Exercise training enhances learning and memory abilities and hippocampal neurogenesis

Peripheral arterial disease (PAD) affects more than 200 million people worldwide and is caused by occlusions resulting from atherosclerosis in arteries supplying blood to the lower limbs. Treatments for limb ischaemia in PAD is an unmet medical need. Novel treatments are sought to improve limb blood supply and function in PAD patients unlikely to benefit from existing treatments such as surgical revascularisation, structured exercise programs and cilostozol. Currently, the main pre-clinical experimental model employed in PAD research is based on induction of acute hind limb ischemia (HLI) which results in rapid natural recovery of blood supply to ischaemic tissues. There are concerns regarding the ability to translate findings from this mouse model to PAD patients and a clinically relevant mouse model of HLI is lacking. Evidence suggests metformin may be a potential treatment for PAD and angiotensin converting enzyme 2 (ACE2) may play a role in limb ischaemia. This thesis aimed to develop a clinically relevant mouse model of PAD that involved a two-stage induction of HLI and examine the effect of exercise training, metformin and ACE2 deficiency in the two-stage model of HLI. Two-stage HLI was induced in male Apolipoprotein E (ApoE-/-) deficient mice by slow onset of severe ischemia over 14 days. This 2-stage HLI model was compared to the acute HLI model and sham controls. Limb blood supply was assessed by Laser Doppler Perfusion Imaging (LDI). Ambulatory ability was assessed using a treadmill test and established scoring scales. Running wheel exercise training was examined in the two-stage mouse model and limb function was assessed by a treadmill exercise test and blood supply was assessed by LDI. Next, the effect of metformin on limb ischaemia was assessed by LDI in the two-stage HLI mouse model. Lastly, the effect of ACE2 deficiency (ACE2-/y) on limb ischaemia was examined in the two-stage mouse model of HLI. HLI was significantly more severe in mice receiving the two-stage compared to the acute HLI induction procedure as assessed by LDI (p=0.013), and reflected a higher ischemic score (p=0.003) and lower average distance travelled on a treadmill exercise test (p=0.045). Mice with two-stage HLI receiving exercise training showed significantly greater improvement in their ambulatory ability on a treadmill test than the sedentary control group (p=0.003). However, limb blood supply was comparable between mice receiving exercise compared to controls (p=0.700). Mice with two-stage HLI administered metformin had greater blood supply than mice with two-stage HLI receiving vehicle control (p<0.001). The two-stage HLI mice receiving metformin had increased adenosine monophosphate kinase alpha (AMPKα) activity (p=0.041), endothelial nitric oxide synthase (e-NOS) activity (p=0.031), nitric oxide (NO) bioavailability (p=0.024), peroxisome proliferator activated receptor 1 alpha (PGC1-α) expression (p=0.026) and decreased thioredoxin interacting protein (TXNIP) expression (p=0.038) compared to mice with two-stage HLI receiving vehicle. ACE2-/y in mice with two-stage HLI had comparable limb ischaemia to ACE2 unmodified control mice with two-stage HLI (p=0.263). In conclusion, this thesis showed that the novel two-stage mouse model of HLI had severe ongoing HLI and functional impairment. Exercise training augmented treadmill walking capacity in the new mouse model which was independent of changes to limb blood supply and mirroring patient response to exercise therapy. Metformin administration improved limb blood supply in the two-stage mouse model of ongoing HLI. Improvement in blood supply was associated with the upregulation of AMPKα activity, increased activation of e-NOS in the ischaemic muscles, increased bioavailability of circulating NO, increased expression of PGC1α and reduced expression of TXNIP. This suggests metformin may have potential to be used as a treatment to improve limb blood supply in PAD patients. ACE2-/ did not worsen limb blood supply after two-stage HLI induction suggesting ACE2 may not play an important role in limb ischemia. The results do not encourage the pursuit of ACE2 for pharmacological management of PAD in clinical trials and ACE2 is unlikely to be an important target for improving limb blood supply or function in patients with PAD.

