Moderate Treadmill Running Research Articles

Age- and Sex-Dependent Effects of Moderate Exercise on Endogenous Pain Inhibition in Rats.

Diffuse noxious inhibitory controls (DNICs), or the pain inhibits pain phenomenon, refer to reduced pain-like behaviors that are displayed following a noxious conditioning stimulus located far from the test stimulus and have also been referred to as "descending control of nociception" when measured in awake-behaving animals. In this study, we sought to determine the impact of moderate long-term exercise on the DCN response and determine if this effect differed across age and sex. After a six-week exercise program consisting of 30 min of moderate treadmill running 5 days a week, the animals' forepaws were injected with capsaicin, and DCN responses were assessed using thermal withdrawal latencies of the hind paw. Young, exercised male and female rats displayed prolonged DCN responses relative to their sedentary counterparts, with the young exercised male group displaying longer-lasting DCN facilitation than the young exercised females. Exercise did not impact DCN responses in either male or female aged rats. Additionally, the serum testosterone levels did not change following exercise in any group. Importantly, the levels of corticosterone did not change following the exercise program, indicating that changes in the DCN response are not due to stress-induced analgesia. Our findings suggest that moderate exercise can facilitate the DCN response in young animals, even when this exercise does not change the levels of serum testosterone.

Exercise Rehabilitation Preserves Cardiorespiratory Muscle Function Following Doxorubicin Treatment

Doxorubicin (DOX) is a highly effective chemotherapeutic agent. Unfortunately, cancer patients who have completed DOX treatment often experience exercise intolerance, reduced cardiac function, dyspnea and unfavorable changes to body composition, ultimately, leading to increased incidence of heart failure. Exercise has been shown to reduce the risk of developing chemotherapy-induced cardiorespiratory dysfunction; however, the ability of cancer patients to exercise during treatment can be limited by cancer type, stage and fatigue. Therefore, these experiments utilized a chronic DOX-induced cardiotoxicity model to determine the effects of rehabilitative exercise on cardiorespiratory muscle function. Female Sprague-Dawley rats were treated with DOX once every three weeks for four total cycles via intravenous infusion (i.e., cumulative dose of ~160mg/m2). One-week following the completion of DOX treatment, rats remained sedentary (Sed-DOX) or were prescribed 10-weeks of moderate intensity treadmill running at 30m/min, 0% grade, 1-hour/day, and 3x/week (Mod-DOX). Body composition, exercise tolerance and echocardiography were assessed at three timepoints: 1) pre-treatment; 2) post-treatment and; 3) post-rehabilitation. Diaphragm muscle specific force production was measured post-rehabilitation. From pre- to post-treatment each group gained weight and no differences existed between groups. However, from post-treatment to post-rehabilitation body weight of the DOX-treated groups did not change and was significantly reduced compared to sedentary saline-treated (Sed-Sal) rats from week 15 onwards. Although mean body weight did not differ between the DOX-treated groups, lean mass increased in Mod-DOX rats between each timepoint with no change in fat mass, while fat mass increased in Sed-DOX rats and an initial increase in lean mass was attenuated from post-treatment to post-rehabilitation. Exercise time to fatigue did not change between timepoints within each group; however, exercise run time from post-treatment to post-rehabilitation was significantly longer in Mod-DOX rats compared to Sed-DOX and Sed-Sal. Cardiac fractional shortening percentage (FS%) was reduced in Sed-DOX rats at post-treatment and post-rehabilitation compared to pre-treatment. Additionally, posterior wall shortening velocity (PWSV) was reduced in Sed-DOX rats at post-treatment compared to pre-treatment. No differences in FS% or PWSV were seen between any timepoint in the Mod-DOX group. Finally, ex vivo diaphragm muscle function showed significant diaphragm muscle weakness in Sed-DOX rats at 15-60Hz stimulations compared to Sed-Sal. Diaphragm force production did not differ in Mod-DOX rats compared to Sed-Sal at any stimulation frequency. These results demonstrate a beneficial effect of moderate intensity rehabilitation exercise for the maintenance of body composition, cardiac function and diaphragm muscle function following DOX treatment compared to sedentary rats. NIH R01 HL144858, NIH R01 HL146443, NIH HL134621. This is the full abstract presented at the American Physiology Summit 2024 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.

