Wheel Exercise Research Articles

Effects of aerobic exercise training on muscle plasticity in a mouse model of cervical spinal cord injury

Cervical spinal cord injury (SCI) results in permanent life-altering motor and respiratory deficits. Other than mechanical ventilation for respiratory insufficiency secondary to cervical SCI, effective treatments are lacking and the development of animal models to explore new therapeutic strategies are needed. The aim of this work was to demonstrate the feasibility of using a mouse model of partial cervical spinal hemisection at the second cervical metameric segment (C2) to investigate the impact of 6 weeks training on forced exercise wheel system on locomotor/respiratory plasticity muscles. To measure run capacity locomotor and respiratory functions, incremental exercise tests and diaphragmatic electromyography were done. In addition, muscle fiber type composition and capillary distribution were assessed at 51 days following chronic C2 injury in diaphragm, extensor digitorum communis (EDC), tibialis anterior (TA) and soleus (SOL) muscles. Six-week exercise training increased the running capacity of trained SCI mice. Fiber type composition in EDC, TA and SOL muscles was not modified by our protocol of exercise. The vascularization was increased in all muscle limbs in SCI trained group. No increase in diaphragmatic electromyography amplitude of the diaphragm muscle on the side of SCI was observed, while the contraction duration was significantly decreased in sedentary group compared to trained group. Cross-sectional area of type IIa myofiber in the contralateral diaphragm side of SCI was smaller in trained group. Fiber type distribution between contralateral and ipsilateral diaphragm in SCI sedentary group was affected, while no difference was observed in trained group. In addition, the vascularization of the diaphragm side contralateral to SCI was increased in trained group. All these results suggest an increase in fatigue resistance and a contribution to the running capacity in SCI trained group. Our exercise protocol could be a promising non-invasive strategy to sustain locomotor and respiratory muscle plasticity following SCI.

Involuntary, forced or voluntary exercise can ameliorate the cognitive deficits by enhancing levels of hippocampal NMDAR1, pAMPAR1 and pCaMKII in a model of vascular dementia

ABSTRACT Objectives: To investigate the effect on vascular dementia of involuntary exercise induced by functional electrical stimulation and of forced and voluntary exercise, focusing on the recovery of cognitive function and using a rat model of dementia. Methods: A demential model was created in Wistar rats who were then given forced exercise, allowed voluntary exercise (wheel running) or had exercise induced through functional electrical stimulation. Their responses were quantified using a Morris water maze and by measuring long-term potentiation in the hippocampus. Immunohistochemical staining was used to evaluate neurogenesis in the hippocampus and Nissl staining was applied to visualize viable neuron loss in the DG sector. In addition, the levels of NMDAR1, AMPAR1, pAMPAR1, pCaMKII, CaMKII, Bcl-2 and Bax in the hippocampus were assessed by western blotting. Results: All of the exercise groups showed a recovery of cognitive performance and improved long-term potentiation. The three modes of exercise all increased the number of DCX immunopositive cells and reduced losses of intact-appearing neurons in the hippocampal DG zones roughly equally. All proved about equally effective in increasing the levels of NMDAR1, pAMPAR1 and pCaMKII and increasing the Bcl-2/Bax ratio to protect neurons from apoptosis. Conclusion: Exercise induced by electrical stimulation has beneficial effects comparable to those of other types of exercise for alleviating the cognitive deficits of vascular dementia.

Voluntary wheel running ameliorates select paclitaxel chemotherapy-induced sickness behaviors and associated melanocortin signaling

