P> 0.15). These findings suggest that submaximal exercise requires a higher diaphragm BF and VC in T2DM compared to healthy counterparts., (Copyright © 2020 Elsevier B.V. All rights reserved.)

Several models of environmental enrichment and physical exercise have been used to explore the experience effects on brain functions and plasticity, mainly in adult animals. In order to examine the early influence of these stimuli on developing brain, the present study used calcium-binding protein parvalbumin as neuroplastic marker in the hippocampal formation of male Wistar rats subjected to environmental enrichment or physical exercise from postnatal days 21 to 60 (P21-P60). In our study, no significant difference in hippocampal expression and distribution of parvalbumin was found between enriched and control rats. However, a significant increase in parvalbumin protein expression as well as in the number of neurons stained with parvalbumin was observed in the hippocampal formation of rats submitted to daily treadmill exercise when compared to the control rats. The hippocampal region with the highest number of parvalbumin neurons in exercised rats was Cornus of Amon 2 e 3 (CA2/CA3). These findings indicate that developing brain may be differentially sensitive to environmental stimulation models. Specifically, our results show that hippocampal expression and distribution of parvalbumin in developing rats may be more influenced by exercise than by enriched environment. The mechanisms are not yet known., Competing Interests: Declaration of Competing Interest The authors declare that they have no conflicts of interest. All authors read and approved the final manuscript., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Exercise therapy plays key roles in functional improvements during neurorehabilitation. However, it may be difficult for some people to properly perform exercise because mobility and endurance might be restricted by neurological deficits due to stroke. Additionally, there is little evidence detailing the biological mechanisms underlying the most effective swimming exercise protocols for neuroplasticity after stroke. Thus, the present study investigated the effects of swimming exercise on neuroplasticity in a cerebral infarction rat model according to the timing and intensity of exercise. A total of 45 male Sprague-Dawley rats (300 ± 50 g, 10 weeks old) were subjected to photothrombotic cerebral infarction and randomly divided into five groups: non-exercise (group A, n = 9); early submaximal (group B, n = 9); early maximal (group C, n = 9); late submaximal (group D, n = 9); and late maximal (group E, n = 9). Swimming exercise was performed five times a week for 4 weeks, and cognition was evaluated with the Morris water maze (MWM) test. Assessments of superoxide dismutase (SOD) activity and malondialdehyde (MDA) levels and immunohistochemical analyses of brain-derived neurotrophic factor (BDNF) were conducted in the ipsilesional hippocampus region. After 4 weeks of exercise, the escape latency was shorter and velocity was greater in group B than in groups A, C, D, and E (p = 0.046, p <  0.001, respectively). Furthermore, SOD activity was higher and MDA levels were lower in group B than in groups A, C, D, and E (p = 0.004, p = 0.019). The immunohistochemistry results revealed that the greatest BDNF immunoreactivity was in group B. Taken together, these results indicate that early submaximal swimming exercise may be the most effective protocol for the recovery of neurological deficits in a rat model of cerebral infarction., (Copyright © 2020. Published by Elsevier Inc.)