Aerobic exercise attenuates high-fat diet–induced renal injury through kidney metabolite modulation in mice

Purpose To investigate the preventive effect of aerobic exercise on renal damage caused by obesity. Methods The mice in the Control (Con) and Control + Exercise (Con + Ex) groups received a standard chow diet for the 21-week duration of the study, while the High-fat diet (HFD) group and High-fat diet + Exercise (HFD + Ex) group were fed an HFD. Mice were acclimated to the laboratory for 1 week, given 12 weeks of being on their respective diets, and then the Con + Ex and HFD + Ex groups were subjected to moderate intensity aerobic treadmill running 45 min/day, 5 days/week for 8 weeks. Results We found that HFD-induced obesity mainly impacts kidney glycerin phospholipids, glycerides, and fatty acyls, and aerobic exercise mainly impacts kidney glycerides, amino acids and organic acids as well as their derivatives. We identified 18 metabolites with significantly altered levels that appear to be involved in aerobic exercise mediated prevention of HFD-induced obesity and renal damage, half of which were amino acids and organic acids and their derivatives. Conclusion Aerobic exercise rewires kidney metabolites to reduce high-fat diet-induced obesity and renal injury.

High Fat High Sugar Diet Reduces Small Intestinal Secretion by Sex-Dependent Mechanisms.

The goal of this study was to determine the influence of high-fat high-sugar diet (Western diet) on intestinal function and subsequently to determine if there were any beneficial effects of exercise, genistein (a naturally occurring phytoestrogen) or both, on the intestine. We measured transepithelial short circuit current (Isc), across freshly isolated segments of jejunum from male and female C57Bl/6J mice randomly assigned to one of the following groups for the 12-week study duration: high-fat high-sugar diet (HFS), HFS with genistein (Gen), HFS with exercise (Ex), or HFS with both genistein and exercise (Gen+Ex) and compared them to lean controls. Genistein concentration was 600 mg genistein/kg diet. Exercise comprised of moderate intensity treadmill running (150 min per week). At the completion of the study, segments of jejunum were frozen for western blot determination of key proteins involved in secretory and absorptive functions, as well as senescence. Intestinal morphology was assessed. Serum cytokine assays were performed. Basal Isc was significantly decreased (by 70%, P<0.05) in HFS females and males versus leans. This decrease was partially mitigated by exercise in both sexes. In females, the HFS-induced decrease in Isc was attributed to a significant loss of CLC2, NKCC1 and CFTR expression whereas in males this was due to a significant loss of Na/K-ATPase, KCa and NKCC1 expression (indicating sex-dependent mechanisms). Exercise mitigated most of the loss of Isc in both sexes. Our data suggested that A2BR levels were dysregulated in HFS fed mice and that concomitant treatment with Gen or Gen+Ex prevented this disruption in females only. Inflammatory state was associated with body weight changes. Our data suggests that the reduced basal jejunal Isc in HFS mice is attributed to sex-dependent mechanisms and while exercise partially mitigated this, it's mechanism of action was unclear. Improved understanding of Western diet induced intestinal dysfunctions may allow for the development of novel drug targets to treat gastrointestinal disturbances in diabetic obesity.

Protective effects of treadmill exercise on apoptotic neuronal damage and astrocyte activation in ovariectomized and/or diabetic rat prefrontal cortex: molecular and histological aspects

Objective Both estrogen deprivation and diabetes mellitus are known as risk factors for neuronal damage. Using an animal model of ovariectomized and/or streptozotocin (STZ)-induced diabetes mellitus, we examined expression of apoptosis-related proteins, neuronal damage, and astrocyte activation in prefrontal cortex of rats with/without treadmill exercise. Methods Adult female Wistar rats were divided into control, ovariectomized (Ovx, bilateral ovariectomy), diabetic (Dia, STZ 60 mg/kg; i.p.), and ovariectomized diabetic (Ovx + Dia) groups. Next, animals in each group were randomly subdivided into non-exercise and exercise subgroups. Animals in the exercise groups underwent moderate treadmill running for 4 weeks (5 days/week). Thereafter, expression of Bax, Bcl-2, and caspase-3, as apoptosis-related proteins, number of neurons, and number of glial fibrillary acidic protein (GFAP)-positive cells in prefrontal cortex were measured using immunoblotting, cresyl violet staining, and immunohistochemistry, respectively. Results In both Dia and Ovx + Dia groups, Bax and caspase-3 protein levels and number of GFAP-positive cells were higher than those in the control group, while Bcl-2 protein level and number of neurons compared were lower than the control group. Beneficial effects of exercise to prevent apoptosis-mediated neuronal damage and astrocyte activation were also observed in the Dia group. Conclusion Based on our results, physical exercise could be beneficial to attenuate diabetes-induced neuronal damage in the prefrontal cortex via inhibition of apoptosis.

