High-intensity exercise training using a rotarod instrument (RotaHIIT) significantly improves exercise capacity in mice.

Voluntary or forced exercise training in mice is used to assess functional capacity as well as potential disease-modifying effects of exercise over a range of cardiovascular disease phenotypes. Compared to voluntary wheel running, forced exercise training enables precise control of exercise workload and volume, and results in superior changes in cardiovascular performance. However, the use of a shock grid with treadmill-based training is associated with stress and risk of injury, and declining compliance with longer periods of training time for many mouse strains. With these limitations in mind, we designed a novel, high-intensity interval training modality (HIIT) for mice that is carried out on a rotarod. Abbreviated as RotaHIIT, this protocol establishes interval workload intensities that are not time or resource intensive, maintains excellent training compliance over time, and results in improved exercise capacity independent of sex when measured by treadmill graded exercise testing (GXT) and rotarod specific acceleration and endurance testing. This protocol may therefore be useful and easily implemented for a broad range of research investigations. As RotaHIIT training was not associated cardiac structural or functional changes, or changes in oxidative capacity in cardiac or skeletal muscle tissue, further studies will be needed to define the physiological adaptations and molecular transducers that are driving the training effect of this exercise modality.

Changes in the hippocampal level of tau but not beta-amyloid may mediate anxiety-like behavior improvement ensuing from exercise in diabetic female rats.

BACKGROUND: In the present study, we investigated the effect of high-intensity interval training (HIIT) on cognitive behaviors in female rats with a high-fat diet + streptozotocin (STZ)-induced type 2 diabetes. METHODS: Twenty-four female rats were divided into four groups randomly (n = 6): control (C), control + exercise (Co + EX), diabetes mellitus (type 2) (T2D), and diabetes mellitus + exercise (T2D + EX). Diabetes was induced by a two-month high-fat diet and a single dose of STZ (35 mg/kg) in the T2D and T2D + EX groups. The Co + EX and T2D + EX groups performed HIIT for eight weeks (five sessions per week, running on a treadmill at 80-100% of VMax, 4-10 intervals). Elevated plus maze (EPM) and open field test (OFT) were used for assessing anxiety-like behaviors, and passive avoidance test (PAT) and Morris water maze (MWM) were applied for evaluating learning and memory. The hippocampal levels of beta-amyloid (Aß) and Tau were also assessed using Western blot. RESULTS: An increase in fasting blood glucose (FBG), hippocampal level of Tau, and a decrease in the percentage of open arm time (%OAT) as an index of anxiety-like behavior were seen in the female diabetic rats which could be reversed by HIIT. In addition, T2D led to a significant decrease in rearing and grooming in the OFT. No significant difference among groups was seen for the latency time in the PAT and learning and memory in the MWM. CONCLUSIONS: HIIT could improve anxiety-like behavior at least in part through changes in hippocampal levels of Tau.

Combined cardiovascular effects of ovariectomy and high-intensity interval training in female spontaneously hypertensive rats.

Hypertensive postmenopausal women are more likely to develop adverse cardiac remodeling and respond less effectively to drug treatment than men. High-intensity interval exercise (HIIE) is a nonpharmacological strategy for the treatment of hypertension; however, the effectiveness in women remains uncertain. This study was designed to evaluate 1) the effects of HIIE training upon morphological and functional markers of cardiovascular health in female SHR and 2) to determine whether the hormonal shift induced by ovariectomy could influence cardiovascular responses to HIIE. Thirty-six SHR were randomly assigned to four groups: ovariectomized sedentary, ovariectomized trained, sham-operated sedentary, and sham-operated trained. The trained rats performed HIIE 5 days/wk for 8 wk. Blood pressure and echocardiographic measurements were performed before and after training in animals. Cardiac response to ß-adrenergic stimulation and the expression of calcium regulatory proteins and estrogen receptors in heart samples were assessed. Endothelium-dependent vasorelaxation in response to acetylcholine was evaluated in aortic rings as well as the expression of nitric oxide synthase isoforms (eNOS and P-eNOS) by Western blotting. In both groups of trained SHR, HIIE induced eccentric cardiac remodeling with greater inotropic and chronotropic effects, as well as an increase in SERCA and ß1AR expression. However, although the trained rats showed improved endothelial function and expression of eNOS and P-eNOS in the aorta, there was no demonstrated effect on blood pressure. In addition, the responses to HIIE training were not affected by ovariectomy. This work highlights the importance of assessing the cardiovascular efficacy and safety of different exercise modalities in women.NEW & NOTEWORTHY This study reports the effects of high-intensity interval exercise (HIIE) training on cardiac and endothelial function in female hypertensive rats. Despite a lack of effect on blood pressure (BP), HIIE training induces eccentric cardiac remodeling with greater functionals effects. Furthermore, training has beneficial effects on endothelial function. However, ovarian hormones do not seem to modulate cardiac and aortic adaptations to this training modality. All this underlines the need to consider training modalities on the cardiovascular system in women.

