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To investigate the role of JAK2/STAT3 signaling pathway in neural function recovery in rats with spinal cord injury (SCI) after treadmill training. Sprague-Dawley rats were randomly divided into four groups: (a) sham group; (b) SCI group; (c) SCI+treadmill training group (SCI/TT); and (d) SCI/TT+AG490 group (a JAK2 inhibitor) ( n  = 12). The 12 Sprague-Dawley rats in each group were randomly assigned into 1 st , 3 rd , 7 th , and 14 th  day subgroups. The Basso-Beattie-Bresnahan (BBB) locomotor rating scale was used to assess the spinal cord function, and JAK2, STAT3, and IL-6 protein expressions in the rat spinal cord were evaluated by western blot. The level of cell apoptosis and expressions of apoptotic proteins were evaluated by TUNEL assay and immunohistochemistry, respectively. Rats in the SCI+TT group showed a significantly higher BBB score after SCI compared with the SCI group and the SCI/TT+AG490 group. Mechanistically, the JAK2/STAT3 signal pathway was immediately activated after SCI compared with sham group, and JAK2 and STAT3 were obviously upregulated when treadmill training was performed ( P  < 0.05). Results of TUNEL assay showed that the apoptotic rate in SCI/TT was significantly lower than that in the SCI group and SCI/TT+AG490 group ( P  < 0.05). Besides, the IL-6 expression in the SCI/TT group was significantly attenuated compared with the SCI group ( P  < 0.05). Our results showed that physical treadmill training can enhance activation of JAK2/STAT3 signal pathway and attenuate apoptosis in the injured spinal cord, resulting in better functional recovery. These results underline the importance of synergistic treatment strategies for SCI., (Copyright © 2024 The Author(s). Published by Wolters Kluwer Health, Inc.)

Mitochondria play a crucial role in maintaining cellular energy supply and serve as a source of energy for repairing nerve damage following a stroke. Given that exercise has the potential to enhance energy metabolism, investigating the impact of exercise on mitochondrial function provides a plausible mechanism for stroke treatment. In our study, we established the middle cerebral artery occlusion (MCAO) model in Sprague-Dawley rats and implemented early exercise intervention. Neurological severity scores, beam-walking test score, and weight were used to evaluate neurological function. The volume of cerebral infarction was measured by MRI. Nerve cell apoptosis was detected by TUNEL staining. Mitochondrial morphology and structure were detected by mitochondrial electron microscopy. Mitochondrial function was assessed using membrane potential and ATP measurements. Western blotting was used to detect the protein expression of AMPK/PGC-1α/GLUT4. Through the above experiments, we found that early exercise improved neurological function in rats after MCAO, reduced cerebral infarction volume and neuronal apoptosis, promoted the recovery of mitochondrial morphology and function. We further examined the protein expression of AMPK/PGC-1α/GLUT4 signaling pathway and confirmed that early exercise was able to increase its expression. Therefore, we suggest that early exercise initiated the AMPK/PGC-1α/GLUT4 signaling pathway, restoring mitochondrial function and augmenting energy supply. This, in turn, effectively improved both nerve and body function in rats following ischemic stroke., (Copyright © 2024 Wolters Kluwer Health, Inc. All rights reserved.)

Introduction: d-Glucosamine (GlcN) is one of the most widely consumed dietary supplements and complementary medicines in the world and has been traditionally used to attenuate osteoarthritis in humans. GlcN extends life span in different animal models. In humans, its supplementation has been strongly associated with decreased total mortality and improved vascular endothelial function. GlcN acts as a suppressor of inflammation, and by inhibiting glycolysis, it can activate the metabolism of stored fat and mitochondrial respiration., Methods: The conventional human GlcN dose is 1500 mg·d-1, but extensive evidence indicates that much higher doses are well tolerated. GlcN is one of the supplements that has experienced a greater use in the last years in elite athletes mainly because of its potential chondroprotective effects that may promote cartilage health. However, the possibility of it being an ergogenic aid has not been explored. We aimed to study the potential beneficial effects of GlcN on mitochondrial content, physical performance, and oxidative stress in mice that were aerobically trained and supplemented with three different doses of glucosamine (250, 500, and 1000 mg·kg-1) for 6 wk. We measured exercise performance (grip strength, motor coordination, and running capacity) before and after the training period. Proteins involved in mitochondrial biogenesis (AMPK, PGC-1, NRF-1, SIRT-1, cytochrome c, citrate synthase), markers of oxidative stress (GSSG/GSH) or damage (malondialdehyde, carbonylated proteins), antioxidant enzymes (NRF-2, SOD1, SOD2, catalase, and PRDX6), and MAPKs (p38 and ERK1/2 were also determined in skeletal muscle., Results and Conclusions: Our results show that GlcN supplementation in aerobically trained mice, at doses equivalent to those conventionally used in humans, increases the protein levels of mitochondrial biogenesis markers, improves motor coordination, and may have a synergistic effect with exercise training on running distance., (Copyright © 2021 by the American College of Sports Medicine.)

Purpose: Physical exercise (PE) combined with nutritional approaches has beneficial effects that are widely advocated to improve metabolic health. Here we used voluntary PE together with vitamin D (VD) supplementation, which has already shown beneficial effects in primary and tertiary prevention in obese mice models, to study their combined additive effects on body weight management, glucose homeostasis, metabolic inflammation, and liver steatosis as key markers of metabolic health., Methods: Ten-week-old male C57BL/6J mice were fed a high-fat/sucrose (HFS) diet for 10 wk, then assigned to a 15-wk intervention period with PE, VD supplementation, or both PE and VD supplementation. Morphological, histological, and molecular phenotype data were characterized., Results: The HFS-induced increases in body mass, adiposity, and adipocyte hypertrophy were improved by PE but not by VD supplementation. The HFS-induced inflammation (highlighted by chemokines mRNA levels) in inguinal adipose tissue was decreased by PE and/or VD supplementation. Furthermore, the intervention combining PE and VD showed additive effects on restoring insulin sensitivity and improving hepatic steatosis, as demonstrated through a normalization of size and number of hepatic lipid droplets and triglyceride content and a significant molecular-level decrease in the expression of genes coding for key enzymes in hepatic de novo lipogenesis., Conclusions: Taken together, our data show beneficial effects of combining PE and VD supplementation on obesity-associated comorbidities such as insulin resistance and hepatic disease in mice. This combined exercise-nutritional support strategy could prove valuable in obesity management programs., (Copyright © 2021 by the American College of Sports Medicine.)

Background: Brown adipose tissue (BAT) is an important tissue for thermogenesis, making it a potential target to decrease the risks of obesity, type 2 diabetes, and cardiovascular disease, and recent studies have also identified BAT as an endocrine organ. Although BAT has been implicated to be protective in cardiovascular disease, to this point there are no studies that identify a direct role for BAT to mediate cardiac function., Methods: To determine the role of BAT on cardiac function, we utilized a model of BAT transplantation. We then performed lipidomics and identified an increase in the lipokine 12,13-dihydroxy-9Z-octadecenoic acid (12,13-diHOME). We utilized a mouse model with sustained overexpression of 12,13-diHOME and investigated the role of 12,13-diHOME in a nitric oxide synthase type 1 deficient (NOS1 -/- ) mouse and in isolated cardiomyocytes to determine effects on function and respiration. We also investigated 12,13-diHOME in a cohort of human patients with heart disease., Results: Here, we determined that transplantation of BAT (+BAT) improves cardiac function via the release of the lipokine 12,13-diHOME. Sustained overexpression of 12,13-diHOME using tissue nanotransfection negated the deleterious effects of a high-fat diet on cardiac function and remodeling, and acute injection of 12,13-diHOME increased cardiac hemodynamics via direct effects on the cardiomyocyte. Furthermore, incubation of cardiomyocytes with 12,13-diHOME increased mitochondrial respiration. The effects of 12,13-diHOME were absent in NOS1 -/- mice and cardiomyocytes. We also provide the first evidence that 12,13-diHOME is decreased in human patients with heart disease., Conclusions: Our results identify an endocrine role for BAT to enhance cardiac function that is mediated by regulation of calcium cycling via 12,13-diHOME and NOS1.

Spinal cord injury (SCI) causes motor dysfunction and depression, which hinders the recovery of motor function. Body weight-supported treadmill training (BWSTT) should be considered an effective method for functional rehabilitation after SCI, as it is an efficacious intervention in healthcare with no side effects. Because exercise exerts different effects on motor function recovery and inhibiting depression after SCI, we aimed to determine the appropriate intensity of BWSTT. In this study, fixed durations, frequencies, and percentages of BWSTT with different speeds of BWSTT (7, 15, and 21 cm/s) were chosen to explore the appropriate intensity, which affected the recovery of motor function and antidepressant effects on SCI rats. Based on our results, BWSTT at 21 cm/s produced the best outcomes for motor function recovery and the spinal cord levels of brain-derived neurotrophic factor (BDNF) and tropomyosin receptor kinase B (TrkB). The antidepressant effects of BWSTT at 15 and 21 cm/s were confirmed based on the increasing sucrose preference, the time spent in the central area and social time, and reduced immobility time. BWSTT at 15 and 21 cm/s improved the modulation of the hypothalamic-pituitary-adrenal axis by decreasing serum corticosterone levels and increasing hippocampal glucocorticoid receptor levels. In addition, higher levels of neurogenesis-related proteins were observed in the hippocampus of the group subjected to BWSTT at 21 cm/s than in the other groups. Thus, BWSTT at 21 cm/s is a potentially favorable treatment that synchronously improves motor function recovery and exerts an antidepressant effect.