Acute exercise in 5‐Fluorouracil cardiotoxicity: Effects on cardiac function and reverse phase protein analysis

Background5‐Fluorouracil (5FU) is a commonly administered chemotherapeutic agent used in the treatment of numerous cancers. Though efficacious in treatment of malignancies, 5FU is associated with dose limiting cardiotoxicity that often necessitates deviation from preferred treatment regimens and increases reliance on other, less effective treatment alternatives. The mechanisms driving these toxicities are poorly understood, but leading theories include direct myocardial damage and coronary vasospasm. Data to support these theories have historically been derived from pre‐clinical animal models utilizing i.p injection of 5FU rather than protocols designed to mimic the drug delivery route utilized in clinical practice (i.v. infusion). Further, others have demonstrated the effectiveness of acute exercise in prevention of cardiotoxicity induced by other chemotherapies, however there are no studies evaluating the efficacy of exercise in prevention of 5FU cardiotoxicity.Purpose &amp; HypothesisThe present investigation assessed the effect of 4 moderate intensity treadmill running bouts prior to administration of a clinically relevant dose of 5FU on the functional cardiovascular wellbeing of rats. We tested the hypotheses that a 2‐hr infusion of 5FU would reduce echocardiographic measures of ejection fraction (EF) and fractional shortening (%FS) compared to a saline infusion, and that completion of an acute exercise protocol prior to 5FU treatment would mitigate these cardiotoxic effects.MethodsMale Sprague‐Dawley rats were randomized to receive 5FU (n=15) or saline (CON, n=11) via a 50 mg/kg jugular bolus followed by a 2‐hr 265 mg/kg continuous infusion. A subset of each group (n=7 ex5FU, n=4 exCON) completed 4 bouts of moderate intensity treadmill running (25 min each) commencing 3 days prior to 5FU/saline treatment with the final run ending 1‐hr prior to treatment onset. The remaining animals acted as sedentary controls (n=7 s5FU, n=8 sCON). Echocardiographic variables were compared between groups at baseline and 2‐hr time points (mixed‐model design). Reverse phase protein analysis (RPPA) was conducted on cardiac tissue excised immediately following completion of the infusion for insight into molecular alterations induced by 5FU and/or exercise.ResultsEF at 2‐hr was reduced in sCON (92±2 vs 86±3%, P=.01), s5FU (91±2 vs 86±2%, P=.03), and ex5FU (87±2 vs 82±1%, P=.02), but not in exCON (91±2 vs 87±1%, P=.35) with no timepoint differences between groups (P=0.23). Similarly, %FS decreased from baseline to 2‐hr in sCON (60±3 vs 52±4%, P=.00), s5FU (59±3 vs 51±3%, P=.03), and ex5FU (53±3 vs 45±1%, P=.04), but not in exCON (58±4 vs 52±1, P=.28) with no differences between groups at either time point (P=0.97). RPAA analysis identified graded key changes in CAV‐1, SMAD, and BCL2L1.ConclusionThe present findings suggest small reductions in EF and %FS following completion of a 2‐hr infusion of 5FU or saline, with no differences between the treatments. Further, reductions in EF and %FS were mitigated by prior exercise in exCON, but not in ex5FU. Future work will place emphasis on quantifying the molecular changes indicated by RPPA to better understand alterations induced by 5FU within the heart at the cellular level.

Moderate tibial loading and treadmill running, but not overloading, protect adult murine bone from destruction by metastasized breast cancer

Osteolytic bone lesions, which develop in many metastatic breast cancer patients, impair bone integrity and lead to adverse skeletal related events that are difficult to treat and sometimes fatal. Moderate mechanical loading has been shown to suppress osteolysis in young mice with breast cancer. In this study, we aimed to investigate the dose-dependent effects of mechanical loading on protecting the integrity of adult skeletons with breast cancer. Localized tibial loading and aerobic treadmill running with three levels of varying intensity were tested in a syngeneic mammary tumor bone metastasis model. Adult C57BL/6J female mice (14-week-old, N=88 mice) received intra-tibial injections of Py8119 triple-negative murine breast cancer cells or PBS and underwent 4 to 5weeks of exercise or acted as sedentary/non-loaded controls. The bone structure was monitored longitudinally with weekly in vivo micro-computed tomography imaging, while the cellular responses in bone and marrow were examined using immunohistochemistry. Moderate treadmill running (16m/min, 50min/day, 5days/week, and 5weeks) and tibial loading (4.5N, 630 με, 4Hz, 300cycles/day, 5days/week, and 4weeks) suppressed tumor-induced bone destruction, as evaluated by full-thickness perforation of tibial cortex and the volume of osteolytic lesions in the cortex. In contrast, tibial loading at higher magnitude (8N, 1100 με) induced woven bone and accelerated bone destruction, compared with the non-loaded controls. The three exercise regimens differentially affected osteocyte apoptosis, osteocyte hypoxia, osteoclast activity, bone marrow vasculature, and tumor proliferation. In conclusion, the relationship between exercise intensity and the risk of breast cancer-induced osteolysis was found to follow a J-shaped curve in a preclinical model, suggesting the need to optimize exercise parameters in order to harness the skeletal benefits of exercise in metastatic breast cancers.

Moderate and intensive mechanical loading differentially modulate the phenotype of tendon stem/progenitor cells in vivo.