Voluntary wheel exercise improves glymphatic clearance and ameliorates colitis-associated cognitive impairment in aged mice by inhibiting TRPV4-induced astrocytic calcium activity.

BACKGROUND AND OBJECTIVES: Chronic colitis exacerbates neuroinflammation, contributing to cognitive impairment during aging, but the mechanism remains unclear. The polarity distribution of astrocytic aquaporin 4 (AQP4) is crucial for the glymphatic system, which is responsible for metabolite clearance in the brain. Physical exercise (PE) improves cognition in the aged. This study aims to investigate the protective mechanism of exercise in colitis-associated cognitive impairment. METHODS: To establish a chronic colitis model, 18-month-old C57BL/6 J female mice received periodic oral administration of 1% wt/vol dextran sodium sulfate (DSS) in drinking water. The mice in the exercise group received four weeks of voluntary wheel exercise. High-throughput sequencing was conducted to screen for differentially expressed genes. Two-photon imaging was performed to investigate the function of the astrocytic calcium activity and in vivo intervention with TRPV4 inhibitor HC-067047. Further, GSK1016790A (GSK1), a TRPV4 agonist, was daily intraperitoneally injected during the exercise period to study the involvement of TRPV4 in PE protection. Colitis pathology was confirmed by histopathology. The novel object recognition (NOR) test, Morris water maze test (MWM), and open field test were performed to measure colitis-induced cognition and anxiety-like behavior. In vivo two-photon imaging and ex vivo imaging of fluorescent CSF tracers to evaluate the function of the glymphatic system. Immunofluorescence staining was used to detect the Aß deposition, polarity distribution of astrocytic AQP4, and astrocytic phenotype. Serum and brain levels of the inflammatory cytokines were tested by Enzyme-linked immunosorbent assay (ELISA). The brain TUNEL assay was used to assess DNA damage. Expression of critical molecules was detected using Western blotting. RESULTS: Voluntary exercise alleviates cognitive impairment and anxiety-like behavior in aged mice with chronic colitis, providing neuroprotection against neuronal damage and apoptosis. Additionally, voluntary exercise promotes the brain clearance of Aß via increased glymphatic clearance. Mechanistically, exercise-induced beneficial effects may be attributed, in part, to the inhibition of TRPV4 expression and TRPV4-related calcium hyperactivity, subsequent promotion of AQP4 polarization, and modulation of astrocyte phenotype. CONCLUSION: The present study reveals a novel role of voluntary exercise in alleviating colitis-related cognitive impairment and anxiety disorder, which is mediated by the promotion of AQP4 polarization and glymphatic clearance of Aß via inhibition of TRPV4-induced astrocytic calcium hyperactivity.

Swimming Exercise Protocol and Care Methods for Pregnant Rats.

The developmental origins of health and disease concept highlights the impact of early environments on chronic non-communicable diseases like diabetes, cardiovascular disease, and cancer. Studies using animal models have investigated how maternal factors such as undernutrition, overnutrition, obesity, and exposure to chemicals or hypoxia affect fetal development and offspring health, leading to issues like low birth weight, high blood pressure, dyslipidemia, and insulin resistance. Given the increasing prevalence of overweight and obesity among reproductive-age women, effective interventions are critical. Maternal exercise during pregnancy has emerged as a key intervention, benefiting both mother and offspring and reducing the risk of disease. This study compares the differences of three exercise models on pregnant rats: voluntary wheel running, motorized treadmills, and swimming. Swimming is the most beneficial option due to its safe and controlled intensity levels. This protocol details the rat breeding methods, swimming training during pregnancy, and post-breeding nursing protocols. This model, suitable for various rat and mouse species, is useful for studying the benefits of maternal exercise on offspring health and intergenerational wellness.