While chemotherapy remains a common cancer treatment, it is associated with debilitating side effects (e.g., anorexia, weight loss, and fatigue) that adversely affect patient quality of life and increase mortality. However, the mechanisms underlying taxane chemotherapy-induced side effects, and effective treatments to ameliorate them, are not well-established. Here, we tested the longitudinal relationship between a clinically-relevant paclitaxel regimen, inflammation, and sickness behaviors (loss of body mass, anorexia, fever, and fatigue) in adult, female mice. Furthermore, we sought to identify the extent to which voluntary exercise (wheel running) attenuates paclitaxel-induced sickness behaviors and underlying central pathways. Body mass and food intake decreased following six doses of chemotherapy treatment relative to vehicle controls, lasting less than 5 days after the last dose. Paclitaxel treatment also transiently decreased locomotion (open field test), voluntary wheel running, home-cage locomotion, and core body temperature without affecting motor coordination (rotarod task). Circulating interleukin (IL)-6 and hypothalamic Il1b gene expression remained elevated in chemotherapy-treated mice at least 3 days after the last dose. Exercise intervention did not ameliorate fatigue or inflammation, but hastened recovery from paclitaxel-induced weight loss. Body mass recovery was associated with the wheel running-induced recovery of body composition, paclitaxel-induced alterations to hypothalamic melanocortin signaling, and associated peripheral circulating hormones (ghrelin and leptin). The present findings demonstrate the benefits of exercise on faster recovery from paclitaxel-induced body mass loss and deficits in melanocortin signaling and suggests the development of therapies targeting the melanocortin pathway to reduce paclitaxel-induced weight loss.

Abstract 13469: Novel Role of Extracellular SOD-derived H 2 O 2 Signaling in Exercise-induced Vascular Adaptation in Type 2 Diabetes

Background: Exercise training promotes vascular adaptation (restoration of endothelial function and angiogenesis) in type2 diabetes (T2D). Since eNOS uncoupling/O 2 - are increased in T2D, exercise may promote vascular adaptation via mechanism other than eNOS-NO axis. Extracellular superoxide dismutase (ecSOD) is a secreted copper (Cu) containing SOD that catalyzes the dismutation of O 2 - to H 2 O 2 and its full activity requires Cu transporter ATP7A. We reported that ATP7A-ecSOD pathway is reduced in T2D and that ecSOD-derived H 2 O 2 promotes VEGFR2 signaling and angiogenesis in endothelial cells. However, role of ATP7A-ecSOD axis and H 2 O 2 signaling in vascular adaptation to exercise in T2D have not been reported. Oxidation of Cysteine residues of targets proteins to generate cysteine sulfenic acid (Cys-OH) is a key initial event in H 2 O 2 -mediated signaling. Results: Here we show that ATP7A protein (49%), ecSOD activity (51%) and extracellular H 2 O 2 levels in blood vessels and skeletal muscles were significantly decreased in high fat diet-induced T2D mice compared to control C57Bl6 mice, which were rescued by volunteer wheel exercise (2 weeks) or in T2D/ATP7A overexpressing mice. In parallel, exercise training restored impaired endothelium-dependent relaxation (EDR) of resistant arteries and angiogenesis (CD31+ capillary, 2.4-fold) in skeletal muscle of T2D mice, which were inhibited by exogenous catalase or in T2D/ecSOD KO mice, but not by L-NAME, suggesting that ecSOD-derived H 2 O 2 , but not eNOS/NO, mediates exercise-induced beneficial effects. Mechanistically, exercise significantly increased Cys-OH formation of PKG1α (2.3-fold), which was shown to induce EDR in H 2 O 2 -, but not NO/cGMP-, dependent manner, in T2D vascular tissues as well as Cys-OH formation of AMPK (3.6-fold) and AMPK downstream angiogenic PGC1α and VEGF protein expression in T2D skeletal muscles. Of note, these exercise-induced Cys oxidation of PKG1α and AMPK were not observed in control or T2D/ecSOD KO mice. Conclusion: Exercise-induced ATP7A-ecSOD axis-mediated out-side in H 2 O 2 signaling plays an important role in promoting vascular adaptation in T2D via Cys oxidation of redox-sensitive kinases required for endothelial function and angiogenesis in skeletal muscles.

Abstract 13373: Exercise Improves Angiogenic Function of Circulating Exosomes in Type 2 Diabetes: Role of Extracellular SOD