To examine the differential mechanobiological responses of specific resident tendon cells, we developed an in vivo model of whole-body irradiation followed by injection of either tendon stem/progenitor cells (TSCs) expressing green fluorescent protein (GFP-TSCs) or mature tenocytes expressing GFP (GFP-TNCs) into the patellar tendons of wild type C57 mice. Injected mice were subjected to short term (3 weeks) treadmill running, specifically moderate treadmill running (MTR) and intensive treadmill running (ITR). In MTR mice, both GFP-TSC and GFP-TNC injected tendons maintained normal cell morphology with elevated expression of tendon related markers collagen I and tenomodulin. In ITR mice injected with GFP-TNCs, cells also maintained an elongated shape similar to the shape found in normal/untreated control mice, as well as elevated expression of tendon related markers. However, ITR mice injected with GFP-TSCs showed abnormal changes, such as cell morphology transitioning to a round shape, elevated chondrogenic differentiation, and increased gene expression of non-tenocyte related genes LPL, Runx-2, and SOX-9. Increased gene expression data was supported by immunostaining showing elevated expression of SOX-9, Runx-2, and PPARγ. This study provides evidence that while MTR maintains tendon homeostasis by promoting the differentiation of TSCs into TNCs, ITR causes the onset of tendinopathy development by inducing non-tenocyte differentiation of TSCs, which may eventually lead to the formation of non-tendinous tissues in tendon tissue after long term mechanical overloading conditions on the tendon.

Wellness Survey Responses and Smartphone App Response Efficiency: Associations With Remote History of Sport-Related Concussion.

Recent research findings have strongly suggested that sport-related concussion (SRC) increases risk for subsequent injury of any type, as well as a potential for long-term adverse effects on neurological and psychological well-being. The primary purpose of this study was to explore the reliability and discriminatory power of clinical testing procedures for detecting persisting effects of SRC. We used a cross-sectional study design to assess both self-reported symptoms commonly associated with post-concussion syndrome, and the effects of mental or physical activity on metrics derived from a smartphone app designed to test perceptual-motor responses. Among 30 physically active college students, 15 participants reported a SRC occurrence prior to testing (M time-since-injury = 4.0 years, SD = 3.1, range = 5 months to 11 years). We found good test-retest reliability for key metrics derived from the smartphone app (ICC ≥ .70); and the internal consistency for the Overall Wellness Index (OWI) for 10 categories of 82 post-concussion symptoms was ideal (Cronbach's α ≥ .80). Moderate intensity treadmill running demonstrated the strongest differential effect on perceptual-motor responses between participants with a history of SRC (HxSRC) and those with no such history (No SRC), which was best represented by the speed-accuracy trade-off quantified by the inverse efficiency index (IEI: group X trial interaction p = .055). Self-reported OWI symptoms ≥4 and post-physical activity IEI ≥ 568 ms provided the strongest discrimination between HxSRC and NoSRC participants (≥1 versus 0: OR = 9.75). Our findings suggest that persisting effects from a remote SRC occurrence can be detected by easily administered screening procedures that have the potential to identify individual athletes who might derive benefit from interventions to restore their optimal function and well-being.

The Role Of Camk2δ-MEF2 Signaling Pathway In Aerobic Exercise-induced Improvement Of Cardiac Function In Hypertension

Objective: The purpose of this study was to investigate the effects of aerobic exercise on the Calcium/calmodulin-dependent protein kinase IIδ(CaMKIIδ)-Myocyte enhancer factor-2(MEF2) signaling pathway in SHR myocardial cells, and the role of the A-kinase anchoring protein 150(AKAP150). METHODS: 12-week-old male SHR and WKY rats were randomly assigned to sedentary groups (WKY-SED, SHR-SED) and exercise training groups (WKY-EX, SHR-EX). Exercise groups were performed a 12-week moderate intensity treadmill running. After 12 weeks, the myocardial cells were enzymatically isolated. The experimental methods include HE staining, the Langendorff technique of isolated heart perfusion, immunohistochemistry, immune cell fluorescence, Western blot. RESULTS: 1) After 12 weeks of exercise, SBP in both WKY-EX and SHR-EX were significantly lower than that of their sedentary counterparts. 2) Compared with the WKY-SED group, the SHR-SED group +dp/dtmax, -dp/dtmax significantly decreased, and the SHR-EX group was significantly higher than the SHR-SED group, +dp/dtmax significantly increased, -dp/dtmax decreased (P<0.01), LVSP increased (P<0.01). 3) The fluorescence intensity of CaM and AKAP150 in the SHR-SED group was higher than WKY-SED group (P<0.01), and the fluorescence intensity of the SHR-EX group AKAP150 was higher than SHR-SED group (P<0.01), and the expression of CaM was lower than the SHR-SED group (P<0.01). 4) The protein expression of p-CaMKIIδ, CaMKIIδ and AKAP150 in the SHR-SED group was higher than that in the WKY-SED group (P<0.01). The expression of p-CaMKIIδ/CaMKIIδ, p-HDAC4/HDAC4 and MEF2 of SHR-EX group are lower than the SHR-SED group (P<0.01). The expression of AKAP150 of SHR-EX was higher than SHR-SED group (P<0.01). CONCLUSION: Aerobic exercise reduced the activity of the CaMKIIδ-MEF2 signaling pathway and increased the expression of AKAP150 in the SHR myocardial, which is one of the molecular mechanisms to improve the function of the heart. Key words: cardiac function; CaMKIIδ-MEF2 signaling pathway; aerobic exercise; AKAP150