Effects evaluation of different exercises on subclinical left ventricular dysfunction in obese rats by speckle-tracking echocardiography.

OBJECTIVE: To identify subclinical left ventricle dysfunction (LVD) in obese rats by speckle-tracking echocardiography, and to evaluate the effects of 12-week Moderate-Intensity Continuous Training (MICT) or High-Intensity Interval Training (HIIT) on LV geometry, histology and function in obese rats. METHODS: Eighteen male standard or obese Sprague-Dawley rats were randomly divided into the Control group, the MICT group, and the HIIT group. Exercise interventions were conducted for 12 weeks, with equal total load and increased intensity gradient. Using dual-energy X-ray, two-dimensional speckle-tracking echocardiography, pulse Doppler, and HE staining to evalucate body shape, LV morphology, structure, and myocardial mechanics function. RESULTS: (1) Both MICT and HIIT have good weight loss shaping effect. (2) The LV of obese rats underwent pathological remodeling, with decreased longitudinal contractility and synchrony, and increased circumferential contractility and synchrony. (3) Exercise can inhibit LV pathological remodeling, improve myocardial mechanical function. HIIT is superior to MICT. (4) The global longitudinal strain of obese rats in the HIIT group showed a significant correlation with Fat% and Lean%. CONCLUSION: Obesity can induce LV pathological remodeling and subclinical dysfunction. Compared with MICT, 12-week HIIT can effectively inhibit the pathological remodeling of LV and promote the benign development of myocardial mechanical function in obese rats.

Effects of short-term exercise and endurance training on skeletal muscle mitochondria damage induced by particular matter, atmospherically relevant artificial PM2.5.

Introduction: This study aimed to investigate the potential of short-term aerobic exercise to mitigate skeletal muscle mitochondrial damage following ambient PM2.5 exposure, and how 12 weeks of endurance training can enhance aerobic fitness to protect against such damage. Methods: Twenty-four male C57BL/6 J mice were split into sedentary (SED, n = 12) and endurance training (ETR, n = 12) groups. The ETR group underwent 12 weeks of training (10-15 m/min, 60 min/day, 4 times/week), confirmed by an Endurance Exercise Capacity (EEC) test. Post-initial training, the SED group was further divided into SSED (SED and sedentary, n = 6) and SPE (SED and PM2.5 + Exercise, n = 6). Similarly, the ETR group was divided into EEX (ETR and Exercise, n = 6) and EPE (ETR and PM2.5 + Exercise, n = 6). These groups underwent 1 week of atmospherically relevant artificial PM2.5 exposure and treadmill running (3 times/week). Following treatments, an EEC test was conducted, and mice were sacrificed for blood and skeletal muscle extraction. Blood samples were analyzed for oxidative stress indicators, while skeletal muscles were assessed for mitochondrial oxidative metabolism, antioxidant capacity, and mitochondrial damage using western blot and transmission electron microscopy (TEM). Results: After 12 weeks of endurance training, the EEC significantly increased (p < 0.000) in the ETR group compared to the SED group. Following a one-week comparison among the four groups with atmospherically relevant artificial PM2.5 exposure and exercise treatment post-endurance training, the EEX group showed improvements in EEC, oxidative metabolism, mitochondrial dynamics, and antioxidant functions. Conversely, these factors decreased in the EPE group compared to the EEX. Additionally, within the SPE group, exercise effects were evident in HK2, LDH, SOD2, and GPX4, while no impact of short-term exercise was observed in all other factors. TEM images revealed no evidence of mitochondrial damage in both the SED and EEX groups, while the majority of mitochondria were damaged in the SPE group. The EPE group also exhibited damaged mitochondria, although significantly less than the SPE group. Conclusion: Atmospherically relevant artificial PM2.5 exposure can elevate oxidative stress, potentially disrupting the benefits of short-term endurance exercise and leading to mitochondrial damage. Nonetheless, increased aerobic fitness through endurance training can mitigate PM2.5-induced mitochondrial damage.

Evaluation of skeletal muscle function in male rats with doxorubicin-induced myopathy following various exercise techniques: the significant role of glucose transporter 4.