Introduction: Cancer-related fatigue and muscle wasting have received significant attention over the last few decades with the goal of establishing interventions that can improve cancer patient life quality and survival. Increased physical activity has shown to reduce cancer-associated fatigue and has been proposed as a promising therapeutic to attenuate cancer-induced wasting. However, significant gaps remain in our understanding of how physical activity affects the compositional and functional changes that initiate muscle wasting. The purpose of the current study was to determine the effect of wheel exercise on body composition and functional indices of cancer cachexia before the development of significant wasting., Methods: Thirteen-week-old male Apc (MIN) and C57BL/6 (B6) mice were given free wheel access (W) or a locked wheel (Sed) for 5 wk., Results: Wheel activity was reduced in the MIN compared with B6; however, wheel access increased complex II expression in isolated skeletal muscle mitochondria regardless of genotype. Wheel access had no effect on tumor burden or plasma interleukin-6 in the MIN. MIN-W increased body weight and lean mass compared with MIN-Sed, and there was a direct correlation between wheel distance and lean mass change. MIN-W increased grip strength and treadmill time to fatigue compared with MIN-Sed. Within MIN-W mice, skeletal muscle fatigability was only improved in high runners (>60 min·d)., Conclusions: Our results suggest that there were therapeutic benefits of increased activity related to body composition, behavior, and whole-body function that were not dependent on exercise duration; however, there was an exercise threshold needed to improve skeletal muscle fatigability in tumor-bearing mice. Interestingly, wheel access was able to improve compositional and functional outcomes without mitigating tumor number or size.

Introduction: Skeletal muscle is the major producing and metabolizing site of lactic acid. A family of monocarboxylate transporter (MCT) proteins, especially MCT1 and MCT4, are involved in the lactate-pyruvate exchange and metabolism. Nuclear factor erythroid 2-related factor 2 (Nrf2) is a pivotal coordinator of antioxidant response and energy metabolism, and has been reported to associate with the physiological functions of the skeletal muscle., Methods: In this study, C57BL/6 J mice were administrated with an Nrf2 activator, sulforaphane (SFN) before taking incremental treadmill exercise to exhaustion under hypoxia; then the effects of SFN on exercise endurance and molecular/biochemical makers of the skeletal muscle were evaluated., Results: The results indicated that SFN pretreatment enhanced the exercise endurance under hypoxia. SFN not only increased the expressions of antioxidant genes and activity of antioxidant enzymes, but also significantly increased the mRNA and protein levels of MCT1 and CD147, but not MCT4. Moreover, the expressions of LDH-B and LDH activity of converting lactate into pyruvate, as well as citrate synthase activity were significantly higher, whereas the LDH activity of converting pyruvate into lactate and blood lactate level were remarkably lower in the SFN-exercise mice than those of the phosphate-buffered saline-exercise group. Furthermore, Atf3Δzip2 (the alternatively spliced isoform of activating transcription factor-3) mRNA was increased by the exercise and further potentiated by SFN., Conclusion: These results show, for the first time, that SFN increases MCT1 expression in the skeletal muscle under acute hypoxic exercise and suggest that Nrf2 activation is a promising strategy to enhance exercise performance under hypoxia.

Purpose: Exercise training and some herbal components have an anticancer function and can suppress tumor growth. However, the role of these protective factors in altering breast cancer-related gene expression is still unknown. Thus, this study aimed to assess the effect of 4 wk of high-intensity interval training (HIIT) and saffron (Crocus sativus L.) aqueous extract (SAE) on Sirtuin-1 (SIRT1), human telomerase reverse transcriptase (hTERT), and p53 gene expression in female mice breast tumor tissue induced by 4T1 cell line., Methods: This study was performed on female BALB/c mice. The 4T1 breast cancer cells were subcutaneously implanted, and mice were randomly sorted into the following groups: control, HIIT, SAE, HIIT + SAE (n = 10 mice per group), and sham (n = 4 mice per group). Mice were sacrificed at the end of the intervention period, and the expression of SIRT-1, hTERT, and p53 was determined by real-time polymerase chain reaction., Results: The mRNA level of SIRT1 was increased in the HIIT + SAE group compared with the HIIT and control groups (P = 0.007 and P = 0.03, respectively). Moreover, the amount of mRNA of p53 was increased after a 4-wk HIIT compared with the control and HIIT + SAE groups in tumor tissue (P = 0.03 and P = 0.02, respectively). No change was found in the mRNA expression of hTERT between groups (P = 0.92)., Conclusions: These findings suggest that HIIT may reduce tumor burden through the upregulation of p53 associated with tumor suppression pathway. In contrast, the combination of HIIT and SAE did not alter p53 and SIRT1 expression levels and may suppress tumor growth by other mechanisms.

Recent study has demonstrated that high-intensity interval training (HIIT) and moderate-intensity continuous training (MICT) have the same effect to alleviate β-amyloid pathology in the hippocampus of APPswe/PS1dE9 (APP/PS1) mice. Activation of nucleotide binding and oligomerization domain-like receptor family pyrin domain containing 3 (NLRP3) inflammasome is pivotal and has been demonstrated to accelerate β-amyloid accumulation. The present study aimed to examine whether the exercise-induced β-amyloid reduction was associated with changes in NLRP3 inflammasome activation. APP/PS1 transgenic mice were randomly assigned to a transgenic sedentary group, HIIT group and MICT group. Nontransgenic littermates were used as wild-type sedentary group. Mice in HIIT and MICT groups were subjected to treadmill exercise for 12 weeks, 5 days/week. The results showed that compared with transgenic sedentary group, β-amyloid deposition in the hippocampus of HIIT and MICT groups were significantly reduced. Moreover, both HIIT and MICT groups displayed significant increases in the expression of microglial phagocytic receptors triggering receptor expressed on myeloid cells 2, CD36 and scavenger receptor class A compared with transgenic sedentary group. In addition, HIIT and MICT had the same effect to inhibit NLRP3 inflammasome activation, as evidenced by significant reduction in IL-1β, active caspase-1p20, NLRP3 and apoptosis-associated speck-like protein containing a caspase activating and recruitment domain (ASC) levels as well as decreased NLRP3/ASC colocalization. These findings indicate that HIIT appears to be an effective intervention as MICT to reduced β-amyloid deposition by regulating NLRP3 inflammasome-controlled microglial phagocytosis.

Motor paralysis is a severe consequence of intracerebral hemorrhage (ICH) that reduces patient quality of life. Rehabilitation is beneficial for stroke patients. However, functional recovery depends on the exercise type, and which factors are effective during rehabilitation are unknown. We aimed to clarify the effect of voluntary and forced exercises for functional recovery in ICH rats. Male Sprague-Dawley rats were divided into three groups: forced treadmill running (F-Ex.), voluntary wheel cage running (V-Ex.) and no exercise (Non-Ex.). The effects of the two exercises on motor recovery were analyzed by determining the motor deficit score and using the beam walking test. Stress and motivation status after rehabilitation were determined by corticosterone concentrations (ELISA) and immunoreactivity of ΔFosB (immunohistochemistry) in the nucleus accumbens, respectively. Significantly enhanced motor functional recovery was observed in the two trained groups compared with that in the Non-Ex. group. Of note, recovery in the V-Ex. group was greater than that in the F-Ex. group. To investigate the motivation and stress related to the exercises, the expression of ΔFosB in the nucleus accumbens and corticosterone concentration were compared after rehabilitation. In the V-Ex. group, there was a significant increase of ΔFosB, and in the F-Ex. Group, there was a high concentration of corticosterone. These data suggest that the effect of training for motor recovery was enhanced by motivation and reduced by stress.

Purpose: Endurance exercise (EXE) preconditioning before DOX treatment confers cardioprotection; however, whether EXE postconditioning (i.e., EXE intervention after the completion of DOX treatment) is cardioprotective remains unknown. Thus, the aim of the present study was to investigate if EXE postconditioning provides cardioprotection by testing the hypothesis that EXE-autophagy upregulation and NADPH oxidase 2 (NOX2) downregulation would be linked to cardioprotection against DOX-induced cardiotoxicity., Methods: C57BL/6 male mice were assigned into three groups: control (CON, n = 10), doxorubicin (DOX, n = 10), and doxorubicin + endurance exercise (DOX + EXE, n = 10). Animals assigned to DOX and DOX + EXE groups were intraperitoneally injected with DOX (5 mg·kg each week for 4 wk). Forty-eight hours after the last DOX treatment, the mice assigned to DOX + EXE performed EXE on a motorized treadmill at a speed of 13-15 m·min for 60 min·d for 4 wk., Results: EXE prevented DOX-induced apoptosis and mitigated tissue damages. Although DOX did not modulate auto/mitophagy, EXE significantly enhanced its flux (increased LC3-II levels, reduced p62 levels, and increased autophagosomes with mitochondria) along with increased mitochondrial fission (DRP1) and reduced fusion markers (OPA1 and MFN2). Interestingly, EXE-induced autophagy against DOX occurred in the absence of alterations of autophagy inducer AMPK or autophagy inhibitor mTOR signaling. EXE prohibited DOX-induced oxidative damages by suppressing NOX2 levels but without modulating other key antioxidant enzymes including MnSOD, CuZnSOD, catalase, and GPX1/2., Conclusion: Our data provide novel findings that EXE-induced auto/mitophagy promotion and NOX2 downregulation are linked to cardioprotection against DOX-induced cardiotoxicity. Importantly, our study shows that EXE postconditioning intervention is effective and efficacious to prevent DOX-induced cardiac injuries.