Exercise Preconditioning-induced Attenuation Of Acute Colitis Is Associated With Gut Microbiota Symbiosis In Wild Type Mice

PURPOSE: To investigate the therapeutic effect of exercise preconditioning against acute colitis induced by high-fat diet (HF) plus mild dextran sulfate sodium (DSS) treatment in wild type mice. METHODS: C57BL/6 male mice aged at 6 weeks were assigned to standard chow (SC, n=10) or HF (n=10) or HF plus DSS (HF+DSS, n=10) or exercise preconditioning (EX) with HF+DSS (EX+HF+DSS, n=10), and the mice were subjected to 15 weeks of dietary treatments, with 12 weeks of a moderate treadmill running (50 minutes per session and 5 days per week) and 2 cycles of 5-day DSS (2% w/v) administration included. Measured parameters included clinical symptoms of acute colitis, pro- and anti-inflammatory and chemotactic cytokines, gut barrier proteins, and immunity cells. Gut microbiota was explored by 16S ribosomal RNA amplification sequencing in fecal samples. RESULTS: Chronic exposure to HF resulted in colitis symptoms (significant weight gain, enlargement of the spleen, and shortening of colon length) and histological changes in the colon, decreased gut barrier proteins (zonula occludens-1 and heat shock protein 70), infiltration of immunity cells (neutrophils and monocytes in the colon and blood), increased expression of toll-like receptor 4 in the colon, and increased pro-inflammatory and chemotactic cytokines (interlukin-6, growth-regulated oncogene-α, and monocyte chemoattractant protein-1) and decreased anti-inflammatory cytokine (adiponectin) in the colon and blood, and those pathologic markers of acute colitis were exacerbated by DSS treatment. Exercise preconditioning alleviated the severity of HF+DSS-induced acute colitis and caused symbiotic modifications in gut microbiota, as shown by a lesser abundance of Bacteroides vulgatus (p=0.050) and a greater abundance of Akkermansia muciniphila (p=0.050). CONCLUSIONS: The current findings suggest that exercise preconditioning alleviates the severity of HF+DSS-induced colitis in conjunction with gut microbiota symbiosis in wild-type mice, implying a preventive/therapeutic potential of promotion of physical fitness via regular exercise against this experimentally-induced acute colitis. This study was supported by the National Research Foundation Grant funded by the Korean Government (NRF-2018R1D1A1B07048153 and 2019R1I1A1A01052817).

Exercise intensity-dependent immunomodulatory effects on encephalomyelitis.

BackgroundExercise training (ET) has beneficial effects on multiple sclerosis and its animal model experimental autoimmune encephalomyelitis (EAE). However, the intensity‐dependent effects of ET on the systemic immune system in EAE remain undefined.Objective(1) To compare the systemic immune modulatory effects of moderate versus high‐intensity ET protocols in protecting against development of EAE; (2) To investigate whether ET affects autoimmunity selectively, or causes general immunosuppression.MethodsHealthy mice performed moderate or high‐intensity treadmill running programs. Proteolipid protein (PLP)‐induced transfer EAE was utilized to examine ET effects specifically on the systemic immune system. Lymph node (LN)‐T cells from trained versus sedentary donor mice were transferred to naïve recipients and EAE severity was assessed, by clinical assessment and histopathological analysis. LN‐T cells derived from donor trained versus sedentary PLP‐immunized mice were analyzed in vitro for proliferation assays by flow cytometry analysis and cytokine and chemokine receptor gene expression using real‐time PCR. T cell‐dependent immune responses of trained versus sedentary mice to the nonautoantigen ovalbumin and susceptibility to Escherichia coli‐induced acute peritonitis were examined.ResultsHigh‐intensity training in healthy donor mice induced significantly greater inhibition than moderate‐intensity training on proliferation and generation of encephalitogenic T cells in response to PLP‐immunization, and on EAE severity upon their transfer into recipient mice. High‐intensity training also inhibited LN‐T cell proliferation in response to ovalbumin immunization. E. coli bacterial counts and dissemination were not affected by training.InterpretationHigh‐intensity training induces superior effects in preventing autoimmunity in EAE, but does not alter immune responses to E. coli infection.