A common anthracycline antibiotic used to treat cancer patients is doxorubicin (DOX). One of the effects of DOX therapy is skeletal muscle fatigue. Our goal in this research was to study the beneficial effect of exercise on DOX-induced damaged muscle fibers and compare the effect of different exercise strategies (prophylactic, post- toxicity and combined) on DOX toxicity. Five groups were created from 40 male rats: group I, control group; group II, DOX was administered intraperitoneally for 2 weeks over 6 equal injections (each 2.5 mg/kg); group III, rats trained for 3 weeks before DOX; group IV, rats trained for 8 weeks after DOX; and group V, rats were trained for 3 weeks before DOX followed by 8 weeks after. Measures of oxidative damage (H2O2, catalase), inflammation (TNF-α), and glucose transporter 4 (GLUT4) expression on skeletal muscle were assessed. Also, Homeostatic Model Assessment for Insulin Resistance (HOMA-IR) was estimated. Skeletal performance was evaluated by contraction time (CT), half relaxation time (1/2 RT), and force-frequency relationship by the end of this research. The current study demonstrated a detrimental effect of DOX on skeletal performance as evidenced by a significant increase in CT and 1/2 RT compared to control; in addition, H2O2, TNF-α, and HOMA-IR were significantly increased with a significant decrease in GLUT4 expression and catalase activity. Combined exercise therapy showed a remarkable improvement in skeletal muscle performance, compared to DOX, CT, and 1/2 RT which were significantly decreased; H2O2 and TNF-α were significantly decreased unlike catalase antioxidant activity that significantly increased; in addition, skeletal muscle glucose metabolism was significantly improved as GLUT4 expression significantly increased and HOMA-IR was significantly decreased. Exercise therapy showed significant improvement in all measured parameters relative to DOX. However, combined exercise therapy showed the best improvement relative to both pre-exercise and post-exercise groups.

Myocardial proteome changes in aortic stenosis rats subjected to long-term aerobic exercise.

The effects of exercise training (ET) on the heart of aortic stenosis (AS) rats are controversial and the mechanisms involved in alterations induced by ET have been poorly clarified. In this study, we analyzed the myocardial proteome to identify proteins modulated by moderate-intensity aerobic ET in rats with chronic supravalvular AS. Wistar rats were divided into four groups: sedentary control (C-Sed), exercised control (C-Ex), sedentary aortic stenosis (AS-Sed), and exercised AS (AS-Ex). ET consisted of five treadmill running sessions per week for 16 weeks. Statistical analysis was performed by ANOVA or Kruskal-Wallis and Goodman tests. Results were discussed at a significance level of 5%. At the end of the experiment, AS-Ex rats had higher functional capacity, lower blood lactate concentration, and better cardiac structural and left ventricular (LV) functional parameters than the AS-Sed. Myocardial proteome analysis showed that AS-Sed had higher relative protein abundance related to the glycolytic pathway, oxidative stress, and inflammation, and lower relative protein abundance related to beta-oxidation than C-Sed. AS-Ex had higher abundance of one protein related to mitochondrial biogenesis and lower relative protein abundance associated with oxidative stress and inflammation than AS-Sed. Proteomic data were validated for proteins related to lipid and glycolytic metabolism. Chronic pressure overload changes the abundance of myocardial proteins that are mainly involved in lipid and glycolytic energy metabolism in rats. Moderate-intensity aerobic training attenuates changes in proteins related to oxidative stress and inflammation and increases the COX4I1 protein, related to mitochondrial biogenesis. Protein changes are combined with improved functional capacity, cardiac remodeling, and LV function in AS rats.

A Chronic High-Intensity Interval Training and Diet-Induced Obesity Model to Maximize Exercise Effort and Induce Physiologic Changes in Rats.