Background: Rats exposed to water avoidance stress (WAS) show increased urinary frequency, increased somatosensory nociceptive reflex responses, as well as altered brain responses to bladder distension, analogous to similar observations made in patients with urologic chronic pelvic pain syndrome (UCPPS). Exercise has been proposed as a potential treatment option for patients with chronic urinary frequency and urgency. We examined the effects of exercise on urinary voiding parameters and functional brain activation during bladder distension in rats exposed to WAS., Methods: Adult, female Wistar Kyoto rats were exposed to 10 days of WAS and thereafter randomized to either voluntary exercise for 3 weeks or sedentary groups. Voiding parameters were assessed at baseline, post-WAS, and weekly for 3 weeks. Thereafter, cerebral blood flow (CBF) mapping was performed during isotonic bladder distension (20 cm H 2 O) after intravenous bolus injection of [ 14 C]-iodoantipyrine. Regional CBF was quantified in autoradiographs of brain slices and analyzed in 3-D reconstructed brains by statistical parametric mapping. Functional connectivity was examined between regions of the micturition circuit through interregional correlation analysis., Results: WAS exposure in sedentary animals (WAS/no-EX) increased voiding frequency and decreased urinary volumes per void. Exercise exposure in WAS animals (WAS/EX) resulted in a progressive decline in voiding frequency back to the baseline, as well as increased urinary volumes per void. Within the micturition circuit, WAS/EX compared to WAS/no-EX demonstrated a significantly lower rCBF response to passive bladder distension in Barrington's nucleus that is part of the spinobulbospinal voiding reflex, as well as in the periaqueductal gray (PAG) which modulates this reflex. Greater rCBF was noted in WAS/EX animals broadly across corticolimbic structures, including the cingulate, medial prefrontal cortex (prelimbic, infralimbic areas), insula, amygdala, and hypothalamus, which provide a 'top-down' decision point where micturition could be inhibited or triggered. WAS/EX showed a significantly greater positive brain functional connectivities compared to WAS/no-EX animals within regions of the extended reflex loop (PAG, Barrington's nucleus, intermediodorsal thalamic nucleus, pons), as well as within regions of the corticolimbic decision-making loop of the micturition circuit, with a strikingly negative correlation between these pathways. Urinary frequency was positively correlated with rCBF in the pons, and negatively correlated with rCBF in the cingulate cortex., Conclusion: Our results suggest that chronic voluntary exercise may decrease urinary frequency at two points of control in the micturition circuit. During the urine storage phase, it may diminish the influence of the reflex micturition circuit itself, and/or it may increase corticolimbic control of voiding. Exercise may be an effective adjunct therapeutic intervention for modifying the urinary symptoms in patients with UCPPS., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Skeletal muscle quality and quantity are negatively impacted with age. Part of this decline in function can be attributed to alterations in mitochondrial turnover, and in the mechanisms that regulate mitochondrial homeostasis. Protein quality control within the mitochondria relies on a number of interconnected processes, namely the mitochondrial unfolded protein response (UPR mt ), protein import and mitophagy. In particular, the post-transcriptional regulation of protein import into the organelle has generated considerable recent interest in view of its dynamic versatility. The capacity for import can be increased by chronic exercise, and diminished by muscle disuse, and defects in the import pathway can be rescued by exercise. Within mitochondria, the unfolded protein response (UPR) is activated if protein import is altered, or if protein misfolding takes place. This UPR generates retrograde signaling to the nucleus to activate compensatory gene expression and protein synthesis. Mitophagy is also elevated with age, contributing to the lower mitochondrial content in aging muscle. However, mitophagy is amenable to exercise adaptations, as it is activated with each exercise bout, presumably to mediate mitochondrial quality control. However, this response is attenuated in older subjects. Although not yet completely elucidated, numerous molecular processes involved in mitochondrial biogenesis and turnover are affected with age. The contrasting and often opposite consequences of exercise and age suggest that exercise can serve as non-pharmacological "mitochondrial medicine" for aging muscle to ameliorate mitochondrial content and function, via pathways that implicate organelle protein quality control mechanisms., Competing Interests: Declaration of competing interest The authors are not aware of any affiliations, memberships, funding or financial holdings that might be perceived as affecting the objectivity of this review., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Major depressive disorders (MDD) and chronic pain (CP) affect significant portion of the world's population and have high comorbidity rate. Social defeat stress (SDS) model was standardized in mice and can trigger depressive-like behavior and chronic pain. Based especially on clinical trials showing an effective preventive and therapeutic effect of physical exercise on CP and symptoms associated with MDD, this study aimed to investigate if the voluntary running wheel exercise can exert these effects in mice submitted to the 10-day SDS protocol, using fluoxetine as positive control. For this, we ran two set of experiments: in the first set mice started performing voluntary running wheel exercise after submitted to SDS and, in the second set, mice performed voluntary running wheel exercise before and during SDS. Mechanical and chemical hyperalgesia was analyzed through electronic von Frey and capsaicin test, respectively. Depressive-like behavior was assessed through social interaction test. Our results showed that the voluntary running wheel exercise was more effective than fluoxetine reversing the SDS-induced persistent hyperalgesia and both, fluoxetine and voluntary running wheel exercise, was effective reversing SDS-induced social avoidance. Also, voluntary running wheel exercise is an effective tool preventing both hyperalgesia and social avoidance induced by SDS. To the best of our knowledge, this was the first study using physical exercise as a therapeutic and preventive tool for chronic pain and depressive-like behavior simultaneously induced by social stress., (Copyright © 2019 IBRO. Published by Elsevier Ltd. All rights reserved.)