Background: Exosomes, key mediators of cell-cell communication, derived from type 2 diabetes mellitus (T2DM) have detrimental effects. Exercise not only improves endothelial dysfunction and angiogenesis in T2DM but also induces secretion of exosomes into circulation. Extracellular superoxide dismutase (ecSOD) is a major secretory Cu containing antioxidant enzyme that catalyzes dismutation of O 2 •- to H 2 O 2 and its full activity requires Cu transporter ATP7A. We reported that ecSOD-derived H 2 O 2 in endothelial cells (ECs) enhances angiogenesis while impaired ATP7A-ecSOD axis in diabetes induces endothelial dysfunction. Here we examined whether exercise-derived exosomes (Exe-Exo) may have pro-angiogenic effects via regulating ATP7A-ecSOD axis in T2DM. Results: Two weeks of voluntary wheel exercise of control C57Bl6 mice increased plasma exosome levels (6.2-fold) characterized by Nanosight, TEM and exosome markers (CD63, CD81, Tsg101). Treatment of HUVECs with equal number of exosomes revealed that angiogenic responses such as EC migration (1.8-fold) and tube formation (1.7-fold) were significantly enhanced by Exe-Exo compared to sedentary-derived exosomes (Sed-Exo). This was associated with increased ATP7A (2.9-fold) and ecSOD (1.4-fold) expression in Exe-Exo. Sed-Exo from high fat-induced T2DM mice significantly decreased EC migration (40%) and tube formation (10%) as well as ATP7A expression (28%) compared to Sed-Exo from control mice, which were restored by T2DM Exe-Exo, but not by T2DM/ecSOD KO Exe-Exo. Furthermore, exosomes overexpressing ecSOD (ecSOD-Exo) which mimic exercise increased angiogenesis and H2O2 levels in ECs, which were inhibited by overexpression of catalase. In vivo, skin wound healing model showed that direct application of T2DM Sed-Exo delayed while T2DM Exe-Exo enhanced wound healing of control mice. Furthermore, defective wound healing in T2DM mice or ecSOD KO mice were rescued by ecSOD-Exo application. Conclusion: Exercise training improves pro-angiogenic function of circulating exosomes in T2DM via increasing ATP7A-ecSOD axis, which may provide an effective therapy for promoting angiogenesis and wound repair in metabolic and cardiovascular diseases.

Running wheel exercise induces therapeutic and preventive effects on inflammatory stimulus-induced persistent hyperalgesia in mice.

Chronic pain affects significant portion of the world's population and physical exercise has been extensively indicated as non-pharmacological clinical intervention to relieve symptoms in chronic pain conditions. In general, studies on pain chronification and physical exercise intervention have focused on neuropathic pain, although chronic pain commonly results from an original inflammatory episode. Based on this, the objective of the present study was to investigate the therapeutic and preventive effect of the running wheel exercise on the persistent hyperalgesia induced by repetitive inflammatory stimulus, a rodent model that simulates clinical conditions of chronic pain that persist even with no more inflammatory stimulus present. To evaluate the therapeutic effect of physical exercise, we first induced persistent hyperalgesia through 14 days of PGE2 hind paw injections and, after that, mice have access to the regular voluntary running wheel. To evaluate the preventive effect of physical exercise, we first left the mice with access to the regular voluntary running wheel and, after that, we performed 14 days of PGE2 hind paw injection. Our results showed that voluntary running wheel exercise reduced persistent mechanical and chemical hyperalgesia intensity induced by repetitive inflammatory stimulus. In addition, we showed that this therapeutic effect is long-lasting and is observed even if started belatedly, i.e. two weeks after the development of hyperalgesia. Also, our results showed that voluntary running wheel exercise absolutely prevented persistent mechanical and chemical hyperalgesia induction. We can conclude that physical exercise has therapeutic and preventive effect on inflammatory stimulus-induced persistent hyperalgesia. Our data from animal experiments bypass placebo effects bias of the human studies and reinforce physical exercise clinical recommendations to treat and prevent chronic pain.

Cardiac up-regulation of NBCe1 emerges as a beneficial consequence of voluntary wheel running in mice