Compared to continuous-moderate or low-intensity training, high-intensity interval training (HIIT) is a more time-efficient alternative method that results in similar physiologic benefits. This paper presents a HIIT protocol that can be used to assess various health markers in a Sprague-Dawley rat model of diet-induced obesity. Female Sprague Dawley rats aged 21 days old were randomly assigned to the following groups: control (CON, n = 10), exercise-trained (TRN, n = 10), high-fat diet (HFD, n = 10), and high-fat diet/exercise training (HFD/TRN, n = 10). The control diets consisted of commercial laboratory chow with 10% kilocalories (kcal) from fat (3.82 kcal/g), and the high-fat diets (HFD) consisted of 45% kcal from fat (4.7 kcal/g). The animals had ad libitum access to their assigned diet throughout the study. After an 8 week diet induction period, the exercise cohorts completed four HIIT sessions per week for 8 weeks. Each HIIT session consisted of 10 intervals of 1 min sprints/2 min rest using a rodent treadmill with a motor-driven belt. After the 8 weeks of training, the animals were sacrificed for tissue collection. The results revealed no differences in the distance run between the TRN and HFD/TRN groups, and the training speed steadily increased over the duration of the study, with a final running speed of 115 cm/s and 111 cm/s for the TRN and HFD/TRN groups, respectively. The weekly caloric intake was decreased (p < 0.05) in the TRN group relative to the CON group but increased (p < 0.05) in the HFD/TRN group relative to the HFD group. Lastly, the animals on the HFD had greater (p < 0.05) adiposity, and the trained animals had reduced (p < 0.05) adiposity relative to controls. This protocol demonstrates an efficient method to evaluate the effects of HIIT on various physiologic outcomes in a diet-induced obesity model.

Genotype determining aerobic exercise capacity associates with behavioral plasticity in middle-aged rats.

Good aerobic fitness associates positively with cognitive performance and brain health and conversely, low aerobic fitness predisposes to neurodegenerative diseases. To study how genotype together with exercise, started at older age, affects brain and behavior, we utilized rats that differ in inherited aerobic fitness. Rats bred for Low Capacity for Running (LCR) are shown to display less synaptic plasticity and more inflammation in the hippocampus and perform worse than rats bred for a High Capacity for Running (HCR) in tasks requiring flexible cognition. Here we used middle-aged (∼ 16 months) HCR and LCR rats to study how genotype and sex associate with anxiety and neural information filtering, termed sensory gating. Further, we assessed how inherited aerobic capacity associates with hippocampus-dependent learning, measured with contextual fear conditioning task. In females, we also investigated the effects of voluntary wheel running (5 weeks) on these characteristics. Our results indicate that independent of sex or voluntary running, HCR rats were more anxious in open-field tasks, exhibited lower sensory gating and learned more efficiently in contextual fear conditioning task than LCR rats. Voluntary running did not markedly affect innate behavior but slightly decreased the differences between female LCR and HCR rats in fear learning. In conclusion, inherited fitness seems to determine cognitive and behavioral traits independent of sex. Although the traits proved to be rather resistant to change at adult age, learning was slightly improved following exercise in LCR females, prone to obesity and poor fitness.

Effects of aging and long-term physical activity on mitochondrial physiology and redox state of the cortex and cerebellum of female rats.

We investigated the effects of aging and long-term physical activity on markers of mitochondrial function and dynamics in the cortex and cerebellum of female rats. Additionally, we interrogated markers of oxidative damage and antioxidants. Thirty-four female Lewis rats were separated into three groups. A young group (YNG, n = 10) was euthanized at 6 months of age. Two other groups were aged to 15 months and included a physical activity group (MA-PA, n = 12) and a sedentary group (MA-SED, n = 12). There were no age effects for any of the variables investigated, except for SOD2 protein levels in the cortex (+6.5%, p = 0.012). Long-term physical activity increased mitochondrial complex IV activity in the cortex compared to YNG (+85%, p = 0.016) and MA-SED (+82%, p = 0.023) and decreased carbonyl levels in the cortex compared to YNG (-12.49%, p = 0.034). Our results suggest that the mitochondrial network and redox state of the brain of females may be more resilient to the aging process than initially thought. Further, voluntary wheel running had minimal beneficial effects on brain markers of oxidative damage and mitochondrial physiology.

[The effects of different exercise modes on Rab5 protein and glucose metabolism in skeletal muscle of type 2 diabetic mellitus rats].