Rationale: αCGRP (α calcitonin gene-related peptide), one of the strongest vasodilators, is cardioprotective in hypertension by reducing the elevated blood pressure., Objective: However, we hypothesize that endogenous, physical activity-induced αCGRP has blood pressure-independent cardioprotective effects in chronic hypertension., Methods and Results: Chronically hypertensive (one-kidney-one-clip surgery) wild-type and αCGRP -/- sedentary or voluntary wheel running mice were treated with vehicle, αCGRP, or the αCGRP receptor antagonist CGRP8-37. Cardiac function and myocardial phenotype were evaluated echocardiographically and by molecular, cellular, and histological analysis, respectively. Blood pressure was similar among all hypertensive experimental groups. Endogenous αCGRP limited pathological remodeling and heart failure in sedentary, chronically hypertensive wild-type mice. In these mice, voluntary wheel running significantly improved myocardial phenotype and function, which was abolished by CGRP8-37 treatment. In αCGRP -/- mice, αCGRP treatment, in contrast to voluntary wheel running, improved myocardial phenotype and function. Specific inhibition of proliferation and myofibroblast differentiation of primary, murine cardiac fibroblasts by αCGRP suggests involvement of these cells in αCGRP-dependent blunting of pathological cardiac remodeling., Conclusions: Endogenous, physical activity-induced αCGRP has blood pressure-independent cardioprotective effects and is crucial for maintaining cardiac function in chronic hypertension. Consequently, inhibiting endogenous αCGRP signaling, as currently approved for migraine prophylaxis, could endanger patients with hypertension.

Background: There is increasing evidence that endurance exercise is associated with increased risk of atrial fibrillation (AF). However, it is unknown if the relationship between endurance exercise and AF is dependent on an atrial myopathy., Methods: Six cardiac-specific TGF (transforming growth factor)-β1 transgenic and 6 wild-type (WT) goats were utilized for these studies. Pacemakers were implanted in all animals for continuous arrhythmia monitoring and AF inducibility. AF inducibility was evaluated using 5 separate 10 s bursts of atrial pacing (160-200 ms). Three months of progressive endurance exercise (up to 90 minutes at 4.5 mph) was performed. Quantitative assessment of circulating microRNAs and inflammatory biomarkers was performed., Results: Sustained AF (≥30 s) was induced with 10 s of atrial pacing in 4 out of 6 transgenic goats compared with 0 out of 6 WT controls at baseline ( P <0.05). No spontaneous AF was observed at baseline. Interestingly, between 2 and 3 months of exercise 3 out of 6 transgenic animals developed self-terminating spontaneous AF compared with 0 out of 6 WT animals ( P <0.05). There was an increase in AF inducibility in both transgenic and WT animals during the first 2 months of exercise with partial normalization at 3 months (transgenic 67%; 100%; 83% versus WT 0%; 67%; 17%). These changes in AF susceptibility were associated with a decrease in circulating microRNA-21 and microRNA-29 during the first 2 months of exercise with partial normalization at 3 months in both transgenic and WT animals. Finally, MMP9 (matrix metallopeptidase 9) was increased during the second and third months of exercise training., Conclusions: This study demonstrates a novel transgenic goat model of cardiac fibrosis (TGF-β1 overexpression) to demonstrate that endurance exercise in the setting of an underlying atrial myopathy increases the incidence of spontaneous AF. Furthermore, endurance exercise seems to increase inducible AF secondary to altered expression of key profibrotic biomarkers that is independent of the presence of an atrial myopathy.

Purpose: To compare the effects of 8-wk eccentric (ECC) versus concentric (CON) training using downhill and uphill running in rats on whole body composition, bone mineral density (BMD), and energy expenditure., Methods: Animals were randomly assigned to one of the following groups: 1) control (CTRL), 2) +15% uphill-running slope (CON), 3) -15% downhill-running slope (ECC15), and 4) -30% downhill-running slope (ECC30). Those programs enabled to achieve conditions of isopower output for CON and ECC15 and of iso-oxygen uptake (V˙O2) for CON and ECC30. Trained rats ran 45 min at 15 m·min five times per week. Total body mass, fat body mass, and lean body mass (LBM) measured through EchoMRI™, and 24-h energy expenditure including basal metabolic rate (BMR) assessed using PhenoMaster/LabMaster™ cage system were obtained before and after training. At sacrifice, the right femur was collected for bone parameters analysis., Results: Although total body mass increased in all groups over the 8-wk period, almost no change occurred for fat body mass in exercised groups (CON, -4.8 ± 6.18 g; ECC15, 0.6 ± 3.32 g; ECC30, 2.6 ± 6.01 g). The gain in LBM was mainly seen for ECC15 (88.9 ± 6.85 g) and ECC30 (101.6 ± 11.07 g). ECC was also seen to positively affect BMD. An increase in BMR from baseline was seen in exercise groups (CON, 13.9 ± 4.13 kJ·d; ECC15, 11.6 ± 5.10 kJ·d; ECC30, 18.3 ± 4.33 kJ·d) but not in CTRL one. This difference disappeared when BMR was normalized for LBM., Conclusions: Results indicate that for iso-V˙O2 training, the impact on LBM and BMD is enhanced with ECC as compared with CON, and that for isopower but lower V˙O2 ECC, an important stimulus for adaptation is still observed. This provides further insights for the use of ECC in populations with cardiorespiratory exercise limitations.

Introduction: Cancer cachexia is characterized by loss of muscle mass and function. Increased protein catabolism, inflammation, impaired anabolism, and mitochondrial function markedly contribute to the pathogenesis of this syndrome. Physical activity has been suggested as a useful tool to prevent or at least delay the onset and progression of cancer-induced muscle wasting. Two main types of exercise can be adopted, namely, resistance and endurance training. The present study is aimed to investigate the effectiveness of a combined (resistance + endurance) exercise protocol in preventing/reverting cancer-induced muscle wasting., Methods: Mice bearing the C26 colon carcinoma have been used as a model of cancer cachexia. They have been exposed to combined exercise training during 6 wk (4 before tumor implantation, 2 during tumor growth). Climbing a 1-m ladder inclined at 85° has been used for resistance training, while aerobic (endurance) exercise has been carried out on the same day using a motorized wheel., Results: In C26-bearing mice, both muscle mass and strength are improved by combined training, while just the latter increased in exercised healthy animals. Such a pattern is associated with modulations of two markers of autophagy, namely, LC3B-I/II ratio, increased in sedentary tumor hosts and reduced in exercised C26-bearing mice, and p62, steadily increased in both sedentary and trained tumor-bearing animals. Finally, combined training is not able to modify PGC-1α protein levels, but it improves succinate dehydrogenase activity, both reduced in the muscle of the C26 hosts., Conclusion: The data reported in the present study show that combined training improves muscle mass and function in the C26 hosts, likely modulating autophagy and improving mitochondrial function; these observations suggest that combined exercise might become part of a multimodal approach to treat cancer cachexia.

The deposition of amyloid-β (Aβ) is one of the major pathological hallmarks of Alzheimer's disease (AD), and a higher cholesterol level is involved in the deposition of Aβ. Previous evidence suggested that exercise exerts neuroprotective effects in a variety of AD models. In the present study, we investigated the effects of a 12-week treadmill exercise program on Aβ deposits in amyloid precursor protein (APP)/presenilin 1 (PS1) transgenic mice and the potential underlying mechanism. After 12 weeks of exercise, Aβ deposits were significantly decreased in the hippocampus. Meanwhile, the amyloidogenic pathway of APP metabolism was inhibited, which was associated with a decrease in BACE1 expression. The APP metabolism mediated by the nonamyloidogenic pathway, as indicated by the increase in ADAM10 levels. Coincidentally, exercise reduced the cholesterol level, as evidenced by a significant decrease in the total cholesterol level and the activity of 3-hydroxy-3-methylglutaryl-coenzyme A reductase, as well as a reduction in the number of lipid rafts, as evidenced by a significant decrease in the flotillin 1 level. These finding suggested that the 12-week treadmill exercise program reduced Aβ deposition in the hippocampus of APP/PS1 mice, possibly by regulating ADAM10 and BACE1 levels and by decreasing cholesterol-mediated lipid raft formation, indicating that exercise represents a therapeutic intervention to treat AD.

Multiple sclerosis (MS) is an inflammatory, neurodegenerative autoimmune disease associated with sensory and motor dysfunction. Although estimates vary, ∼50% of patients with MS experience pain during their disease. The mechanisms underlying the development of pain are not fully understood, and no effective treatment for MS-related pain is available. Previous work from our laboratory demonstrated that voluntary exercise (wheel running) can reduce nociceptive behaviours at the disease onset in female mice with experimental autoimmune encephalomyelitis (EAE), an animal model used to study the immunopathogenesis of MS. However, given the established sex differences in the underlying mechanisms of chronic pain and MS, we wanted to investigate whether wheel running would also be effective at preventing nociceptive behaviours in male mice with EAE. C57BL/6 mice of both sexes were given access to running wheels for 1 hour/day until the disease onset, when nociceptive behaviour was assessed using von Frey hairs. Daily running effectively reduced nociceptive behaviour in female mice, but not in male mice. We explored the potential biological mechanisms for these effects and found that the reduction in nociceptive behaviour in female mice was associated with reduced levels of inflammatory cytokines from myelin-reactive T cells as well as reduced dorsal root ganglia excitability as seen by decreased calcium responses. These changes were not seen in male mice. Instead, running increased the levels of inflammatory cytokines and potentiated Ca responses in dorsal root ganglia cells. Our results show that voluntary wheel running has sex-dependent effects on nociceptive behaviour and inflammatory responses in male and female mice with EAE.