Decreased exercise capacity, which is an independent predictor of the poor prognosis of patients with heart failure (HF), is attributed to markedly impaired skeletal muscle mitochondrial function and fatty acid oxidation. Previous studies reported that the administration of an inhibitor of sodium-glucose cotransporter 2 (SGLT2) increases ketone body production and fat utilization in type 2 diabetic mice. In this study, we investigated the effects of SGLT2 inhibitor administration on exercise endurance and skeletal muscle mitochondrial function with fatty acid oxidation in a murine model of HF after the induction of myocardial infarction (MI). Two weeks post-MI, HF mice were divided into 2 groups, i.e., with or without treatment with the SGLT2 inhibitor empagliflozin (Empa, 300 mg/kg of food). Consistent with previous studies, urinary glucose and blood beta-hydroxybutyrate levels were increased in the HF+Empa mice compared with the sham and HF mice 4 weeks after the start of Empa administration. Exercise endurance capacity was limited in the HF mice but was ameliorated in the HF+Empa mice, without any effects on cardiac function, food intake, spontaneous physical activity, skeletal muscle strength, and skeletal muscle weight. Mitochondrial oxidative phosphorylation capacity with fatty acid substrates was reduced in the skeletal muscle of HF mice, and this decrease was ameliorated in the HF+Empa mice. Our results demonstrate that SGLT2 inhibitors may be novel therapeutics against reduced exercise endurance capacity in HF, by improving mitochondrial fatty acid oxidation in skeletal muscle., (Copyright © 2019 The Authors. Published by Elsevier B.V. All rights reserved.)

Myostatin is an inhibitor of skeletal muscle growth and might be involved in adaptations to caloric restriction (CR). We compared responses to 12-week 30% CR in male mice of Berlin high strain with myostatin dysfunction (BEH) and wild-type myostatin (BEH+/+). BEH mice were heavier than BEH+/+ mice (58.8 ± 2.0 versus 53.1 ± 2.7 g, p < 0.001), had 1.8-fold greater hind limb muscle mass and were less (p < 0.05) physically active when fed ad libitum. After CR, BEH and BEH+/+ strains experienced similar weight loss (24.7 ± 5.7 versus 20.6 ± 6.5%, p > 0.05, respectively) and decreases (p < 0.001) in plasma IGF-1 and total cholesterol, but loss of hind limb muscle mass was greater (p < 0.001) in BEH mice than BEH+/+ mice. BEH mice had better (p < 0.001) glucose tolerance and showed smaller (p < 0.05) improvements of it than BEH+/+ mice after CR (1038.2 ± 174.7 versus 744.4 ± 95.8 glucose mM× 120 min, p < 0.01 for BEH; 1365.8 ± 218.5 versus 831.5 ± 134.4 glucose mM ×120 min, p < 0.001, for BEH+/+, respectively). In summary, myostatin dysfunction is associated with muscle hypertrophy and high glucose tolerance, but greater muscle wasting and smaller improvements in glucose tolerance in response to CR., (Copyright © 2019 Elsevier Inc. All rights reserved.)