Investigate the relationship between sedentary behavior and physical function in adults with knee osteoarthritis (OA), controlling for moderate-vigorous physical activity (MVPA) levels. Sedentary behavior was objectively measured by accelerometer on 1,168 participants ages 49-83 years in the Osteoarthritis Initiative with radiographic knee OA at the 48-month clinic visit. Physical function was assessed using 20-meter walk and chair stand testing. Sedentary behavior was identified by accelerometer activity counts/minute <100. The cross-sectional association between sedentary quartiles and physical function was examined by multiple linear regression, adjusting for demographic factors (age, sex, race/ethnicity, education level), health factors (comorbidity, body mass index, knee pain, knee OA severity, presence of knee symptoms), and average daily MVPA minutes. Adults with knee OA spent two-thirds of their daily time in sedentary behavior. The average gait speed among the most sedentary quartile was 3.88 feet/second, which was significantly slower than the speed of the less sedentary groups (4.23, 4.33, and 4.33 feet/second, respectively). The average chair stand rate among the most sedentary group was significantly lower (25.9 stands/minute) than the rates of the less sedentary behavior groups (28.9, 29.1, and 31.1 stands/minute, respectively). These trends remained significant in multivariable analyses adjusted for demographic factors, health factors, and average daily MVPA minutes. Being less sedentary was related to better physical function in adults with knee OA independent of MVPA time. These findings support guidelines to encourage adults with knee OA to decrease time spent in sedentary behavior in order to improve physical function.

The purpose of this study was to determine whether chronic voluntary wheel running (RUN) prevents impairments in insulin‐stimulated vasodilation (ISD) associated with obesity and type 2 diabetes (T2D) independent of the effects of RUN on adiposity. We randomized Otsuka Long Evans Tokushima Fatty (OLETF) rats, a model of hyperphagia‐induced obesity and T2D, to: 1) RUN, 2) caloric restriction (CR), or 3) sedentary (SED) groups (n=6‐8/group) at 4 wks of age. At 40 wks, body weights of RUN and CR were similar, and both were lower than SED (520±22, 503±12, 648±31 g, respectively; P&lt;0.05). Fasting blood glucose and glucose area under the curve (AUC) following an intraperitoneal glucose tolerance test were higher in SED than CR or RUN (54651±2309, 45792±4267, 37891±4647 mg/dL*120; P&lt;0.05) and greater in CR than RUN (P&lt;0.05). ISD in second‐order arterioles isolated from gastrocnemius muscle (recruited in RUN) was greater in RUN than CR or SED at insulin doses = 10 μIU/mL (66±17, 17±9, 11±7 % change from baseline; P&lt;0.05) but did not differ between SED and CR. These effects were ablated in the presence of an endothelial nitric oxide (NO) synthase inhibitor, suggesting enhanced ISD in response to chronic exercise is NO‐mediated and independent of attenuating excess adiposity. Funding: MU Department of Internal Medicine, MU Institute for Clinical &amp; Translational Sciences, NIH HL36088 (MHL).

Effect of aerobic exercise on BDNF/proBDNF expression in the ischemic hippocampus and depression recovery of rats after stroke

Abnormal neural precursor cell regulation in the early postnatal Fragile X mouse hippocampus

ObjectiveTo investigate the response of the infrapatellar fat pad (IFP) to running at different intensities and further explore the underlying mechanisms of these responses under different running-induced loadings.MethodsAnimals were randomly assigned into the sedentary (SED), low-intensity running (LIR), medium-intensity running (MIR), and high-intensity running (HIR) groups. The rats in the LIR, MIR, and HIR groups were subjected to an 8-week treadmill running protocol. In each group, the IFP was examined at the baseline and at the 8th week to perform histomorphology, immunohistochemistry, and mRNA expression analyses.ResultsCompared with LIR and MIR, HIR for 8 weeks led to a substantial increase in the surface cellularity (1.67 ± 1.15), fibrosis (1.29 ± 0.36), and vascularity (33.31 ± 8.43) of the IFP but did not increase IFP inflammation or M1 macrophage polarization. Low-to-medium-intensity running resulted in unchanged or decreased fibrosis, vascularity, and surface cellularity in the IFP compared to those of the SED group. Furthermore, serum leptin and visfatin levels were significantly lower in the LIR and MIR groups than in the SED group or the HIR group (P < 0.05).ConclusionThe effect of running on IFP remodeling was intensity dependent. In contrast to LIR and MIR, HIR increased the fibrosis and vascularity of the IFP. HIR-induced IFP fibrosis was probably due to mechanical stress, rather than pathological proinflammatory M1/M2 polarization.