Introduction: The elevation of brain-derived neurotrophic factor (BDNF) levels in the brain and the subsequent phosphorylation of its cognate tropomyosin-related kinase B (TrkB) receptors at tyrosine 816 (pTrkB) are largely involved in the positive effect of aerobic exercise on brain functioning. Although BDNF levels were reported to increase in proportion with exercise intensity, the effect of the type of contraction is unknown. Therefore, the cerebral BDNF/TrkB pathway was investigated after uphill and downhill treadmill activities at equivalent intensity to preferentially induce eccentric and concentric contractions, respectively., Methods: A treadmill activity (30 min·d for seven consecutive days) either in a horizontal position at two different speeds to modulate intensity (experiment 1) or at three different inclinations (null, -10%, and +5%) but at equivalent intensity to modulate the type of contraction (experiment 2) was induced in rats. Both experiments included sedentary rats. Levels of BDNF, pTrkB, synaptophysin (marker of synaptogenesis), endothelial nitric oxide synthase phosphorylated at serine 1177 (peNOS), and c-fos levels (indicators of elevation in blood flow in the cerebrovasculature and neuronal activity, respectively) were measured in motor- and cognition-related brain regions using Western blotting analysis., Results: Experiment 1 indicated that treadmill activity induces an intensity-dependent increase in peNOS, c-fos, and BDNF levels. Experiment 2 showed that intensity of exercise as well as activation of the cerebral BDNF pathway, and synaptogenesis did not differ among horizontal, uphill, and downhill treadmill activities., Conclusion: The cerebral response of the BDNF pathway to a treadmill activity is dependent on exercise intensity, but not on the type of contraction (eccentric vs concentric).

Rationale: Physical exercise provides benefits for various organ systems, and some of systemic effects of exercise are mediated through modulation of muscle-derived secreted factors, also known as myokines. Myonectin/C1q (complement component 1q)/TNF (tumor necrosis factor)-related protein 15/erythroferrone is a myokine that is upregulated in skeletal muscle and blood by exercise., Objective: We investigated the role of myonectin in myocardial ischemic injury., Methods and Results: Ischemia-reperfusion in myonectin-knockout mice led to enhancement of myocardial infarct size, cardiac dysfunction, apoptosis, and proinflammatory gene expression compared with wild-type mice. Conversely, transgenic overexpression of myonectin in skeletal muscle reduced myocardial damage after ischemia-reperfusion. Treadmill exercise increased circulating myonectin levels in wild-type mice, and it reduced infarct size after ischemia-reperfusion in wild-type mice, but not in myonectin-knockout mice. Treatment of cultured cardiomyocytes with myonectin protein attenuated hypoxia/reoxygenation-induced apoptosis via S1P (sphingosine-1-phosphate)-dependent activation of cAMP/Akt cascades. Similarly, myonectin suppressed inflammatory response to lipopolysaccharide in cultured macrophages through the S1P/cAMP/Akt-dependent signaling pathway. Moreover, blockade of S1P-dependent pathway reversed myonectin-mediated reduction of myocardial infarct size in mice after ischemia-reperfusion., Conclusions: These data indicate that myonectin functions as an endurance exercise-induced myokine which ameliorates acute myocardial ischemic injury by suppressing apoptosis and inflammation in the heart, suggesting that myonectin mediates some of the beneficial actions of exercise on cardiovascular health.

The β-amyloid (Aβ) deposition is one of the major pathological hallmark of Alzheimer's disease. Dysfunction in autophagy has been reported to lead to the Aβ deposition. The current study aimed to investigate the effects of treadmill exercise on autophagy activity and the Aβ deposition and to demonstrate whether exercise-induced reduction in the Aβ deposition was associated with changes in autophagy activity. APP/PS1 transgenic mice were divided into transgenic sedentary (TG-SED, n=12) and transgenic exercise (TG-EXE, n=12) groups. Wild-type mice were also divided into sedentary (WT-SED, n=12) and exercise (WT-EXE, n=12) groups. The WT-EXE and TG-EXE mice were subjected to treadmill exercise for 12 weeks. The levels of Aβ plaques and soluble forms of Aβ, autophagy markers light chain 3 and P62, and lysosomal marker lysosome-associated membrane protein 1 (Lamp1) were measured in the hippocampus. Both Aβ plaques and soluble forms of Aβ (Aβ40 and Aβ42) were significantly increased in TG-SED mice compared with WT-SED mice, whereas exercise reduced Aβ deposition in APP/PS1 transgenic mice. Coincidentally, TG-SED mice displayed a decrease in autophagy activity as evidenced by a significant increase in the levels of light chain 3-II and P62, as well as an accumulation of lysosome as evidenced by a significant over-expression of Lamp1. Interestingly, exercise increased autophagy activity as evidenced by a significant reduction in the levels of P62 and Lamp1 in TG-EXE mice. These findings suggest that treadmill exercise is efficient in decreasing Aβ deposition by enhancing autophagy-lysosomal activity in APP/PS1 transgenic mice, demonstrating a possible approach in Alzheimer's disease prevention and treatment.

Purpose: Aerobic training (AT) and high-intensity intermittent training (HIIT) reduce arterial stiffness, whereas resistance training (RT) induces deterioration of or no change in arterial stiffness. However, the molecular mechanism of these effects of different exercise modes remains unclear. This study aimed to clarify the difference of different exercise effects on endothelial nitric oxide synthase (eNOS) signaling pathway and arterial stiffness in rats and humans., Methods: In the animal study, forty 10-wk-old male Sprague-Dawley rats were randomly divided into four groups: sedentary control (CON), AT (treadmill running, 60 min at 30 m·min, 5 d·wk for 8 wk), RT (ladder climbing, 8-10 sets per day, 3 d·wk for 8 wk), and HIIT (14 repeats of 20-s swimming session with 10-s pause between sessions, 4 d·wk for 6 wk from 12-wk-old) groups (n = 10 in each group). In the human study, we confirmed the effects of 6-wk HIIT and 8-wk AT interventions on central arterial stiffness and plasma nitrite/nitrate level in untrained healthy young men in randomized controlled trial (HIIT, AT, and CON; n = 7 in each group)., Results: In the animal study, the effect on aortic pulse wave velocity (PWV), as an index of central arterial stiffness, after HIIT was the same as the decrease in aortic PWV and increase in arterial eNOS/Akt phosphorylation after AT, which was not changed by RT. A negative correlation between aortic PWV and eNOS phosphorylation was observed (r = -0.38, P < 0.05). In the human study, HIIT- and AT-induced changes in carotid-femoral PWV (HIIT -115.3 ± 63.4 and AT -157.7 ± 45.7 vs CON 71.3 ± 61.1 m·s, each P < 0.05) decreased, and plasma nitrite/nitrate level increased compared with those in CON., Conclusions: HIIT may reduce central arterial stiffness via the increase in aortic nitric oxide bioavailability despite it being done in a short time and short term and has the same effects as AT.

Background: Late exercise preconditioning (LEP) is confirmed to have a protective effect on acute cardiovascular stress. However, the mechanisms by which mitophagy participates in exercise preconditioning (EP)-induced cardioprotection remain unclear. LEP may involve mitophagy mediated by the receptors PARK2 gene-encoded E3 ubiquitin ligase (Parkin) and BCL2/adenovirus E1B 19 kDa protein-interacting protein 3 (Bnip3) to scavenge damaged mitochondria., Methods: Our EP protocol involved four 10-minute periods of running, separated by 10-minute recovery intervals, plus a period of exhaustive running at 24 hours after EP. We assessed this late protective effect by injection of the autophagy inhibitor wortmannin, transmission electron microscopy, laser scanning confocal microscopy, and other molecular biotechnology methods; we simultaneously detected related markers, analyzed the specific relationships between mitophagy proteins, and assessed mitochondrial translocation., Results: Exhaustive exercise (EE) causes serious injuries to cardiomyofibrils, inducing hypoxia-ischemia and changing the ultrastructure. EE fails to clear excessively generated mitochondria to link with LC3 accumulation. After EP, increased autophagy levels at 30 minutes were converted to mitophagy within 24 hours. We found that LEP significantly suppressed EE-induced injuries, which we confirmed by observing decreased levels of the mitochondria-localized proteins COX4/1 and TOM20. LEP to exhaustion caused mitochondrial degradation by increasing the efficiency of LC3-outer mitochondrial membrane translocation in a Parkin-mediated manner, in which activated protein kinase and TOM70 may play both key roles. However, we did not observe mitophagy to be associated with Bnip3 mediation in LEP-induced cardioprotection. However, Bnip3 may play a role in inducing mitochondrial LC3-II increases. Wortmannin had no effect on LC3 translocation; instead, it influenced LC3-I to convert to LC3-II. Thus, suppressing mitophagy led to the attenuation of EP-induced cardioprotection.

Peripheral nerve injury (PNI) activates the immune system, resulting in increased proinflammatory cytokines at the site of injury and in the spinal cord dorsal horn. Exercise modulates the immune system promoting an anti-inflammatory phenotype of macrophages in uninjured muscle, and increases in anti-inflammatory cytokines can promote healing and analgesia. We proposed that PNI will decrease, and treadmill exercise will increase, release of anti-inflammatory cytokines at the site of injury and in the spinal cord. We show that 2 weeks of treadmill exercise improves neuropathic pain behaviors in mice: mechanical hyperalgesia, escape and avoidance behavior, and spontaneous locomotor activity. Peripheral nerve injury reduced anti-inflammatory cytokines (interleukin-4 [IL-4], IL-1ra, and IL-5) at the site of nerve injury and in the spinal dorsal horn, whereas exercise restored IL-4, IL-1ra, and IL-5 concentrations to preinjury levels. IL4 mice and mice treated with IL-4 antibody did not develop analgesia to treadmill exercise. Using immunohistochemical staining of the sciatic nerve, treadmill exercise increased the percentage of M2 macrophages (secretes anti-inflammatory cytokines) and decreased M1 macrophages (secretes proinflammatory cytokines) when compared with sedentary mice. The increased M2 and decreased M1 macrophages in exercised mice did not occur in IL-4 mice. In the spinal cord, PNI increased glial cell activation, brain-derived neurotrophic factor and β-nerve growth factor levels, and decreased IL-4 and IL-1ra levels, whereas treadmill exercise suppressed glial cells activation (Glial Fibrillary Acidic Protein and Iba1 immunoreactivity), reduced brain-derived neurotrophic factor and β-nerve growth factor, and increased IL-4, IL-1ra, and IL-5 concentrations. Our results suggest that IL-4 mediates the analgesia produced by low-intensity exercise by modulating peripheral and central neuroimmune responses in mice with neuropathic pain.