Physical training stimulates the development of physiologic cardiac hypertrophy (CH), being a key event in this process the inhibition of the Na+/H+ exchanger. However, the role of the sodium bicarbonate cotransporter (NBC) has not been explored yet under this circumstance. C57/Bl6 mice were allowed to voluntary exercise (wheel running) for five weeks. Cardiac mass was evaluated by echocardiography and histomorphometry detecting that training promoted the development of physiological CH (heart weight/tibia length ratio, mg/mm: 6.54 ± 0.20 vs 8.81 ± 0.24; interstitial collagen content, %: 3.14 ± 0.63 vs. 1.57 ± 0.27; and cross-sectional area of cardiomyocytes, μm2: 200.6 ± 8.92 vs. 281.9 ± 24.05; sedentary (Sed) and exercised (Ex) mice, respectively). The activity of the electrogenic isoform of the cardiac NBC (NBCe1) was estimated by recording intracellular pH under high potassium concentration and by measuring action potential duration (APD). NBCe1 activity was significantly increased in isolated cardiomyocytes of trained mice. Additionally, the APD was shorter and the alkalization due to high extracellular potassium-induced depolarization was greater in this group, indicating that the NBCe1 was hyperactive. These results are online with the observed myocardial up-regulation of the NBCe1 (Western Blot, %: 100 ± 13.86 vs. 202 ± 29.98; Sed vs. Ex, n = 6 each group). In addition, we detected a reduction in H2O2 production in the myocardium of trained mice.These results support that voluntary training induces the development of physiologic CH with up-regulation of the cardiac NBCe1 in mice. Furthermore, the improvement in the antioxidant capacity contributes to the beneficial cardiovascular consequences of physical training.

Voluntary Exercise Suppresses Choroidal Neovascularization in Mice.

PurposeTo determine the effect of voluntary exercise on choroidal neovascularization (CNV) in mice.MethodsAge-matched wild-type C57BL/6J mice were housed in cages equipped with or without running wheels. After four weeks of voluntary running or sedentariness, mice were subjected to laser injury to induce CNV. After surgical recovery, mice were placed back in cages with or without exercise wheels for seven days. CNV lesion volumes were measured by confocal microscopy. The effect of wheel running only in the seven days after injury was also evaluated. Macrophage abundance and cytokine expression were quantified.ResultsIn the first study, exercise-trained mice exhibited a 45% reduction in CNV volume compared to sedentary mice. In the replication study, a 32% reduction in CNV volume in exercise-trained mice was observed (P = 0.029). Combining these two studies, voluntary exercise was found to reduce CNV by 41% (P = 0.0005). Exercise-trained male and female mice had similar CNV volumes (P = 0.99). The daily running distance did not correlate with CNV lesion size. Exercise only after the laser injury without a preconditioning period did not reduce CNV size (P = 0.41). CNV lesions of exercise-trained mice also exhibited significantly lower F4/80+ macrophage staining and Vegfa and Ccl2 mRNA expression.ConclusionsThese findings provide the first experimental evidence that voluntary exercise improves CNV outcomes. These studies indicate that exercise before laser treatment is required to improve CNV outcomes.

The Effect of Wheel Exercise on Functional Indices of Cachexia in Tumor-bearing Mice.

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. 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. 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). 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.

SIRT1-dependent mechanisms and effects of resveratrol for amelioration of muscle wasting in NASH mice

BackgroundIn non-alcoholic steatohepatitis (NASH), muscle wasting was an aggravating factor for the progression of hepatic steatosis. This study explores the potential benefits of chronic treatment with resveratrol, a strong activator...

휠 운동이 우울증 모델 쥐의 신경세포생성 과정에 미치는 영향

휠 운동이 우울증 모델 쥐의 신경세포생성 과정에 미치는 영향

Exercise retards hepatocarcinogenesis in obese mice independently of weight control