To evaluate group differences in coronary risk which could be attributed to the modality of habitual exercise, selected physiologic and lipid indices of coronary artery disease (CAD) were measured in 57 endurance trained (ET), strength trained (ST), or sedentary (SED) men (19 per group, aged 21 to 44 yr). Initial data reduction accomplished with principle component analysis identified three factors with eigenvalues greater than one. Orthogonal rotation of the preliminary solution demonstrated that low density lipoprotein cholesterol (LDL-C), percent body fat (%BF) and VO2max, and high density lipoprotein cholesterol (HDL-C) could be used to represent Factors 1, 2, and 3, respectively. The subsequent MANOVA using these variables proved significant. Post hoc analysis via simultaneous confidence intervals indicated that LDL-C group differences were not significant. Values for %BF and HCL-C in the ST group (14.0% and 1.17 mmol.l-1, respectively) were between but did not differ significantly from respective values in the ET (11.8% and 1.34 mmol.l-1) and SED (18.7% and 1.13 mmol.l-1) groups. However, %BF and HDL-C differences between the ET and SED groups were significant. The VO2max of the ET subjects (63.2 ml.kg-1.min-1) was significantly higher than that of either the ST or SED subjects (49.5 and 46.7 ml.kg-1.min-1, respectively). These results suggest that ET is the most effective modality of exercise for CAD risk reduction while benefits derived from ST are minimal.

Objective To investigate the effects of exercise on learning and memory after cerebral ischemia. Methods Ninety Sprague-Dawley rats were randomly divided into a sham-operated group, a model group and a treadmill training group (n=30 for each), which were further subdivided into groups to receive 7 days, 14 days or 28 days of training with 10 rats in each. The training was treadmill running at 10 m/min for 30 min a day. Cerebral ischemia was induced in the model and training groups using permanent, bilateral common carotid artery occlusion. The training began three days after the operation. Morris water maze tests were used to measure the rats′ learning and memory ability, and Nissl staining was employed to detect the survival rates of pyramidal neurons in the CA1 area of the hippocampus. Results The average escape latency in the treadmill trained group had shortened significantly by day 7, then further by days 14 and 28. It was significantly shorter than the model group′s average at each time point. The average platform crossing time increased significantly compared with the model group′s average. Few dead neurons were observed in the sham-operated group. On days 14 and 28 the average survival rate of pyramidal neurons in the model group was significantly lower than in the treadmill training group or the sham-operated group, though there was no significant difference on day 7. Conclusion Treadmill training can improve learning and memory after cerebral ischemia, at least in rats. Better effects can be observed after longer training. Key words: Cerebral ischemia; Treadmill training; Learning and memory; Exercise

Background: Activities of daily living consists of isometric &amp; isotonic contraction. Isometric contraction is a static contraction that exerts pressure overload on the heart. Studies have been carried out demonstrating hemodynamic effects of isotonic exercises however limited studies are available on myocardial load with isometric exercises. Aims and Objectives: To study the myocardial load at 30% and 50% of maximal voluntary isometric contraction (MVIC) in individuals with active and sedentary lifestyle. Study design and setting: Observational cross-sectional study was carried out in a tertiary care hospital. Materials and Methods: 140 healthy subjects (70 each in active &amp; sedentary group) were recruited for the study. Baseline demographics of both groups were comparable. Hemodynamic parameters were taken at rest. Subject performed 30% and 50% MVIC and hemodynamic parameters were recorded during and post contraction. Statistical Analysis: Paired t test was used to compare the myocardial load between 30% and 50% MVIC in both groups. Repeated measures ANOVA was used to compare the myocardial load between active &amp; sedentary groups at 30% and 50% MVIC. Result: There was a statistically significant difference in heart rate, systolic blood pressure &amp;rate pressure product between 30% and 50% in active as well as sedentary groups. There was statistically no significant difference in heart rate, systolic blood pressure &amp; rate pressure product between active &amp; sedentary groups at 30% and 50% MVIC. Conclusion: The myocardial load during activities at submaximal intensities (&lt;50%) is within the physiological limits and can be performed safely in individuals with active and sedentary lifestyle.