Influence of MLC901 Alone and with Moderate Exercise on Pain Response Concurrent Due to Stress of Male Mice.

Background: Physical exercise is known to have a positive effect on pain responses induced by stress, while chronic stress causes a negative effect on cognitive abilities. Depending on the type, duration, and intensity of the stressor, it can induce analgesia or hyperalgesia. Furthermore, the beneficial effects of traditional Chinese medicine MLC901 on stress processes have been reported. Here, the effects of MLC901 and moderate physical activity on pain response in restraint-stressed mice was investigated. Materials and Methods: Male NMRI mice were used in this study and were restrained in plexiglass mesh restrainers for induction of chronic restraint stress. Treadmill exercise was carried out for moderated exercise, 5 days/week for 4 weeks. MLC901 was intraperitoneally administered in the experimental groups. The pain response of the adult NMRI mice was detected via the hot-plate test. Results: It was showed that intraperitoneal administration of MLC901 dose (0.4 but not 0.1 and 0.2 mg/kg; once/2 days; for 25 days) resulted in the decreased percentage of time in the hot plate, indicating hyperalgesia. Moreover, restraint stress for 3 but not 6 and 9 hours/day elicit hyperalgesia in mice. The data showed that subthreshold dose of MLC901 (0.1 mg/kg) reduced hyperalgesia in 3-day stressed mice. Moderate treadmill running (10 meters/min for 30 min/day, 5 days/ week) potentiated the effect of 6 and 9 days on pain (induced hyperalgesia) that was blocked by MLC901 (0.1 mg/kg). Conclusion: Our findings indicated that subthreshold dose of MLC901 alone or when it associated with moderate exercise decreased hyperalgesia induced by stress, indicating the protective effect of MLC901.

Influence of MLC901 Alone and with Moderate Exercise on Pain Response Concurrent Due to Stress of Male Mice

Background: Physical exercise is known to have a positive effect on pain responses induced by stress, while chronic stress causes a negative effect on cognitive abilities. Depending on the type, duration, and intensity of the stressor, it can induce analgesia or hyperalgesia. Furthermore, the beneficial effects of traditional Chinese medicine MLC901 on stress processes have been reported. Here, the effects of MLC901 and moderate physical activity on pain response in restraint-stressed mice was investigated. Materials and Methods: Male NMRI mice were used in this study and were restrained in plexiglass mesh restrainers for induction of chronic restraint stress. Treadmill exercise was carried out for moderated exercise, 5 days/week for 4 weeks. MLC901 was intraperitoneally administered in the experimental groups. The pain response of the adult NMRI mice was detected via the hot-plate test. Results: It was showed that intraperitoneal administration of MLC901 dose (0.4 but not 0.1 and 0.2 mg/kg; once/2 days; for 25 days) resulted in the decreased percentage of time in the hot plate, indicating hyperalgesia. Moreover, restraint stress for 3 but not 6 and 9 hours/day elicit hyperalgesia in mice. The data showed that subthreshold dose of MLC901 (0.1 mg/kg) reduced hyperalgesia in 3-day stressed mice. Moderate treadmill running (10 meters/min for 30 min/day, 5 days/week) potentiated the effect of 6 and 9 days on pain (induced hyperalgesia) that was blocked by MLC901 (0.1 mg/kg). Conclusion: Our findings indicated that subthreshold dose of MLC901 alone or when it associated with moderate exercise decreased hyperalgesia induced by stress, indicating the protective effect of MLC901. [GMJ.2019;8:e1253]

Kinetics of Reactive Oxygen Species and Total Antioxidant Capacity during Moderate Treadmill Running after 8 Weeks of Endurance Training

The purpose of this study is to investigate the effect of aerobic exercise intensity on the kinetics of reactive oxygen species and total antioxidant capacity during the moderate intensity of treadmill running. Twelve healthy collegiate male students participated and were randomly divided into two groups. Each group of subjects trained at 80% and 50% HRmax respectively for 30 min per session, 3 times per week for 8 weeks. After 48 hours of the training session, treadmill running task was imposed on each group at 70% of VO2max for 90 minutes. Metabolic data were monitored using a gas analysis system. Blood samples were taken from the finger before exercise and after 30 minutes, 60 minutes, and 90 minutes of exercise for measuring the blood lactate, derivatives of Reactive Oxygen Metabolites (d‐ROM), and biological antioxidant potential (BAP). All data were analyzed by two‐way ANOVA of SPSS 18.0. The differences between pre and post training were significant in d‐ROM and BAP (p&lt;.05). The changes of d‐ROM were significantly increased by aerobic training, and there were significant differences among exercise durations (p&lt;.05). The changes of BAP were not significantly different between training intensity groups, and there were significant differences among exercise durations (p&lt;.05). As shown above, the occurrence of d‐ROM and BAP were altered by training intensity and exercise duration. In other words, the occurrence of reactive oxygen by high intensive training was abundant and there were significant changes in 30 minutes of exercise based on exercise duration. On the other hand, there were significant changes in total antioxidant capacity in 60 minutes of exercise based on exercise duration. In conclusion, low‐intensity training and within 60 minutes of exercise might be suitable in the point of defending the cellular damage caused by exercise.This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.