Obesity and type 2 diabetes increase hepatocellular carcinoma (HCC) incidence in humans and accelerate diethylnitrosamine (DEN)-induced hepatocarcinogenesis inmice. We investigated whether exercise reduces HCC development in obese/diabetic Alms1 mutant (foz/foz) mice and studied protective mechanisms. We measured HCC development in DEN-injected male foz/foz and wild-type (WT) littermates housed with or without an exercise wheel from week 4 until 12 or 24 weeks, and in foz/foz mice pair-fed to WT littermates. We also studied HCC development in DEN-injected Jnk1-/-.foz/foz mice generated by cross breeding, as well as their genetic controls. Dysplastic hepatocytes were identified by glutathione-S-transferase pi form (GST-pi) immunohistochemistry, liver nodules were counted, and HCC was analysed by histopathology. Exercising foz/foz mice maintained similar weight as WT mice up to 10 weeks, but then gained weight and were obese by 24 weeks; a similar body weight profile was obtained by pair-feeding foz/foz mice to WT. At 12 weeks, livers of exercising foz/foz mice exhibited fewer GST-pi positive hepatocytes than sedentary counterparts; by 24 weeks, fewer exercising foz/foz mice developed HCC (15% vs. 64%, p <0.05). Conversely, pair-feeding foz/foz mice failed to reduce HCC incidence. In these insulin-resistant foz/foz mice, exercise failed to activate hepatic AMPK or Akt/mTORC1. Instead, it improved insulin sensitivity, ameliorated steatosis and liver injury, activated p53 to increase p27 expression, and prevented JNK activation. This was associated with suppression of hepatocellular proliferation. DEN-injected Jnk1-/-.foz/foz mice failed to develop liver tumours or HCC at 24 weeks. Direct effects of exercise dampen proliferation of dysplastic hepatocytes to reduce 3-month dysplastic foci and 6-month incidence of DEN-induced HCC in obese, insulin-resistant mice. The effects of exercise that potentially slow hepatocarcinogenesis include p53-mediated induction of p27 and prevention of JNK activation. Fatty liver disease commonly occurs alongside obesity and diabetes, contributing to rapidly increasing rates of liver cancer throughout the world. Herein, we show that exercise reduces the incidence and progression of hepatocellular carcinoma in mouse models. The effect of exercise on cancer risk was shown to be independent of changes in weight. Exercise could be a protective mechanism against liver cancer in at-risk individuals.

Myocardial oxidative stress and inflammation emerges during recovery from exertional heat stroke in female but not male mice

INTRODUCTIONEpidemiological reports have shown an association between heat stroke and increased risk of cardiovascular disease later in life. Using a preclinical model of exertional heat stroke (EHS), we reported metabolic disturbances in the myocardium of female mice that emerge after 9–14 d of recovery. However, it is unknown whether these metabolic changes are accompanied by oxidative stress and inflammation in the myocardium.PURPOSETo determine whether EHS exposure induces oxidative stress and inflammation in the ventricular myocardium during recovery.METHODSMale and female C57BL6 mice underwent surgical implantation of telemetry devices to monitor core temperature, followed by 3 weeks of exercise wheel running, and an EHS trial, consisting of forced wheel running in 37.5°C, 40% humidity. Results were compared to matched exercise controls (EXC), that performed the same exercise at ~22°C and recovered for 4 d. Ventricular samples were collected at 30 min, 3 h, 24 h, 4 d, 9 d and 14 d post EHS for metabolomics testing (n=8/group). Portions of the ventricles from the 14 d time point were also preserved in formalin, sectioned and stained with H&amp;E. The entire cross section of each ventricular section was divided into a grid and each section of the grid graded from 0–3 based on severity of inflammation.RESULTSFemale mice exhibited greater heat tolerance but were exposed to much higher durations of exercise and heat load during the EHS protocol, as previously described. Metabolomic analyses determined that the myocardium of females exhibited multiple markers of oxidative stress that were not seen in males. Glutathione levels decreased by ~40% by 4 d and recovered at later timepoints. Oxidized glutathione increased by ~25% at 24 h post EHS and returned to baseline levels in later recovery periods. The oxidation product, 13‐HODE/9‐HODE continued to increase beyond 3 h post EHS, reaching ~400% of EXC (P&lt;0.001) at 14 d. Other markers such as 4‐hydroxy‐nonenal glutathione, methionine sulfone and trimethylamine N‐oxide showed biphasic responses, characterized by a significant elevation at 30 min, a recovery at 3 h, and then large elevations, reaching 200%–400% of EXC. Histological markers of inflammation were also elevated in females in the 14 d EHS hearts compared to EXC (P&lt;0.001). This was not seen in male hearts.CONCLUSIONSOur data suggest that EHS in females, but not males, results in oxidative stress and increased inflammation in the ventricular myocardium during recovery. We speculate that sex differences arose from either the greater heat load experienced by females or by unique sex‐dependent differences in metabolic control. Though the translation of these results to the human condition is highly speculative, it is possible that such EHS‐induced cardiovascular events may comprise an origin of the cardiovascular susceptibilities to disease later in life that have been previously observed in heat stroke victims.Support or Funding InformationSupported by DoD Grant W81XWH‐15‐2‐0038 and the BK and Betty Stevens Professorship. Author’s views do not reflect US Army or DoD policy or endorsements.