Maximal rate of heart rate (HR) increase (rHRI) as a measure of HR acceleration during the transition from rest to exercise, or during an increase in workload, tracks exercise performance. rHRI assessed at relative rather than absolute workloads may track performance better, and a field test would increase applicability. This study therefore aimed to evaluate the sensitivity of rHRI assessed at individualised relative workloads during treadmill and overground running for tracking exercise performance. Treadmill running performance (5 km time trial; 5TTT) and rHRI were assessed in 11 male runners following 1 week of light training (LT), 2 weeks of heavy training (HT) and a 10-day taper (T). rHRI was the first derivative maximum of a sigmoidal curve fit to HR data collected during 5 min of treadmill running at 65% peak HR (rHRI65%), and subsequent transition to 85% peak HR (rHRI85%). Participants ran at the same speeds overground, paced by a foot-mounted accelerometer. Time to complete 5TTT likely increased following HT (ES = 0.14 ± 0.03), and almost certainly decreased following T (ES = − 0.30 ± 0.07). Treadmill and field rHRI65% likely increased after HT in comparison to LT (ES ≤ 0.48 ± 0.32), and was unchanged at T. Treadmill and field rHRI85% was unchanged at HT in comparison to LT, and likely decreased at T in comparison to LT (ES ≤ − 0.55 ± 0.50). 5TTT was not correlated with treadmill or field rHRI65% or rHRI85%. rHRI65% was highly correlated between treadmill and field tests across LT, HT and T (r ≥ 0.63), but correlations for rHRI85% were trivial to moderate (r ≤ 0.42). rHRI assessed at relative exercise intensities does not track performance. rHRI assessed during the transition from rest to running overground and on a treadmill at the same running speed were highly correlated, suggesting that rHRI can be validly assessed under field conditions at 65% of peak HR.

REARFOOT KINEMATIC DIFFERENCES BETWEEN LEVEL TREADMILL AND LEVEL GROUND RUNNING

Treadmill exercise is the most common form of exercise used in studies involving laboratory rodents. However, oxygen consumption (VO2) is not usually monitored since the measurement of this parameter is particularly difficult in small, exercising animals. The purpose of this study was to develop a regression equation for predicting submaximal VO2 in mice during treadmill running. Twenty female mice of three strains were tested, in an Oxyscan metabolic treadmill, on different days at running speeds of 10, 13, 15, 17, and 20 m/min at a 0% grade. Each mouse was placed in the treadmill chamber for a 10-min period before running commenced. Running speed was increased in 2-min intervals by 5 m/min until the assigned speed was reached. Each mouse then ran for 10 min to reach steady state, followed by another 20 min at the steady-state plateau. During this period a 30-s expired gas sample was collected every minute. Gas samples were analyzed for O2 and CO2, using an Oxyscan gas analyzer. Trials were conducted during the nocturnal phase of the animals' photoperiod, and running speeds were assigned randomly to minimize order effects. This approach provided highly reliable measures of oxygen consumption (r = 0.96). By using the running speeds (10-20 m/min) and the animal's body weight it was possible to predict the submaximal oxygen consumption (mL/min) during running with a high degree of accuracy (i.e., R2 = 0.85). In an independent group of animals (n = 14) we compared the predicted VO2 with the measured VO2. This yielded a good correlation coefficient (r = 0.79) and a low prediction error (+2.4 +/- 2.9%).(ABSTRACT TRUNCATED AT 250 WORDS)

Running economy (RE) is one of the important indicators for evaluating endurance. However, treadmill running (TR) test, seems not to be specific enough for team sport, considering their running characteristics with change of direction. PURPOSE: To investigate the RE of TR and 20m-shuttle running (SR). METHODS: 18 physically-active collegiate man (22.4 ± 2.4yrs, 177.4 ± 7.5cm, 69.3 ± 8.2kg, VO2max: 48.9 ± 6.2 ml/kg/min, training experience: 4.6 ± 1.6yrs) volunteered to participate in one increamental TR (8, 10, 12 and 14km/h) and one increamental SR (6, 8, 10 and 12km/h), with the duration of 5 min for each step, and the interval of 1 min between each 2 steps. The VO2max was also assessed in combination with the TR test. The portable gas metabolism system (K4b2, Cosmed, Italy) was used to measure the breathing gas during running. The RE for each speed was calculated as the averaged VO2 of the last 1 min during each step. RESULTS: At the same running speed (8, 10 and 12km/h), the RE of the SR are lower (oxygen consumption is higher ) than the TR (34 ± 3.6 vs. 32.5 ± 4.9 ml/kg/min, 47.9 ± 5 vs. 37.9 ± 5.9 ml/kg/min, 54.9 ± 6.2 vs. 42.0 ± 7 ml/kg/min), with the difference significant at the two higher speed (p<0.05). CONCLUSIONS: At the same running speed, the RE of SR is lower than that of TR. Assessment of RE with TR might overestimate the RE in running with change of direction. Running test with change of direction (e.g. SR) is recommended for examining the RE in team sport players.