Genistein and Exercise Reverse Hyperglycemia and Hyperinsulinemia Induced by High Fat/High Sucrose Diet via Influences on Hepatic Gluconeogenesis in Mice

Consumption of a high fat/high sugar (HFHS) diet has not only been identified as risk factor for obesity, but it also predisposes towards type 2 diabetes mellitus (T2DM), by resulting in hyperglycemia and impaired insulin signaling. A targeted metabolic pathway for treatment of T2DM is hepatic gluconeogenesis. Gluconeogenesis is responsible for maintaining blood glucose levels during times of exercise, fasting, and stress. Insulin is responsible for suppressing gluconeogenic activity. However, as the liver becomes insulin resistant, hepatic gluconeogenesis becomes over activated exacerbating T2DM pathology. We aimed to assess whether genistein and/or exercise regulate hepatic gluconeogenesis. C57BL/6J male and female mice aged 5–6 weeks were randomly assigned to one of the following groups (n=8–10/group): lean control (Ln), high fat/high sucrose diet (HFHS), HFHS+Gen (genistein), HFHS+Ex (exercise), and HFHS+Gen+Ex. The HFD consisted of 60% saturated fat, 20% carbohydrate, 20% protein and included sucrose and fructose (42 g/L) in the drinking water. Exercise consisted of daily moderate treadmill running for a total duration of 150 minutes/week for 12 weeks. Genistein dose was 600 mg genistein/kg HF diet. C57BL/6J mice fed HFHS exhibited phenotypes seen in T2DM pathology; including rapid weight gain, hyperinsulinemia and hyperglycemia. Our results demonstrate that serum glucose and insulin levels in males were rescued by Gen+Ex treatment combined compared to controls. Corticosterone levels were significantly elevated in females fed HFHS diet (2755±375 pg/mL, n=6) compared to Ln controls (1449 ± 275 pg/mL, n=7), with significant recovery by Gen+Ex (964±234 pg/mL, n=7). Measures of total protein expression of renal 11βHSD2 (responsible for the conversion of active cortisol to inactive cortisone) however, showed no significant difference indicating that 11βHSD2 may not be playing a role in corticosterone deactivation. We are currently determining total protein expression levels of hepatic 11βHSD1 (responsible for the conversion of corticosterone to its active form). Current studies are also evaluating the roles of two rate limiting enzymes; phosphoenolpyruvate carboxykinase (PEPCK) and glucose‐6‐phosphotase (G6Pase). These studies provide evidence of the protective role that genistein and exercise may provide to ameliorate diabetic‐obesity induced by HFHS diet.Support or Funding InformationSupport: Layla Al‐Nakkash, Tom Broderick were supported by Midwestern‐Arizona Alzheimer's Consortium and Midwestern University Intramural Funds. Chaheyla St Aubin and Amy Fisher were supported by the Department of Biomedical Sciences.This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.

CITED2 mediates the cross-talk between mechanical loading and IL-4 to promote chondroprotection.

Osteoarthritis (OA) pathogenesis is mediated largely through the actions of proteolytic enzymes such as matrix metalloproteinase (MMP) 13. The transcriptional regulator CITED2, which suppresses the expression of MMP13 in chondrocytes, is induced by interleukin (IL)-4 in T cells and macrophages, and by moderate mechanical loading in chondrocytes. We tested the hypothesis that CITED2 mediates cross-talk between IL-4 signaling and mechanical loading-induced pathways that result in chondroprotection, at least in part, by downregulating MMP13. IL-4 induced CITED2 gene expression in human chondrocytes in a dose- and time-dependent manner through JAK/STAT signaling. Mechanical loading combined with IL-4 resulted in additive effects on inducing CITED2 expression and downregulating of MMP13 in human chondrocytes in vitro. In vivo, IL-4 gene knockout (KO) mice exhibited reduced basal levels of CITED2 expression in chondrocytes. While moderate treadmill running induced CITED2 expression and reduced MMP13 expression in wild-type mice, these effects were blunted (for CITED2) or abolished (for MMP13) in chondrocytes of IL-4 gene KO mice. Moreover, intra-articular injections of mouse recombinant IL-4 combined with regular cage activity mitigated post-traumatic OA to a greater degree compared to immobilized mice treated with IL-4 alone. These data suggest that using moderate loading to enhance IL-4 may be a potential therapeutic strategy for chondroprotection in OA.