Issues of peripheral circulation have been increasingly suggested as an underlying cause of musculoskeletal pain in many conditions, including sickle cell anemia and peripheral vascular disease. We have previously shown in our model of transient ischemia and reperfusion (I/R) injury of the forelimb that individual group III and IV muscle afferents display altered chemosensitivity and mechanical thresholds 1 day after injury. Functional alterations corresponded to increased evoked and spontaneous pain-related behaviors and decreased muscle strength and voluntary activity-all actions that echo clinical symptoms of ischemic myalgia. These behavioral and physiological changes appeared to originate in part from the action of increased interleukin 1β (IL1β) in the injured muscles at its upregulated IL1 receptor 1 within the dorsal root ganglion. Here, we describe that two days of voluntary wheel running prior to I/R blocks both injury-induced IL1β enhancement and the subsequent development of ischemic myalgia-like behaviors. Furthermore, the protective effects of 2 days prior exercise on the I/R-evoked increases in pain-related behaviors were also paralleled with systemic injection of the IL1 receptor antagonist during I/R. Interleukin 1 receptor antagonist treatment additionally prevented the I/R-induced changes in mechanical and chemical sensitivity of individual primary muscle afferents. Altogether, these data strengthen the evidence that transient I/R injury sensitizes group III and IV muscle afferents via increased IL1β in the muscles to stimulate ischemic myalgia development. Targeting IL1β may, therefore, be an effective treatment strategy for this insidious type of muscle pain.

Rationale: Mitochondria play a dual role in the heart, responsible for meeting energetic demands and regulating cell death. Paradigms have held that mitochondrial fission and fragmentation are the result of pathological stresses, such as ischemia, are an indicator of poor mitochondrial health, and lead to mitophagy and cell death. However, recent studies demonstrate that inhibiting fission also results in decreased mitochondrial function and cardiac impairment, suggesting that fission is important for maintaining cardiac and mitochondrial bioenergetic homeostasis., Objective: The purpose of this study is to determine whether mitochondrial fission and fragmentation can be an adaptive mechanism used by the heart to augment mitochondrial and cardiac function during a normal physiological stress, such as exercise., Methods and Results: We demonstrate a novel role for cardiac mitochondrial fission as a normal adaptation to increased energetic demand. During submaximal exercise, physiological mitochondrial fragmentation results in enhanced, rather than impaired, mitochondrial function and is mediated, in part, by β1-adrenergic receptor signaling. Similar to pathological fragmentation, physiological fragmentation is induced by activation of dynamin-related protein 1; however, unlike pathological fragmentation, membrane potential is maintained and regulators of mitophagy are downregulated. Inhibition of fission with P110, Mdivi-1 (mitochondrial division inhibitor), or in mice with cardiac-specific dynamin-related protein 1 ablation significantly decreases exercise capacity., Conclusions: These findings demonstrate the requirement for physiological mitochondrial fragmentation to meet the energetic demands of exercise, as well as providing additional support for the evolving conceptual framework, where mitochondrial fission and fragmentation play a role in the balance between mitochondrial maintenance of normal physiology and response to disease., (© 2017 American Heart Association, Inc.)

It has been suggested that serotonin (5-HT) may be implicated in functional recovery after stroke; however, the underlying molecular mechanisms remain unknown. Here, the role of 5-HT was verified using ritanserin, a potent 5-HT2A receptor antagonist, and protein expression and modification were analyzed to further understand the association between paralysis recovery and molecular mechanisms in the brain. Experimental cerebral cortex infarctions were induced by photothrombosis in rats. Voluntary exercise was initiated 2 days after surgery. Motor performance was then measured using the rotarod test. Differences in protein expression and phosphorylation in the perilesional cortex were analyzed using western blot. In behavioral evaluations, performance in the rotarod test was significantly increased by exercise. However, there was a significantly lower value in time until falling after combined exercise and ritanserin administration compared with that of exercise alone. Protein expression analysis revealed that phosphorylation of protein kinase C (PKC) α, PKCε, and growth-associated protein 43 (GAP43) was significantly upregulated by exercise. These effects were attenuated by ritanserin administration. These data suggest that 5-HT may be related to the underlying mechanisms of exercise-dependent paralysis recovery, that is, exercise-dependent plasticity through the phosphorylation of PKC and GAP43.

Rationale: Downregulation of the pacemaking ion channel, HCN4 (hyperpolarization-activated cyclic nucleotide gated channel 4), and the corresponding ionic current, I f , underlies exercise training-induced sinus bradycardia in rodents. If this occurs in humans, it could explain the increased incidence of bradyarrhythmias in veteran athletes, and it will be important to understand the underlying processes., Objective: To test the role of HCN4 in the training-induced bradycardia in human athletes and investigate the role of microRNAs (miRs) in the repression of HCN4., Methods and Results: As in rodents, the intrinsic heart rate was significantly lower in human athletes than in nonathletes, and in all subjects, the rate-lowering effect of the HCN selective blocker, ivabradine, was significantly correlated with the intrinsic heart rate, consistent with HCN repression in athletes. Next-generation sequencing and quantitative real-time reverse transcription polymerase chain reaction showed remodeling of miRs in the sinus node of swim-trained mice. Computational predictions highlighted a prominent role for miR-423-5p. Interaction between miR-423-5p and HCN4 was confirmed by a dose-dependent reduction in HCN4 3'-untranslated region luciferase reporter activity on cotransfection with precursor miR-423-5p (abolished by mutation of predicted recognition elements). Knockdown of miR-423-5p with anti-miR-423-5p reversed training-induced bradycardia via rescue of HCN4 and I f . Further experiments showed that in the sinus node of swim-trained mice, upregulation of miR-423-5p (intronic miR) and its host gene, NSRP1, is driven by an upregulation of the transcription factor Nkx2.5., Conclusions: HCN remodeling likely occurs in human athletes, as well as in rodent models. miR-423-5p contributes to training-induced bradycardia by targeting HCN4. This work presents the first evidence of miR control of HCN4 and heart rate. miR-423-5p could be a therapeutic target for pathological sinus node dysfunction in veteran athletes., (© 2017 The Authors.)

Background and Purpose: This study was designed to compare the effects of high-intensity interval training (HIT) and moderate-intensity aerobic training (MOD) on functional recovery and cerebral plasticity during the first 2 weeks after cerebral ischemia., Methods: Rats were randomized as follows: control (n=15), SHAM (n=9), middle cerebral artery occlusion (n=13), middle cerebral artery occlusion at day 1 (n=7), MOD (n=13), and HIT (n=13). Incremental tests were performed at day 1 (D1) and 14 (D14) to identify the running speed associated with the lactate threshold ( S LT ) and the maximal speed ( S max ). Functional tests were performed at D1, D7, and D14. Microglia form, cytokines, p75 NTR (pan-neurotrophin receptor p75), potassium-chloride cotransporter type 2, and sodium-potassium-chloride cotransporter type 1 expression were made at D15., Results: HIT was more effective to improve the endurance performance than MOD and induced a fast recovery of the impaired forelimb grip force. The ionized calcium binding adaptor molecule 1 (Iba-1)-positive cells with amoeboid form and the pro- and anti-inflammatory cytokine expression were lower in HIT group, mainly in the ipsilesional hemisphere. A p75 NTR overexpression is observed on the ipsilesional side together with a restored sodium-potassium-chloride cotransporter type 1/potassium-chloride cotransporter type 2 ratio on the contralesional side., Conclusions: Low-volume HIT based on lactate threshold seems to be more effective after cerebral ischemia than work-matched MOD to improve aerobic fitness and grip strength and might promote cerebral plasticity., (© 2017 American Heart Association, Inc.)

Dexamethasone (DEX) causes rarefaction. In contrast, training (T) prevents rarefaction and stimulates angiogenesis. This study investigated the mechanisms responsible for the preventive role of T in DEX-induced rarefaction. Rats underwent T or were kept sedentary (8 weeks) and were treated with DEX or saline during the following 14 days. Tibialis anterior muscle was used for measurements of capillary density (CD), capillary-to-fiber ratio (C:F ratio), superoxide dismutase CuZn (SOD-1), superoxide dismutase MnSOD (SOD-2), catalase (CAT) mRNA as well as SOD-1, SOD-2, CAT, vascular endothelial growth factor (VEGF), vascular endothelial growth factor receptor-2 (VEGF-R2), cyclooxygenase-2 (COX-2), B-cell lymphoma 2 (Bcl-2), Bd-2-like protein 4 (Bax), p-Bax, and caspase-3 cleaved protein levels. DEX decreased CD (-38.1%), C:F ratio (-30.0%), VEGF (-19.0%), VEGFR-2 (-20.1%), COX-2 (-22.8%), Bcl-2 (-20.5%), Bcl-2/Bax ratio (-13.7%), p-Bax/Bax (-20.0%) and increased SOD-2 (+41.6%) and caspase-3 cleaved (+24.1%). Conversely, T prevented reductions in CD (+54.2%), C:F ratio (+32.9%), VEGF (+25.3%), VEGFR-2 (+22.2%), COX-2 (+31.5%), Bcl-2 (+35.5%), Bcl-2/Bax ratio (+19.9%), p-Bax/Bax (+32.1%), and caspase-3 cleaved increase (-7.8%). T increased CAT mRNA (+21.5%) in the DEX-treated group. In conclusion, T prevented the DEX-induced rarefaction by increasing antioxidant enzymes resulting in a better balance between apoptotic and anti-apoptotic protein levels.