BackgroundIt is unknown whether high-intensity interval exercise (HIIE) may potentiate or attenuate the cardiotoxic effect of chemotherapy agents such as doxorubicin (DOX) when performed shortly after treatment. The study aimed to investigate the effect of acute HIIE on cardiac function and structure performed either 1, 2 or 3 days after DOX injection in an animal model.MethodsFemale C57bl/6 mice (n = 28), 70 days old, received a bolus 20 mg/kg intravenous tail vein DOX injection. Three exercise groups performed 1 HIIE session (16 sets of 1 min at 85–90% of peak running speed) at 1 (n = 7), 2 (n = 7), and 3 days (n = 8) following the DOX injection. A sedentary (SED) group of mice (n = 6) did not exercise. Animals underwent echocardiography under light anesthesia (isoflurane 0.5-1%) before and 7 days after the DOX injection. Animals were sacrificed on day 9 and hearts were collected for morphometric and histological analysis.ResultsAnimals exercising on day 3 had the smallest pre-post reduction in left ventricular fractional shortening (LVFS) (MΔ= -1.7 ± 3.3; p = 0.406) and the SED group had the largest reduction (MΔ=-6.8 ± 7.5; p = 0.009). After reclassification of animals according to their exercise compliance (performing > 8/16 of high-intensity bouts), LVFS in compliant mice was unchanged over time (LVFS MΔ= -1.3 ± 5.6; p = 0.396) while non-compliant animals had a LVFS reduction similar to sedentary animals. There were no significant differences in myocardial histology between groups.ConclusionsIn this pilot murine study, one single HIIE session did not exacerbate acute doxorubicin-induced cardiotoxicity. The timing of the HIIE session following DOX injection and the level of compliance to exercise could influence the negative impact of DOX on cardiac function.

BackgroundTwo related lifestyle behaviors associated with sleep disturbance are sedentary behavior and physical exercise participation. We aimed to use a population-based study to disentangle the relationships between sedentary behavior, exercise, and sleep disturbance based on blood-cell-based inflammatory biomarkers.MethodsA total of 22,599 participants from the National Health and Nutrition Examination Survey (NHANES) were included in the analyses. Sleep disturbance was assessed according to the NHANES questionnaire. Exercise participation ansd sedentary behavior were evaluated by the global physical activity questionnaire. The inflammatory biomarkers in the examination were white blood cell (WBC) count, neutrophil count (NEU), neutrophil-to-lymphocyte ratio (NLR), and systemic immune inflammation index (SII). A complex multistage sampling design and weighted multivariable logistic regression were applied for further analysis. Mediation models were constructed to figure out the mediating role of inflammatory biomarkers.ResultsThe weighted prevalence of sleep disturbance was 24.17%. Sedentary behavior and exercise were associated with sleep disturbance after full adjustment [for sedentary behavior, OR (95% CI): 1.261 (1.154, 1.377); for exercise, OR (95% CI): 0.849 (0.757, 0.953)]. In severe sedentary behavior groups, the mitigation effect of exercise on sleep disturbance was observed [OR (95% CI): 0.687 (0.551, 0.857)]. For the mechanism, strong associations were detected between inflammatory biomarkers and sleep disturbance. Mediation analysis showed that WBC, NEU, NLR, and SII mediated the statistical association between sedentary behavior and sleep disturbance with proportions (%) of 2.09, 2.27, 1.76, and 0.82, respectively.ConclusionsOur data suggested that sedentary behavior was a risk factor for sleep disturbance. Blood-cell-based inflammatory biomarkers were an easily accessible and cost-effective strategy for identifying sleep disturbance and also significantly mediated the association between sedentary behavior and sleep disturbance. Exercise was proved to be effective in severe sedentary behavior groups to improve sleep disturbance symptoms, while the internal mechanism needed further exploration.