There is a gap in the knowledge regarding the regulation of glucose uptake in skeletal muscle during the development of insulin resistance in the elderly. Rho-Kinase (Rock) signaling has been demonstrated as a crucial mechanism related to glucose metabolism and insulin sensitivity in skeletal muscle. This kinase is involved in the insulin receptor substrate 1 (IRS1) phosphorylation, leading to glucose uptake stimulation in the skeletal muscle; however, the mechanisms elucidating the role of Rock regulation in the context of advanced ages are still limited. In this study, we submitted old Fischer 344 rats to short-term treadmill physical exercise protocol (5 days) and evaluated the glucose tolerance and proteins involved with Rock/insulin signaling in the skeletal muscle. Compared to young rats, the old rats showed glucose intolerance, hyperinsulinemia, and decreased phosphorylation in the proteins related to the insulin signaling pathway in the skeletal muscle, without changes in body mass and adiposity. Otherwise, when these rats were submitted to physical exercise, it was found decreased fasting glucose, higher glucose tolerance, decreased insulinemia, and upregulation of Rock2/pIRS1/pAkt/pGSK3β/GLUT4 pathway in the skeletal muscle. In summary, the aging process did not change Rock signaling, but the physical exercise was able to increase Rock2 content and insulin signaling pathway in the skeletal muscle. This finding suggests the benefic role of physical exercise to advanced ages, promoting insulin-sensitive effects with Rho-kinase contribution., (Copyright © 2019 Elsevier Inc. All rights reserved.)

It is known that a single session of high-intensity interval exercise (HIIE) contributes to the increase of the reactive species of oxygen, accompanied by a greater antioxidant activity. However, it is poorly understood if a single session of HIIE has similar effects on the brain tissue. This study evaluated the effects of a single HIIE on the hippocampal redox status. Sixteen males Wistar rats were allocated into HIIE (n = 8) and control (n = 8) groups. Maximum oxygen consumption (VO 2max ) was evaluated using a treadmill at 10° inclination in a metabolic chamber. HIIE group was submitted to a single run on the treadmill composed by 10 bouts of high-intensity exercise of 1 min each (85-100% of VO 2max ), at 28 m/min, 10° inclination, interspersed by 2 min of active recovery, at 10 m/min, with no inclination. Analysis of the redox status at the hippocampus were conducted 24 h after the HIIE session. It was not identified lipid peroxidation in the hippocampus of the HIIE group (Control 1.9 ± 0.31, vs HIIT 2.2 ± 0.53 nmol MDA/mg protein (p > .05). However, the activity of the superoxide dismutase (Control 2.614 ± 0.225 vs HIIT 3.718 ± 0.4589 U/mg protein), and the non-enzymatic total antioxidant capacity (Control 1584 ± 75.88 vs HIIT 1984 ± 137.7 nM FeSO4/mg protein) were enhanced (p < .05) after the exercise session. These results indicate that the antioxidant mechanisms are enhanced even after a single session of HIIE. A single session of HIIE does not induce lipid peroxidation and improves the antioxidant defenses in Wistar rats' hippocampus., (Copyright © 2019 Elsevier Inc. All rights reserved.)