Objective: To investigate the effects of continuing exercise and load-bearing interval exercise on skeletal muscle tissue cell morphology, Ras-related proteins 5 (Rab5) mRNA and protein expression and glucose metabolism in skeletal muscle of type 2 diabetic mellitus (T2DM) rats. Methods: Eight SD rats were selected as controls group (CR), the others SD rats were fed with high fat and high sugar diet for 6 weeks before injecting STZ (35 mg/kg) to construct the T2DM model. Twenty-four T2DM rats were randomly devided into T2DM model group (DRM), continuing exercise group (DCRE) and load-bearing interval exercise group (DWRE), 8 rats in each group. DCRE exercise protocol, that was 15 m/min (10 min), 20 m/min (40 min), 15 m/min (10 min), during the first 1～2 weeks, and 18 m/min (10 min), 25 m/min (40 min), 15 m/min (10 min), during the second 3～8 weeks. DWRE exercise protocol: load weight 15% / 1～2 weeks, 30% / 3～4 weeks, 45% / 5～8 weeks, with 15 m/min (5 min), 12 groups and 3 min rest between groups. After 8 weeks, pathological and morphological changes of skeletal muscle were observed by HE. Rab5 and Glucose transporte 4 (GLUT4) mRNA expressions of skeletal muscle were tested by qRT-PCR. Rab5 protein expression in skeletal muscle was tested by immunofluorescence histochemistry and Western blot, and plasma Rab5 and Glycosylated Hemoglobin (GHb) concentrations were detected by ELISA. Results: Comparison with CR, DRM showed pathological damage of skeletal muscle, the expressions of Rab5 mRNA, protein and GLUT4 mRNA were all decreased in skeletal muscle (P＜0.01), the serum levels of Rab5 and GHb were both significantly elevated (P＜0.01). Comparison with DRM, both DCRE and DWRE significantly improved pathological damages of skeletal muscle, the expressions of Rab5 mRNA, protein and GLUT4 mRNA were all increased in skeletal muscle (P＜ 0.05, P＜0.01), the serum levels of Rab5 and GHb were decreased (P＜0.05, P＜0.01), and there was no statistical difference between DCRE and DWRE groups (P＞0.05). Conclusion: Two exercise modes can improve the pathological injury of skeletal muscle in type 2 diabetic rats, and enhance GLUT4 transport capacity by improving the expression of Rab5 gene and protein in skeletal muscle, and alleviate the imbalance of glucose metabolism homeostasis in skeletal muscle. However, there was no significant difference between the effects of two exercise modes on Rab5 protein and glucose metabolism in skeletal muscle.

Effect of Water Depth on Limb and Back Kinematics in Horses Walking on a Water Treadmill.

Water treadmill (WT) exercise is frequently used for training/rehabilitation of horses. There is limited study into the effect of water depth on limb/back kinematics warranting investigation. The objective was to determine the effect of walking in different water depths, at the same speed, on limb/back kinematics measured simultaneously in a group of horses. Six horses (age:15 ± 6.5 years) completed a standardized WT exercise session (19 minutes duration; speed:1.6 m/s; water depths: 0.0/7.5/21.0/32.0/47.0 cm). Ten waterproof light-emitting-diode tea-light-markers and reflective-spheres were affixed to the skin at predetermined locations; inertial-measurement-units were fixed to the poll/withers/left and right tubera coxae (TC)/sacrum to determine range-of-motion (ROM) changes of these locations. Univariable-mixed-effects-linear-regression-analyses were carried out, with a significance value of P ≤ .05. At maximum carpal/tarsal flexion during swing, regression analyses showed a clear and consistent nonlinear increase in carpal and tarsal flexion at increasing water depths (P < 0.0001 for both variables). As water depth increased there was a significant increase in thoracic spine flexion-extension ROM (P < 0.0001 at all thoracic sites) and increased dorsoventral and mediolateral ROM of the sacrum/left and right TC (P < 0.001 for all variables) as water depth increased. Results suggest that horses responded to an increase in water depth until a threshold depth was reached when the biomechanical response levelled off, and there was increased pelvic roll. In conclusion, changes in limb kinematics brought about by relatively modest increases in water depth at walking speed of 1.6 m/s are sufficient to induce significant changes in back/pelvic movement highlighting key issues with relevance for WT program design.

Exercise Normalized the Hippocampal Renin-Angiotensin System and Restored Spatial Memory Function, Neurogenesis, and Blood-Brain Barrier Permeability in the 2K1C-Hypertensive Mouse.