Evaluation of the effects of different intensities of forced running wheel exercise on oxidative stress biomarkers in muscle, liver and serum of untrained rats.

Exercise induces different effects on antioxidant status depending on its intensity. The forced running wheel (FRW) model maintains a constant intensity and volume during exercise. The aim of the present study was to investigate the effects of FRW exercise at different running speeds on several serum biochemical parameters of liver and muscle functions and on oxidative stress biomarkers in skeletal muscle, liver and serum in the rat. Thirty-six male Wistar rats were randomly divided into six groups. Five groups participated in constant power tests at intensities of 10, 13, 14.5, 16, and 17.5 m/min, and a non-exercise group was chosen as the control. Serum, muscle and liver tissues were collected after the tests and analyzed. At speeds >16 m/min, exercise on an FRW significantly increased several serum biochemical parameters, malondialdehyde level and superoxide dismutase activity in all tissues of exercise rats compared with control rats; FRW exercise also increased catalase activity in the liver and glutathione S-transferase activity in muscle, whereas it decreased glutathione level in all tissues and catalase activity in muscle and serum. These data suggest that FRW exercise in rats activates an adaptation of the antioxidant system response in skeletal muscle at speeds <16 m/min, whereas it induces oxidative stress at higher speeds in muscle, liver and serum. In addition, we observed a correlation between the systematic and local oxidative stress status in rats after exercise on FRW.

강제 휠 운동이 스트레스 호르몬에 미치는 변화

강제 휠 운동이 스트레스 호르몬에 미치는 변화

Exercise modulates the levels of growth inhibitor genes before and after multiple sclerosis

Multiple sclerosis (MS) is a neurodegenerative disease of the central nervous system. The animal model of MS, experimental autoimmune encephalomyelitis (EAE), is commonly used for studies of human inflammatory demyelinating diseases and has been shown to be suitable for studying the effects of exercise on MS pathophysiology. The present study was conducted to determine the impact of forced swimming and voluntary running wheel exercises before and after the induction of EAE on expression of Nogo-A, NgR, and ROCK genes in the brain tissue. A total of 96 C57BL/6 mice were randomly divided into two groups, namely exercises before (EXb, n = 48) and after (EXa, n = 48) induction of EAE. Each group was divided into four subgroups: Forced Swimming + EAE (n = 12), Voluntary Running Wheel + EAE (n = 12), NoEX-EAE (n = 12), and Control group (n = 12). Animals performed either swimming exercise for 30 min per day or running wheel for one hour per day, five days per week for four weeks. Results of Luxal Fast Blue (LFB) staining demonstrated that the degree of demyelination was significantly less in the experimental exercised compared to NoEX-EAE groups (P < .05). Amazingly, both modes of exercise reduced the severity of MS symptoms in mice exposed to swimming and wheel running, evaluated as body weight, clinical scores, degree of demyelination, and gene expressions, regardless of whether the exercise was performed before or after EAE induction.

Therapeutic and Preventive Effect of Voluntary Running Wheel Exercise on Social Defeat Stress (SDS)-induced Depressive-like Behavior and Chronic Pain in Mice

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.

Angiotensin receptor blockade mimics the effect of exercise on recovery after orthopaedic trauma by decreasing pain and improving muscle regeneration.