Regular physical activity prevents the development of chronic muscle pain through the modulation of central mechanisms that involve rostral ventromedial medulla (RVM). We tested if pharmacological blockade or genetic deletion of mu-opioid receptors in physically active mice modulates excitatory and inhibitory systems in the RVM in an activity-induced hyperalgesia model. We examined response frequency to mechanical stimulation of the paw, muscle withdrawal thresholds, and expression of phosphorylation of the NR1 subunit of the N-methyl-D-aspartate receptor (p-NR1) and serotonin transporter (SERT) in the RVM. Mice that had performed 5 days of voluntary wheel running prior to the induction of the model were compared with sedentary mice. Sedentary mice showed significant increases in mechanical paw withdrawal frequency and a reduction in muscle withdrawal threshold; wheel running prevented the increase in paw withdrawal frequency. Naloxone-treated and MOR mice had increases in withdrawal frequency that were significantly greater than that in physically active control mice and similar to sedentary mice. Immunohistochemistry in the RVM showed increases in p-NR1 and SERT expression in sedentary mice 24 hours after the induction of the model. Wheel running prevented the increase in SERT, but not p-NR1. Physically active, naloxone-treated, and MOR mice showed significant increases in SERT immunoreactivity when compared with wild-type physically active control mice. Blockade of SERT in the RVM in sedentary mice reversed the activity-induced hyperalgesia of the paw and muscle. These results suggest that analgesia induced by 5 days of wheel running is mediated by mu-opioid receptors through the modulation of SERT, but not p-NR1, in RVM.

Background and Purpose: Preclinical studies suggest that exercise can enhance cognition after cerebral ischemia but often use long training regiments and test cognition during or acutely after training. The cognitive changes may result from enhanced physical fitness and may only provide acute benefit. We sought to determine whether a short period of exercise after cerebral ischemia could improve cognitive outcomes when measured days after completion of exercise training in 2 cerebral ischemia models., Methods: Focal or global cerebral ischemia was induced in Sprague-Dawley rats. Rats recovered (3-4 days) then were subject to no exercise (0 m/min), mild (6 m/min), moderate (10 m/min), or heavy (15-18 m/min) treadmill exercise (5-6 days). Cognition was tested 8 to 10 days after the last exercise session with hippocampal-dependent contextual fear conditioning., Results: A short training period of moderate exercise enhanced cognitive function for a week after exercise completion in both models of cerebral ischemia., Conclusions: Utilization of this exercise paradigm can further the elucidation of exercise-mediated factors involved in cognitive recovery independent of changes in physical fitness., (© 2017 American Heart Association, Inc.)

Purpose: Cigarette smoking is the main risk factor for chronic obstructive pulmonary disease and emphysema. However, evidence on the extrapulmonary effects of smoke exposure that precede lung impairments remains unclear at present, as are data on nonpharmacological treatments such as exercise training., Methods: Three groups of mice, including control (n = 10), smoking (n = 10), and smoking with 6 wk of high-intensity interval treadmill running (n = 11), were exposed to 20 wk of fresh air or whole-body cigarette smoke. Exercise capacity (peak oxygen uptake) and lung destruction (histology) were subsequently measured, whereas the heart, peripheral endothelium (aorta), and respiratory (diaphragm) and limb (extensor digitorum longus and soleus) skeletal muscles were assessed for in vivo and in vitro function, in situ mitochondrial respiration, and molecular alterations., Results: Smoking reduced body weight by 26% (P < 0.05) without overt airway destruction (P > 0.05). Smoking impaired exercise capacity by 15% while inducing right ventricular dysfunction by ~20%, endothelial dysfunction by ~20%, and diaphragm muscle weakness by ~15% (all P < 0.05), but these were either attenuated or reversed by exercise training (P < 0.05). Compared with controls, smoking mice had normal limb muscle and mitochondrial function (cardiac and skeletal muscle fibers); however, diaphragm measures of oxidative stress and protein degradation were increased by 111% and 65%, respectively (P < 0.05), but these were attenuated by exercise training (P < 0.05)., Conclusions: Prolonged cigarette smoking reduced exercise capacity concomitant with functional impairments to the heart, peripheral endothelium, and respiratory muscle that preceded the development of overt emphysema. However, high-intensity exercise training was able to reverse these smoke-induced extrapulmonary impairments.

Purpose: Physical exercise has been shown to be protective against colon carcinogenesis. Physical exercise, however, covers a wide range of modalities, from which different effects on the human body have been reported. We sought to clarify whether aerobic and resistance trainings would differently affect the development of early carcinogenic events in the colon., Methods: Male BALB/c, C57/BL6, and interleukin 10 knockout (IL-10; on C57/BL6 background) mice were exposed to the carcinogen N-methyl-N'-nitro-N-nitrosoguanidine. BALB/c mice were subjected to either aerobic (swimming) or resistance trainings (climbing a ladder with load attached to the tail). C57/BL6 and IL-10 mice only swam., Results: In BALB/c carcinogen-exposed mice, aerobic and resistance trainings decreased serum creatine kinase levels (P < 0.001). Although aerobic and resistance trainings reduced the generation of lipid thiobarbituric reactive species (P < 0.01 and P < 0.001), only aerobic exercises enhanced serum glutathione levels aside from carcinogenic exposure (P < 0.05). Carcinogen-exposed and aerobic-trained mice developed 36% less colon preneoplastic lesions than its control group (P < 0.05). Aerobic training reduced colonic subepithelial cyclooxygenase-2 expression in carcinogen-exposed mice (P < 0.001). Interestingly, in this same group, colonic IL-10 expression was upregulated sevenfold (P < 0.001). Current findings were confirmed in C57/BL6 carcinogen-exposed mice, in which aerobic training promoted antipreneoplastic effects (P < 0.05). Knocking IL-10 out of C57/BL6 mice abrogated antipreneoplastic effects of aerobic training on the colon tissue (P > 0.05)., Conclusions: IL-10 is a pivotal element for antipreneoplastic effects of aerobic training on the colon.

Background: Training intensity may play a key role in magnifying the protective effect of physical exercise against nonalcoholic fatty liver disease (NAFLD)., Purpose: This study aimed to test the hypothesis that vigorous-intensity and interval training is as effective as moderate-intensity and continuous exercise training on NAFLD in high-fat diet (HFD)-induced obese mice., Methods: C57BL/6 mice (N = 40) were fed a standard-chow diet (n = 10) or HFD (n = 30) for 16 wk. After the initial 8-wk dietary treatments, HFD mice were further divided into HFD only (n = 10), HFD plus vigorous-intensity and interval treadmill running (VIT) (n = 10), and HFD plus moderate-intensity and continuous treadmill running (MIT) (n = 10) for the remaining 8-wk period., Results: Chronic exposure to HFD resulted in hepatic steatosis in conjunction with an obese and impaired glucose tolerance condition characterized by dyslipidemia, hyperinsulinemia elevated markers for the liver damage, and hypoadiponectinemia. Although VIT and MIT alleviated the NAFLD conditions, the former was more effective at alleviating hepatic steatosis than the latter. The intensity-dependent benefit of exercise training against hepatic steatosis was associated with greater activation of VIT on hepatic AMP-mediated protein kinase in conjunction with greater suppressive effect of VIT on hypoadiponectinemia, downregulation of the Adiponectin receptor 2 signaling pathway, and upregulation of the NF-κB signaling pathway in the liver., Conclusions: The current findings suggest that VIT is an alternative way of exercise training to combat hepatic steatosis associated with an obese and impaired glucose tolerance phenotype.

Purpose: As our society becomes increasingly sedentary, compliance with exercise regimens that require numerous high-energy activities each week become less likely. Alternatively, given an osteogenic exercise intervention that required minimal effort, it is reasonable to presume that participation would be enhanced. Insertion of brief rest intervals between each cycle of mechanical loading holds potential to achieve this result because substantial osteoblast function is activated by many fewer loading repetitions within each loading bout. Here, we examined the complementary hypothesis that the number of bouts per week of rest-inserted loading could be reduced from three bouts per week without loss of osteogenic efficacy., Methods: We conducted a series of 3-wk in vivo experiments that noninvasively exposed the right tibiae of mice to either cyclic (1 Hz) or rest-inserted loading interventions and quantified osteoblast function via dynamic histomorphometry., Results: Although reducing loading bouts from three bouts per week (i.e., nine total bouts) to one bout per week (i.e., three total bouts) effectively mitigated the osteogenic benefit of cyclic loading, the same reduction did not significantly reduce periosteal bone formation parameters induced by rest-inserted loading. The osteogenic response was robust to the timing of the rest-inserted loading bouts (three bouts in the first week vs one bout per week for 3 wk). However, elimination of any single bout of the three one-bout-per-week bouts mitigated the osteogenic response to rest-inserted loading. Finally, periosteal osteoblast function assessed after the 3-wk intervention was not sensitive to the timing or number of rest-inserted loading bouts., Conclusions: We conclude that rest-inserted loading holds potential to retain the osteogenic benefits of mechanical loading with significantly reduced frequency of bouts of activity while also enabling greater flexibility in the timing of the activity.