Hypertension is associated with blood-brain barrier alteration and brain function decline. Previously, we established the 2-kidney,1-clip (2K1C) hypertensive mice model by renin-angiotensin system (RAS) stimulating. We found that 2K1C-induced hypertension would impair hippocampus-related memory function and decrease adult hippocampal neurogenesis. Even though large studies have investigated the mechanism of hypertension affecting brain function, there remains a lack of efficient ways to halt this vicious effect. The previous study indicated that running exercise ameliorates neurogenesis and spatial memory function in aging mice. Moreover, studies showed that exercise could normalize RAS activity, which might be associated with neurogenesis impairment. Thus, we hypothesize that running exercise could ameliorate neurogenesis and spatial memory function impairment in the 2K1C-hypertension mice. In this study, we performed 2K1C surgery on eight-weeks-old C57BL/6 mice and put them on treadmill exercise one month after the surgery. The results indicate that running exercise improves the spatial memory and neurogenesis impairment of the 2K1C-mice. Moreover, running exercise normalized the activated RAS and blood-brain barrier leakage of the hippocampus, although the blood pressure was not decreased. In conclusion, running exercise could halt hypertension-induced brain impairment through RAS normalization.

A Simple and Inexpensive Running Wheel Model for Progressive Resistance Training in Mice.

Previously developed rodent resistance-based exercise models, including synergistic ablation, electrical stimulation, weighted-ladder climbing, and most recently, weighted-sled pulling, are highly effective at providing a hypertrophic stimulus to induce skeletal muscle adaptations. While these models have proven invaluable for skeletal muscle research, they are either invasive or involuntary and labor-intensive. Fortunately, many rodent strains voluntarily run long distances when given access to a running wheel. Loaded wheel running (LWR) models in rodents are capable of inducing adaptations commonly observed with resistance training in humans, such as increased muscle mass and fiber hypertrophy, as well as stimulation of muscle protein synthesis. However, the addition of moderate wheel load either fails to deter mice from running great distances, which is more reflective of an endurance/resistance training model, or the mice discontinue running nearly entirely due to the method of load application. Therefore, a novel high-load wheel running model (HLWR) has been developed for mice where external resistance is applied and progressively increased, enabling mice to continue running with much higher loads than previously utilized. Preliminary results from this novel HLWR model suggest it provides sufficient stimulus to induce hypertrophic adaptations over the 9 week training protocol. Herein, the specific procedures to execute this simple yet inexpensive progressive resistance-based exercise training model in mice are described.

Neuroprotective Effect of HIIT against GFAP Hypertrophy through Mitochondrial Dynamics in APP/PS1 Mice.

Alzheimer's disease (AD) is characterized by the accumulation of ß-amyloid (Aß) plaques and tau neurofibrillary tangles in the brain. Although the exact details of the neuronal protective effect of high-intensity interval training (HIIT) on AD remain unclear, the preclinical phase of AD appears to be the important time point for such intervention. The described experiment investigates the neuroprotective effect of HIIT on AD in APP/PS1 mice. In total, 14 C57BL6 healthy control (C) mice and 14 APP/PS1 AD mice were each randomly assigned into two groups, one that did not participate in HIIT (C and AD groups, respectively) and the other subject to HIIT intervention (control HIIT (CE) and AD HIIT (ADE) groups, respectively). Visualization of hippocampal neuronal cells via HE and Congo red staining showed significant improvement in cell status and a significant reduction in amyloidosis in ADE compared with AD. The results of behavioral analysis show that the HIIT intervention significantly improved cognitive decline and reduced spatial exploration in both the C and AD groups. Immunofluorescence showed that the overall brain and the hippocampus of aged rats in the C and AD groups had different degrees of neuroglial responses and astrocyte GFAP proliferation and hypertrophy, with obvious improvement in the CE and ADE groups after 10 weeks of HIIT intervention. These results show that HIIT significantly improves the status of mitochondrial kinetic proteins and related proteins, with the mechanism differing between the normal aging C and the AD groups. 10 weeks of HIIT improved the imbalance in mitochondrial dynamics present in normal control mice and in AD mice. We conclude that preclinical training intervention has a significant positive effect on the exploratory behavior and cognitive functioning of mice.

Exercise improves angiogenic function of circulating exosomes in type 2 diabetes: Role of exosomal SOD3.