The study aimed to explore the molecular mechanism of fluoxetine as an adjunct to therapeutic exercise to improve motor recovery using a rat cerebral ischemic model with middle cerebral artery occlusion (MCAO). We hypothesized that the nucleus accumbens (NAc) may be one of the responding areas to fluoxetine where relevant elevations in 5-hydroxytryptamine (5-HT) and ΔFosB were associated with motor behavioral recovery. Male Sprague-Dawley rats were randomly divided into five groups: rats without intervention; rats that underwent MCAO without exercise or fluoxetine; rats that underwent MCAO treated only with fluoxetine; rats that underwent MCAO treated only with exercise; and rats that underwent MCAO treated with both exercise and fluoxetine. Motor function and motivation were assessed by the fault footsteps test and the forced swimming test. 5-HT level in the bilateral NAc and the expression of 5-HT 2C receptor (5-HT 2C R) and ΔFosB in the ipsilesional (left) NAc were measured. Correlation was explored by Pearson correlation analysis. Our results indicated that either treatment helped improve the grasp dexterity of the affected limb, motor motivation, and resilience to adverse environment in MCAO rats. The dual treatment with fluoxetine and exercise may hasten the recovery process. The dual treatment helped restore the balance of 5-HT level between the bilateral NAc by significantly increasing its level in the ipsilesional side. Either treatment could resume the expression of 5-HT 2C R in the ipsilesional side of the NAc close to the normal level, which was correlated with motor recovery. The dual treatment significantly increased the expression of ΔFosB in the ipsilesional side of the NAc, which was correlated with the balance of 5-HT in the bilateral NAc, but not directly with motor recovery. In conclusion, the NAc may play an important role in driving physical motivation, which was possibly related to motor recovery after stroke. Fluoxetine may hasten the effectiveness of therapeutic exercise, possibly via regulating 5-HT and its receptors in the NAc., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Sleep fragmentation (SF) commonly occurs in several pathologic conditions and is especially associated with impairments of hippocampus-dependent neurocognitive functions. Although the effects of SF on hippocampus in terms of protein or gene levels were examined in several studies, the impact of SF at the metabolite level has not been investigated. Thus, in this study, the differentially expressed large-scale metabolite profiles of hippocampus in a rat model of SF were investigated using untargeted metabolomics approaches. Forty-eight rats were divided into the following 4 groups: 4-day SF group, 4-day exercise control (EC) group, 15-day SF group, and 15-day EC group (n = 12, each). SF was accomplished by forced exercise using a walking wheel system with 30-s on/90-s off cycles, and EC condition was set at 10-min on/30-min off. The metabolite profiles of rat hippocampi in the SF and EC groups were analyzed using liquid chromatography/mass spectrometry. Multivariate analysis revealed distinctive metabolic profiles and marker signals between the SF and corresponding EC groups. Metabolic changes were significant only in the 15-day SF group. In the 15-day SF group, L-tryptophan, myristoylcarnitine, and palmitoylcarnitine were significantly increased, while adenosine monophosphate, hypoxanthine, L-glutamate, L-aspartate, L-methionine, and glycerophosphocholine were decreased compared to the EC group. The alanine, aspartate, and glutamate metabolism pathway was observed as the common key pathway in the 15-day SF groups. The results from this untargeted metabolomics study provide a perspective on metabolic impact of SF on the hippocampus., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Neuroschistosomiasis is a severe form of presentation of schistosomiasis in which Schistosoma spp. affects the central nervous system. This is the first study performed to analyze whether there is any relationship between physical effort and the appearance of neuroschistosomiasis, through clinical, molecular and immunological evaluations. An experimental controlled study using 64 male Balb/c inbred mice divided into four groups according to presence or absence of S. mansoni infection and submitted to physical effort or resting was conducted. Thirteen weeks after exercise training, S. mansoni DNA was detected in the brain or spinal cord in about 30% of the infected animals moreover, only S. mansoni-positive samples showed positive labeling for S. mansoni antigens in the brain or spinal cord, with a striking reaction inside the microglia. However, the behavioral tests did not show any clinical symptoms of neuroschistosomiasis in animals submitted to physical effort or in resting. In animals with S. mansoni-positive DNA, immunohistochemical data revealed astrogliosis and microgliosis, elevated IL-10 levels and decreased TNF-α expression. This study demonstrated that isometric exercise does not promote neuroschistosomiasis, furthermore, ectopic forms of schistosomiasis in the central nervous system were largely asymptomatic and exhibited a Th2 immune response profile. More experimental studies are necessary in order to characterize the pathological process of experimental neuroschistosomiasis., (Copyright © 2019. Published by Elsevier Inc.)