Loss of upper arm strength after stroke is a leading cause of disability. Strategies that can enhance the benefits of rehabilitative training could improve motor function after stroke. Recent studies in a rat model of ischemic stroke have demonstrated that vagus nerve stimulation (VNS) paired with rehabilitative training substantially improves recovery of forelimb strength compared with extensive rehabilitative training without VNS. Here we report that the timing and amount of stimulation affect the degree of forelimb strength recovery. Similar amounts of Delayed VNS delivered 2 h after daily rehabilitative training sessions resulted in significantly less improvement compared with that on delivery of VNS that is paired with identical rehabilitative training. Significantly less recovery also occurred when several-fold more VNS was delivered during rehabilitative training. Both delayed and additional VNS confer moderately improved recovery compared with extensive rehabilitative training without VNS, but fail to enhance recovery to the same degree as VNS that is timed to occur with successful movements. These findings confirm that VNS paired with rehabilitative training holds promise for restoring forelimb strength poststroke and indicate that both the timing and the amount of VNS should be optimized to maximize therapeutic benefits.

Purpose: Hepatic mitochondrial adaptations to exercise are largely unknown. In this study, we sought to determine the effects of various exercise modalities on measures of hepatic mitochondrial function and metabolism., Methods: Male Sprague-Dawley rats were randomly assigned (n = 8-10 per group) into sedentary (SED), voluntary wheel running (VWR), VWR with food pulled during the dark cycle (VMR-OF), treadmill endurance exercise (TM-END; 30 m·min, 12% gradient, 60 min·d, 5 d·wk), or treadmill interval sprint training (TM-IST; 50 m·min, 12% gradient, 6 × 2.5 min bouts, 5 d·wk) groups for a 4-wk intervention., Results: Hepatic mitochondrial state 3 and maximal uncoupled respiration were significantly (P < 0.05) increased in all four exercise groups compared with SED animals. In addition, hepatic mitochondrial [1-C] pyruvate oxidation to CO2, an index of pyruvate dehydrogenase (PDH) activity, was significantly increased in VWR-OF, TM-END, and TM-IST rats (P < 0.05), whereas exercise-induced increases in [2-C] pyruvate oxidation and [1-C] palmitate oxidation to CO2 did not reach statistical significance. Hepatic mitochondrial sirtuin 3 protein content, which putatively increases activity of mitochondrial proteins, was elevated in the VWR, VWR-OF, and TM-END groups (P < 0.05). In addition, only VWR-OF animals experienced increases in hepatic cytochrome c protein content and phosphoenolpyruvate carboxykinase mRNA, whereas PGC-1α mRNA expression and phospho-CREB protein content was increased in VWR-OF and TM-END groups., Conclusion: Four weeks of exercise training, regardless of exercise modality, significantly increased hepatic mitochondrial respiration and evoked other unique improvements in mitochondrial metabolism that do not appear to be dependent on increases in mitochondrial content.

Background and Purpose: Although several studies have shown beneficial effects of training in animal stroke models, the most effective training strategy and the optimal time to initiate training have not been identified. The present meta-analysis was performed to compare the efficacy of different training strategies and to determine the optimal time window for training in animal stroke models., Methods: We searched the literature for studies analyzing the efficacy of training in animal models of ischemic stroke. Training was categorized into forced physical training, voluntary physical training, constraint-induced movement therapy, and skilled reaching training. Two reviewers independently extracted data on study quality, infarct size, and neurological outcome. Data were pooled by means of a meta-analysis., Results: Thirty-five studies with >880 animals were included. A meta-analysis of all treatments showed that training reduced the infarct volume by 14% (95% confidence interval, 2%-25%) and improved the cognitive function by 33% (95% confidence interval, 8%-50%), the neuroscore by 13.4% (95% confidence interval, 1.5%-25.3%), and the running function by 6.6% (95% confidence interval, 1.4%-11.9%). Forced physical training reduced the infarct volume and enhanced the running function most effectively, whereas skilled reaching training improved the limb function most effectively. A meta-regression illustrated that training was particularly efficacious when initiated between 1 and 5 days after stroke onset., Conclusions: Our meta-analysis confirms that training reduces the infarct volume and improves the functional recovery in animal stroke models. Forced physical training and skilled reaching training were identified as particularly effective training strategies. The efficacy of training is time dependent.

Recent research suggests that exercise can be effective in reducing pain in animals and humans with neuropathic pain. To investigate mechanisms in which exercise may improve hyperalgesia associated with prediabetes, C57Bl/6 mice were fed either standard chow or a high-fat diet for 12 weeks and were provided access to running wheels (exercised) or without access (sedentary). The high-fat diet induced a number of prediabetic symptoms, including increased weight, blood glucose, and insulin levels. Exercise reduced but did not restore these metabolic abnormalities to normal levels. In addition, mice fed a high-fat diet developed significant cutaneous and visceral hyperalgesia, similar to mice that develop neuropathy associated with diabetes. Finally, a high-fat diet significantly modulated neurotrophin protein expression in peripheral tissues and altered the composition of epidermal innervation. Over time, mice that exercised normalized with regards to their behavioral hypersensitivity, neurotrophin levels, and epidermal innervation. These results confirm that elevated hypersensitivity and associated neuropathic changes can be induced by a high-fat diet and exercise may alleviate these neuropathic symptoms. These findings suggest that exercise intervention could significantly improve aspects of neuropathy and pain associated with obesity and diabetes. Additionally, this work could potentially help clinicians determine those patients who will develop painful versus insensate neuropathy using intraepidermal nerve fiber quantification., (Copyright © 2013 International Association for the Study of Pain. Published by Elsevier B.V. All rights reserved.)

Objectives: High physical activity levels are associated with wide-ranging health benefits, disease prevention, and longevity. In the present study, we examined the impact of regular physical exercise on the severity of organ injury and survival probability, as well as characteristics of the systemic immune and metabolic response during severe polymicrobial sepsis., Design: Animal study., Setting: University laboratory., Subjects: Male C57BL/6N mice., Interventions: Mice were trained for 6 weeks by treadmill and voluntary wheel running or housed normally. Polymicrobial sepsis in mice was induced by injection of fecal slurry. Subsequently, mice were randomized into the following groups: healthy controls, 6 hours postsepsis, and 24 hours postsepsis., Measurements and Main Results: Blood and organ samples were collected and investigated by measuring clinical chemistry variables, cytokines, plasma metabolites, and bacterial clearance. Organ morphology and damage were characterized by histological staining. Physical exercise improved survival and the ability of bacterial clearance in blood and organs. The release of pro- and anti-inflammatory cytokines, including interleukin-6 and interleukin-10, was diminished in trained compared to untrained mice during sepsis. The sepsis-associated acute kidney tubular damage was less pronounced in pretrained animals. By metabolic profiling and regression analysis, we detected lysophosphatidylcholine 14:0, tryptophan, as well as pimelylcarnitine linked with levels of neutrophil gelatinase-associated lipocalin representing acute tubular injury (corrected R=0.910; p<0.001). We identified plasma lysophosphatidylcholine 16:0, lysophosphatidylcholine 17:0, and lysophosphatidylcholine 18:0 as significant metabolites discriminating between trained and untrained mice during sepsis., Conclusions: Regular physical exercise reduces sepsis-associated acute kidney injury and death. As a specific mechanism of exercise-induced adaptation, we identified various lysophosphatidylcholines that might function as surrogate for improved outcome in sepsis.

Purpose: Training for improvement of oxidative capacity of muscle fibers may be attenuated when concurrently training for peak power. However, because of fiber type-specific recruitment, such attenuation may only account for high-oxidative muscle fibers. Here, we investigate the effects of concurrent training on oxidative capacity (as measured by succinate dehydrogenase (SDH) activity) by using task-specific recruitment of the high- and low-oxidative compartment of rat medial gastrocnemius muscle (GM)., Methods: Forty rats were subjected to 6 wk of peak power training (PT, n = 10), endurance training (ET, n = 10), concurrent peak power and endurance training (PET, n = 10), or no training (control, n = 10). SDH activity, mRNA expression of SDH, peroxisome proliferator-activated receptor-γ coactivator 1α (PGC-1α), receptor-interacting protein 140, and BCL2/adenovirus E1B 19 kDa-interacting protein 3 as well as PGC-1α protein levels were analyzed in the low- and high-oxidative region of the GM., Results: In the low-oxidative compartment, PT and PET induced a 30% decrease in SDH activity of Type IIB fibers compared with controls and ET (P < 0.001) without changes in mRNA or protein levels. In the high-oxidative compartment, after ET, SDH mRNA levels were 42% higher and RIP140 mRNA levels 33% lower compared with controls, which did not result in changes in SDH activity., Conclusion: These results indicate that in compartmentalized rat GM, peak power on top of endurance training attenuated transcription of mRNA for mitochondrial proteins in high-oxidative muscle fibers. In low-oxidative Type IIB fibers, peak power training substantially decreased SDH activity, which was not related to lower SDH mRNA levels. It is concluded that PT and PET enhanced mitochondrial degradation in the low-oxidative compartment of rat GM.

Introduction: Hypogonadism is associated with obesity and other features of metabolic syndrome in males., Purpose: The purpose of this study was to compare lean and obese male Zucker rats on their reproductive endocrine function in response to aerobic exercise training., Methods: Lean (Fa/Fa) and obese (fa/fa) male Zucker rats at 2 months of age were randomly assigned to a sedentary and an aerobic exercise training group (lean sedentary, n = 7; lean exercise, n = 8; obese sedentary, n = 7; obese exercise, n = 7). The exercise group walked on a rat treadmill, starting at 10 m · min(-1) for 20 min and building up to 20 m · min(-1) for 60 min, five times per week for 8 wk. Serum levels of total and free testosterone and testicular levels of testosterone, as well as epididymal and inguinal adipose tissue monocyte chemotactic protein 1 release levels, were measured., Results: There were significant obesity-by-exercise interactions on serum levels of total and free testosterone and testicular levels of testosterone (all P < 0.05). Compared to lean sedentary rats, obese sedentary rats had lower serum and testicular testosterone levels (0.72- to 0.74-fold, all P < 0.001). There were no group differences between lean sedentary and lean exercise rats on serum and testicular testosterone levels. However, compared to the obese sedentary group, the obese exercise group had higher serum and testicular testosterone levels (1.37- to 1.47-fold, all P < 0.05). In the whole cohort, serum and testicular testosterone levels were inversely related to epididymal adipose tissue monocyte chemotactic protein 1 secretion (r = -0.40 to r = -0.45, all P < 0.05)., Conclusions: Our results support that aerobic exercise training could improve severe obesity-related hypogonadism in male Zucker rats. The underlying mechanism needs to be further clarified.