CITED2 mediates the mechanical loading-induced suppression of adipokines in the infrapatellar fat pad.

Adipokines secreted from the infrapatellar fat pad (IPFP), such as adipsin and adiponectin, have been implicated in osteoarthritis pathogenesis. CITED2, a mechanosensitive transcriptional regulator with chondroprotective activity, may modulate their expression. Cited2 haploinsufficient mice (Cited2+/- ) on a high-fat diet (HFD) exhibited increased body weight and increased IPFP area compared to wild-type (WT) mice on an HFD. While an exercise regimen of moderate treadmill running induced the expression of CITED2, as well as PGC-1α, and reduced the expression of adipsin and adiponectin in the IPFP of WT mice on an HFD, Cited2 haploinsufficiency abolished the loading-induced expression of PGC-1α and loading-induced suppression of adipsin and adiponectin. Furthermore, knocking down or knocking out CITED2 in adipose stem cells (ASCs)/preadipocytes derived from the IPFP in vitro led to the increased expression of adipsin and adiponectin and reduced PGC-1α, and abolished the loading-induced suppression of adipsin and adiponectin and loading-induced expression of PGC-1α. Overexpression of PGC-1α in these ASC/preadipocytes reversed the effects caused by CITED2 deficiency. The current data suggest that CITED2 is a critical regulator in physiologic loading-induced chondroprotection in the context of an HFD and PGC-1α is required for the inhibitory effects of CITED2 on the expression of adipokines such as adipsin and adiponectin in the IPFP.

Influence of Moderate and Severe Exercise on Memory Formation and Anxiety-like Behaviors in Male Wistar Rat

Introduction: Recent researchers have showed that regular exercise induces positive effects on cognitive functions. Exercise intensity and timing of cognitive assessment may have an interactive effect on cognitive changes. Previous researches suggest that moderate intensity treadmill running has the most consistent benefit to cognitive function. In contrast, studies find positive, negative, or null effects to cognitive function after high intensity treadmill running. The primary objective of the present study was to compare the cognitive effects of intensity treadmill running protocol 1 (Low intensity), protocol 2 (Moderate intensity) and protocol 1 plus 2 (High intensity). Materials and Methods: Male Wistar rats were divided into four groups (n=7 in each group) including: sedentary (Non-exercise), protocol 1, protocol 2, and combination of protocol 1 and 2. Step-through passive avoidance and elevated-plus maze apparatus have been used to test parameters of passive avoidance learning and anxiety-like behaviors. Results: These findings showed that combination of both protocols (Protocol 1 with protocol 2) decreased step-through latency in the passive avoidance apparatus indicating memory impairment [P 0.05] and locomotor activity %OAT [P<0.05] compared to control group but not others. Conclusion: High intensity exercise not only induced beneficial effect but also impaired memory formation.

Fat and Lean Mass Predict Bone Mass During Energy Restriction in Sedentary and Exercising Rodents.

Energy restriction (ER) causes bone loss, but the impact of exercise during ER is less understood. In this study, we examined the impact of metabolic hormones and body composition on both total body bone mineral content (BMC) and local (proximal tibia) volumetric bone mineral density (vBMD) during short- (4 weeks) and long-term (12 weeks) ER with and without exercise in adult female rats. Our first goal was to balance energy between sedentary and exercising groups to determine the impact of exercise during ER. Second, we aimed to determine the strongest predictors of bone outcomes during ER with energy-matched exercising groups.Methods: Female Sprague–Dawley rats were divided into three sedentary groups (ad libitum, –20% ER, and –40% ER) and three exercising groups (ad libitum, –10% ER, and –30% ER). Approximately a 10% increase in energy expenditure was achieved via moderate treadmill running (∼60–100 min 4 days/week) in EX groups. n per group = 25–35. Data were analyzed as a 2 × 3 ANOVA with multiple linear regression to predict bone mass outcomes.Results: At 4 weeks, fat and lean mass and serum insulin-like growth factor-I (IGF-I) predicted total body BMC (R2 = 0.538). Fat mass decreased with ER at all levels, while lean mass was not altered. Serum IGF-I declined in the most severe ER groups (–40 and –30%). At 12 weeks, only fat and lean mass predicted total body BMC (R2 = 0.718). Fat mass declined with ER level regardless of exercise status and lean mass increased due to exercise (+5.6–6.7% vs. energy-matched sedentary groups). At the same time point, BMC declined with ER, but increased with exercise (+7.0–12.5% vs. energy-matched sedentary groups). None of our models predicted vBMD at the proximal tibia at either time point.Conclusion: Both fat and lean mass statistically predicted total body BMC during both short- and long-term ER. Fat and lean mass decreased with ER, while lean mass increased with EX at each energy level. Measures that predicted total body skeletal changes did not predict site-specific changes. These data highlight the importance of maintaining lean mass through exercise during periods of ER.