Intrinsic exercise capacity is predictive of both lifespan and healthspan but whether adaptive exercise capacity influences the benefits achieved from aerobic training implemented later in life is not known., Aim: To determine if exercise late in life provides any functional improvements or underlying beneficial biochemical adaptations in rats bred to have a high response to training (HRT rats) or little to no response to training (LRT rats)., Methods: Adult (11 months) and old (22 months) female LRT and HRT rats either remained sedentary (SED) or were exercised (EXER) on a treadmill 2-3 times/week at 60% of their initial maximum running speed and distance for 4 months. At 26 months of age, exercise capacity was re-evaluated and extensor digitorum longus, gastrocnemius (GTN), and tibialis anterior (TA) muscles were excised for histological and biochemical analysis., Results: Both SED-HRT and SED-LRT rats showed decreased exercise capacity from 22 to 26 months, but with 4 months of treadmill training, EXER-HRT rats displayed a 50% improvement in exercise capacity while EXER-LRT rats maintained pre-training levels. Protein levels of antioxidant enzymes PRDX3, CuZnSOD, and PRXV were 6-fold greater in TA muscles of aged HRT rats compared to LRT rats. PGC-1α protein levels were ~2-fold greater in GTN and TA muscles of aged HRT than in LRT rats and TFAM protein was similarly elevated in GTN muscles of aged HRT rats compared with LRT rats. BNIP3 protein levels were 5-fold greater in TA muscles of aged HRT than in LRT rats while PINK1 protein content was reduced by 78% in GTN muscles of aged HRT rats compared with LRT rats., Conclusion: HRT rats retained the ability to improve exercise capacity into late life and that ability was associated with inherent and adaptive changes in antioxidant enzyme levels and markers of and mitochondrial quality related to healthspan benefits in aging. Moreover, low intensity exercise prevented the age-associated decline in functional exercise capacity in LRT rats., (Copyright © 2019 Elsevier Inc. All rights reserved.)

We investigated whether wheel running for just 30 min on 5 days each week, an exercise routine based on recommended levels of physical activity for adults, regulates body weight and food intake in mice. Male C57BL/6 mice were divided into groups and given ad libitum access to high-fat food and standard chow or standard chow only. For 30 min on 5 days each week, mice were treated with an in-cage running wheel which was either open to allow voluntary exercise or locked and could not rotate for control. Wheel running reduced weight gain and fat mass among mice fed high-fat food and standard chow, but not mice fed standard chow only. Wheel running decreased high-fat food consumption. Standard chow intake was unchanged. Mice provided with a locked running wheel but pair-fed the same amount of food as wheel running mice also displayed reduced weight gain and fat mass. We conclude that voluntary wheel running for 30 min on 5 days each week reduced weight gain and fat mass in mice by preferentially decreasing high-fat food intake. This model of voluntary wheel running can be used to investigate mechanisms underlying the benefits of exercise on body weight and food intake, informing obesity intervention strategies for humans., (Copyright © 2019 Elsevier Inc. All rights reserved.)