Purpose: We tested the hypothesis that low-intensity vibration training in mice improves contractile function of hindlimb skeletal muscles and promotes exercise-related cellular adaptations., Methods: We subjected C57BL/6J mice to 6 wk, 5 d·wk, 15 min·d of sham or low-intensity vibration (45 Hz, 1.0g) while housed in traditional cages (Sham-Active, n = 8; Vibrated-Active, n = 10) or in small cages to restrict physical activity (Sham-Restricted, n = 8; Vibrated-Restricted, n = 8). Contractile function and resistance to fatigue were tested in vivo (anterior and posterior crural muscles) and ex vivo on the soleus muscle. Tibialis anterior and soleus muscles were evaluated histologically for alterations in oxidative metabolism, capillarity, and fiber types. Epididymal fat pad and hindlimb muscle masses were measured. Two-way ANOVAs were used to determine the effects of vibration and physical inactivity., Results: Vibration training resulted in a 10% increase in maximal isometric torque (P = 0.038) and 16% faster maximal rate of relaxation (P = 0.030) of the anterior crural muscles. Posterior crural muscles were unaffected by vibration, except greater rates of contraction in Vibrated-Restricted mice compared with Vibrated-Active and Sham-Restricted mice (P = 0.022). Soleus muscle maximal isometric tetanic force tended to be greater (P = 0.057), and maximal relaxation was 20% faster (P = 0.005) in vibrated compared with sham mice. The restriction of physical activity induced muscle weakness but was not required for vibration to be effective in improving strength or relaxation. Vibration training did not affect muscle fatigability or any indicator of cellular adaptation investigated (P ≥ 0.431). Fat pad but not hindlimb muscle masses were affected by vibration training., Conclusion: Vibration training in mice improved muscle contractility, specifically strength and relaxation rates, with no indication of adverse effects to muscle function or cellular adaptations.

In the last decade, a considerable number of articles has shown that exercise is effective in improving motor performance in Parkinson disease. In particular, recent studies have focused on the efficacy of intensive exercise in achieving optimal results in the rehabilitation of patients with Parkinson disease. The effects of intensive exercise in promoting cell proliferation and neuronal differentiation in animal models are reported in a large cohort of studies, and these neuroplastic effects are probably related to increased expression of a variety of neurotrophic factors. The authors outline the relation between intensive exercises and neuroplastic activity on animal models of Parkinson disease and discuss the clinical results of different intensive strategies on motor performance and disease progression in patients with Parkinson disease.

Background: Several studies have demonstrated antinociception induced by exercise; however, the specific mechanisms for this effect are not well understood. Thus, we investigated the involvement of α2-adrenergic receptors (α2-ARs) in the antinociceptive effect produced by exercise in rats and mice., Methods: Male Wistar rats performed acute aerobic (AA) and acute resistance exercise protocols, and male α2A/α2C-ARs knockout mice and their wild-type mice were also submitted to AA., Results: After the exercise protocols, the nociceptive threshold of rats and wild type was increased, (except in knockout mice). This effect was reversed by yohimbine, a nonselective α2-ARs antagonist (4 mg/kg, subcutaneously [s.c.]); rauwolscine, a selective α2C-ARs antagonist (4 mg/kg, s.c.); BRL 44408, a selective α2A-ARs antagonist (4 mg/kg, s.c.) and guanethidine, a selective inhibitor of transmission in adrenergic nerves (30 mg/kg, intraperitoneal). Furthermore, when given intrathecally or intracerebroventricularly, yohimbine did not alter antinociception induced by exercise protocols. In addition, α2-ARs expression in rat brains did not change after AA and acute resistance exercise., Conclusion: These results suggest a peripheral involvement of α2-ARs in the antinociception induced by aerobic and resistance exercise.

Purpose: The purpose of this study was to determine the minimum amount of resistance exercise that would stimulate bone formation, via an elevation in bone mineral density (BMD), during the growth period in male rats., Methods: Forty male rats were randomly divided into control group (Con, n = 8), one ladder climb resistance-trained group (1LC, n = 8), two ladder climb resistance-trained group (2LC, n = 8), three ladder climb resistance-trained group (3LC, n = 8), and four ladder climb resistance-trained group (4LC, n = 8). All exercised groups were conditioned to climb a vertical ladder with weights appended to their tail 3 d·wk(-1) for a total of 6 wk., Results: After 6 wk, left tibia BMD (mean ± SE) was significantly greater for 2LC, 3LC, and 4LC (0.233 ± 0.003 g·cm(-2)) when compared with Con (0.218 ± 0.003 g·cm). Left femur BMD was significantly greater for 2LC, 3LC, and 4LC (0.318 ± 0.003 g·cm(-2)) when compared with 1LC (0.299 ± 0.008 g·cm(-2)) and Con (0.289 ± 0.010 g·cm(-2)).There were no significant differences in BMD between 2LC, 3LC, and 4LC groups., Conclusion: The results suggest that during growth, a low amount of resistance exercise was just as effective as high volumes of strength training for stimulating bone modeling.

Objective: Whole-body periodic acceleration (WBPA) has been developed as a passive exercise technique to improve endothelial function by increasing shear stress through repetitive movements in spinal axis direction. We investigated the effects of WBPA on blood flow recovery in a mouse model of hindlimb ischemia and in patients with peripheral arterial disease., Methods and Results: After unilateral femoral artery excision, mice were assigned to either the WBPA (n=15) or the control (n=13) group. WBPA was applied at 150 cpm for 45 minutes under anesthesia once a day. WBPA significantly increased blood flow recovery after ischemic surgery, as determined by laser Doppler perfusion imaging. Sections of ischemic adductor muscle stained with anti-CD31 antibody showed a significant increase in capillary density in WBPA mice compared with control mice. WBPA increased the phosphorylation of endothelial nitric oxide synthase (eNOS) in skeletal muscle. The proangiogenic effect of WBPA on ischemic limb was blunted in eNOS-deficient mice, suggesting that the stimulatory effects of WBPA on revascularization are eNOS dependent. Quantitative real-time polymerase chain reaction analysis showed significant increases in angiogenic growth factor expression in ischemic hindlimb by WBPA. Facilitated blood flow recovery was observed in a mouse model of diabetes despite there being no changes in glucose tolerance and insulin sensitivity. Furthermore, both a single session and 7-day repeated sessions of WBPA significantly improved blood flow in the lower extremity of patients with peripheral arterial disease., Conclusions: WBPA increased blood supply to ischemic lower extremities through activation of eNOS signaling and upregulation of proangiogenic growth factor in ischemic skeletal muscle. WBPA is a potentially suitable noninvasive intervention to facilitate therapeutic angiogenesis.

Exercise has been found to influence molecular systems important for maintaining neural function and plasticity as well as treatment of neurologic disorders. The stimuli required to elicit plasticity are thought to be activity dependent. Several protocols of physical exercise have been used to explore its effects on brain function. However, it is becoming increasingly recognized that no single physical exercise model is likely to fulfill all therapeutic needs. Varied interpretations of data derived from animal models have given rise to the lack of uniformity in the description and control of various features of the physical exercise stimulus, ranging from low to high intensity, intermittent to sustained, short to long durations, and different modes of activity. This article first describes the characteristics of the most frequently used animal models and goes on to review brain plasticity in intact animals and the usefulness of these models for the study of brain disorders. In this regard, animal models that investigate the beneficial effects of exercise on the brain before and after brain injury are discussed. A challenge for future studies is to better evaluate the usefulness of physical exercise protocols for preventing or treating brain disorders.

Background: Sleep apnea, hypertension, atherosclerosis, and obesity are features of metabolic syndrome associated with decreased restorative sleep and increased pain. These traits are relevant for anesthesiology because they confer increased risks of a negative anesthetic outcome. This study tested the one-tailed hypothesis that rats bred for low intrinsic aerobic capacity have enhanced nociception and disordered sleep., Methods: Rats were developed from a breeding strategy that selected for low aerobic capacity runners (LCR) and high aerobic capacity runners (HCR). Four phenotypes were quantified. Rats underwent von Frey sensory testing (n = 12), thermal nociceptive testing (n = 12), electrographic recordings of sleep and wakefulness (n = 16), and thermal nociceptive testing (n = 14) before and for 6 weeks after a unilateral chronic neuropathy of the sciatic nerve., Results: Paw withdrawal latency to a thermal nociceptive stimulus was significantly (P < 0.01) lower in LCR than HCR rats. There were also significant differences in sleep, with LCR rats spending significantly (P < 0.01) more time awake (18%) and less time in nonrapid eye movement sleep (-19%) than HCR rats. Nonrapid eye movement sleep episodes were of shorter duration (-34%) in LCR than HCR rats. Rapid eye movement sleep of LCR rats was significantly more fragmented than rapid eye movement sleep of HCR rats. LCR rats required 2 weeks longer than HCR rats to recover from peripheral neuropathy., Conclusions: Rodents with low aerobic capacity exhibit features homologous to human metabolic syndrome. This rodent model offers a novel tool for characterizing the mechanisms through which low aerobic function and obesity might confer increased risks for anesthesia.