Our tibial fracture orthopaedic injury model in mice recapitulates the major manifestations of complex trauma, including nociceptive sensitization, bone fracture, muscle fibrosis and muscle fibre loss. Delayed exercise after complex orthopaedic trauma results in decreased muscle fibrosis and improved pain Losartan, an angiotensin-receptor blocker with anti-fibrotic abilities, recapitulates the effect of exercise on post-injury recovery and may provide an enhanced recovery option for those who are unable to exercise after injury ABSTRACT: Chronic pain and disability after limb injury are major public health problems. Early mobilization after injury improves functional outcomes for patients, although when and how to implement rehabilitation strategies remains a clinical challenge. Additionally, whether the beneficial effects of exercise can be reproduced using pharmacological tools remains unknown and may benefit patients who are unable to exercise as a result of immobilization. We developed a murine model of orthopaedic trauma combining tibia fracture and pin fixation with muscle damage. Behavioural measures included mechanical nociceptive thresholds and distances run on exercise wheels. Bone healing was quantified using microcomputed tomagraphic scanning, and muscle fibre size distribution and fibrosis were followed using immunohistochemistry. We found that the model provided robust mechanical allodynia, fibrosis and a shift to smaller average muscle fibre size lasting up to 5weeks from injury. We also observed that allowing 'late' (weeks 1-2) rather than 'early' (weeks 0-1) exercise after injury resulted in greater overall running activity and greater reversal of allodynia. In parallel, the late running paradigm was associated with reduced muscle fibrosis, earlier increase in muscle fibre diameter and a short-term benefit in reducing callus volume. Providing the anti-fibrotic angiotensin receptor blocker losartan to mice in drinking water reduced both allodynia and muscle fibrosis. Combining losartan and late exercise provided no additional benefit. We conclude that early healing after orthopaedic trauma must be allowed prior to the initiation of exercise to achieve optimal pain, functional and physiological outcomes and that losartan is a viable candidate for translational studies.

Treadmill and wheel exercise protect against JNK/NF-κB induced inflammation in experimental models of knee osteoarthritis

Osteoarthritis (OA) remains a challenge for clinicians and effective treatments are lacking. In this study, we investigated JNK/NF-κB signaling in knee OA patients. Rats were used to establish an OA model and were divided into six groups; (1) Control (sterile saline injection only); (2) Controls with treadmill exercise (treadmill); (3) Controls with wheel exercise (wheel); (4) OA (MIA injection); (5) OA with treadmill exercise (OA + treadmill); and (6) OA with wheel exercise (OA + wheel). The results showed that, compared to the OA group, the OA + treadmill and OA + wheel groups had lower levels of IL-1β, IL-6 and TNF-α, and similar levels of p-P65, p-JNK, and P-IκBα. Furthermore, treatment with the JNK agonist anisomycin enhanced the damage to the joint cartilage and increased the levels of IL-1β, IL-6 and TNF-α. Taken together, these data suggest that treadmill and wheel exercise protect against inflammation through the regulation of JNK/NF-κB signaling in experimental models of knee OA.

Long-Term Voluntary Physical Exercise Exerts Neuroprotective Effects and Motor Disturbance Alleviation in a Rat Model of Parkinson's Disease.

Background Parkinson's disease (PD) is the second most prevalent neurodegenerative disorder affecting 7–10 million individuals. The pathologic hallmark of PD is nigrostriatal dopaminergic neuron loss, leading to several motor and nonmotor disturbances, such as akinesia, gait disturbance, depression, and anxiety. Recent animal studies have demonstrated that physical exercise improves behavioral and neuropathological deficits in PD. However, the exact underlying mechanism underlying this effect remains unclear. In this study, we investigated whether long-term exercise has neuroprotective effects on dopaminergic nigrostriatal neurons and whether it further alleviates impairment of the gait pattern, locomotor activity, akinesia, and anxiety-like behavior in PD rats. Methods A hemiparkinsonian rat model, generated by unilateral injection of 6-hydroxydopamine (6-OHDA) into the medial forebrain bundle, was applied to evaluate neuroprotective effects and motor behaviors. Comprehensive spatiotemporal gait analysis, open-field locomotor activity, akinesia, apomorphine-induced rotational analysis, and dopaminergic neuron degeneration level were assessed every week and up to 8 weeks after daily voluntary running wheel exercise. Results Compared with the sham-treated group, we found that 10 weeks of voluntary exercise (i.e., 2-week exercise before PD lesion and 8-week exercise post-PD lesion) significantly reduced 6-OHDA-induced motor deficits in the gait pattern, akinesia, and rotational behavior in the exercise group. Immunohistochemically, a tyrosine hydroxylase-positive neuron in the substantia nigra was significantly preserved in the exercise group. Conclusions Our results demonstrated that long-term exercise training is effective for neuroprotection and further attenuates motor declines induced by 6-OHDA in an experimental model of PD. Our data further highlighted potential therapeutic effects of long-term physical exercise relevant to clinical effects for further potential application on human PD subjects.