A single session of aerobic exercise may offer one means to "prime" motor regions to be more receptive to the acquisition of a motor skill; however, the mechanisms whereby this priming may occur are not clear. One possible explanation may be related to the post-translational modification of plasticity-related receptors and their associated intracellular signaling molecules, given that these proteins are integral to the development of synaptic plasticity. In particular, phosphorylation governs the biophysical properties (e.g., Ca 2+ conductance) and the migratory patterns (i.e., trafficking) of plasticity-related receptors by altering the relative density of specific receptor subunits at synapses. We hypothesized that a single session of exercise would alter the subunit phosphorylation of plasticity-related receptors (AMPA receptors, NMDA receptors) and signaling molecules (PKA, CaMKII) in a manner that would serve to prime motor cortex. Young, male Sprague-Dawley rats (n = 24) were assigned to either exercise (Moderate, Exhaustion), or non-exercising (Sedentary) groups. Immediately following a single session of treadmill exercise, whole tissue homogenates were prepared from both the motor cortex and hippocampus. We observed a robust (1.2-2.0× greater than sedentary) increase in tyrosine phosphorylation of AMPA (GluA1,2) and NMDA (GluN2A,B) receptor subunits, and a clear indication that exercise preferentially affects pPKA over pCaMKII. The changes were found, specifically, following moderate, but not maximal, acute aerobic exercise in both motor cortex and hippocampus. Given the requirement for these proteins during the early phases of plasticity induction, the possibility exists that exercise-induced priming may occur by altering the phosphorylation of plasticity-related proteins., (Copyright © 2019 IBRO. Published by Elsevier Ltd. All rights reserved.)

The mechanisms involved in unloading-induced skeletal muscle loss may be age-specific, and the evidence for exercise preconditioning-induced protection against disuse muscle atrophy in aged rats is limited. Therefore, in this study, we investigated age-related differences in the activation of the HDAC4/Gadd45α pathway following hindlimb unloading (HU). We also assessed the protective effect of preconditioning exercise on this pathway in young and old rat gastrocnemius muscle. Three-month-old (young, n = 18) and 24-month-old (old, n = 18) male Wistar rats were assigned to the following groups: control group (n = 6), seven days of HU group (n = 6), and a bout of exercise preconditioning prior to HU (Ex+HU) group (n = 6). Rats of both ages in the Ex + HU group ran continuously on a motor-driven treadmill (0° slope, 20 m/min, 15 min) prior to HU. The gastrocnemius muscles were removed after 7 days of HU and analyzed for protein content and mRNA expression. Gastrocnemius muscle weight was significantly higher in the Ex+HU group than in the HU group of old rats, but not in young rats. Levels of HDAC4 protein and mRNA were significantly increased in the old HU group. However, the increase was significantly suppressed in the old Ex+HU group. Moreover, the protective effect of exercise preconditioning had a positive effect on Gadd45α mRNA and protein levels only in the old Ex+HU group. No exercise preconditioning-related protection was observed in the young rats. Our data indicated that a single bout of preconditioning exercise prior to HU may exert a protective effect in disuse muscle atrophy in old rats and that these effects may be partially mediated by the HDAC4/Gadd45α axis., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Physical exercise is now generally considered as a strategy to maintain cognitive abilities and to prevent age-related cognitive decline. In the present study, Wistar rats were subjected to moderate intensity treadmill exercise for 6 months prior to sacrifice at 12-, 24- and 32-month of age. This chronic physical intervention was tested on motility in the Open field (OF). Cognitive functions were measured in the Morris water maze (MWM) for spatial learning and in the Novel object recognition (NOR) tests. Since learning and memory are closely associated with cholinergic forebrain function ChAT fiber density after exercise training was assessed in hippocampus, and motor- and somatosensory cortical areas. Furthermore, quantification of ChAT-positive fiber aberrations as a neuropathological marker was also carried out in these brain areas. Our results show that in OF chronic exercise maintained horizontal locomotor activity in all age groups. Rearing activity, MWM and notably NOR performance were improved only in the 32-months old animals. Regarding cholinergic neuronal innervation, apart from a general age-related decline, exercise increased ChAT fiber density in the hippocampus CA1 area and in the motor cortex notably in the 32-months group. Massive ChAT fiber aberrations in all investigated areas which developed in senescence were clearly attenuated by exercise. The results suggest that moderate intensity chronic exercise in the rat is especially beneficial in advanced age. In conclusion, chronic exercise attenuates the age-related decline in cognitive and motor behaviors as well as age-related cholinergic fiber reduction, reduces malformations of cholinergic forebrain innervation., (Copyright © 2019 IBRO. Published by Elsevier Ltd. All rights reserved.)