Exosomes, key mediators of cell-cell communication, derived from type 2 diabetes mellitus (T2DM) exhibit detrimental effects. Exercise improves endothelial function in part via the secretion of exosomes into circulation. Extracellular superoxide dismutase (SOD3) is a major secretory copper (Cu) antioxidant enzyme that catalyzes the dismutation of O2•- to H2 O2 whose activity requires the Cu transporter ATP7A. However, the role of SOD3 in exercise-induced angiogenic effects of circulating plasma exosomes on endothelial cells (ECs) in T2DM remains unknown. Here, we show that both SOD3 and ATP7A proteins were present in plasma exosomes in mice, which was significantly increased after two weeks of volunteer wheel exercise. A single bout of exercise in humans also showed a significant increase in SOD3 and ATP7A protein expression in plasma exosomes. Plasma exosomes from T2DM mice significantly reduced angiogenic responses in human ECs or mouse skin wound healing models, which was associated with a decrease in ATP7A, but not SOD3 expression in exosomes. Exercise training in T2DM mice restored the angiogenic effects of T2DM exosomes in ECs by increasing ATP7A in exosomes, which was not observed in exercised T2DM/SOD3-/- mice. Furthermore, exosomes overexpressing SOD3 significantly enhanced angiogenesis in ECs by increasing local H2 O2  levels in a heparin-binding domain-dependent manner as well as restored defective wound healing and angiogenesis in T2DM or SOD3-/- mice. In conclusion, exercise improves the angiogenic potential of circulating exosomes in T2DM in a SOD3-dependent manner. Exosomal SOD3 may provide an exercise mimetic therapy that supports neovascularization and wound repair in cardiometabolic disease.

Beneficial effects of voluntary wheel running on activity rhythms, metabolic state, and affect in a diurnal model of circadian disruption.

Emerging evidence suggests that disruption of circadian rhythmicity contributes to development of comorbid depression, cardiovascular diseases (CVD), and type 2 diabetes mellitus (T2DM). Physical exercise synchronizes the circadian system and has ameliorating effects on the depression- and anxiety-like phenotype induced by circadian disruption in mice and sand rats. We explored the beneficial effects of voluntary wheel running on daily rhythms, and the development of depression, T2DM, and CVD in a diurnal animal model, the fat sand rat (Psammomys obesus). Voluntary exercise strengthened general activity rhythms, improved memory and lowered anxiety- and depressive-like behaviors, enhanced oral glucose tolerance, and decreased plasma insulin levels and liver weight. Animals with access to a running wheel had larger heart weight and heart/body weight ratio, and thicker left ventricular wall. Our results demonstrate that exercising ameliorates pathological-like daily rhythms in activity and blood glucose levels, glucose tolerance and depressive- and anxiety-like behaviors in the sand rat model, supporting the important role of physical activity in modulating the "circadian syndrome" and circadian rhythm-related diseases. We suggest that the utilization of a diurnal rodent animal model may offer an effective way to further explore metabolic, cardiovascular, and affective-like behavioral changes related to chronodisruption and their underlying mechanisms.

Sex differences in endurance exercise capacity and skeletal muscle lipid metabolism in mice.

Previous studies suggest that sex differences in lipid metabolism exist with females demonstrating a higher utilization of lipids during exercise, which is mediated partly by increased utilization of muscle triglycerides. However, whether these changes in lipid metabolism contribute directly to endurance exercise performance is unclear. Therefore, the objective of this study was to investigate the contribution of exercise substrate metabolism to sex differences in endurance exercise capacity (EEC) in mice. Male and female C57BL/6-NCrl mice were subjected to an EEC test until exhaustion on a motorized treadmill. The treadmill was set at a 10% incline, and the speed gradually increased from 10.2 m/min to 22.2 m/min at fixed intervals for up to 2.5 h. Tissues and blood were harvested in mice immediately following the EEC. A cohort of sedentary, non-exercised male and female mice were used as controls. Females outperformed males by ~25% on the EEC. Serum levels of both fatty acids and ketone bodies were ~50% higher in females at the end of the EEC. In sedentary female mice, skeletal muscle triglyceride content was significantly greater compared to sedentary males. Gene expression analysis demonstrated that genes involved in skeletal muscle fatty acid oxidation were significantly higher in females with no changes in genes associated with glucose uptake or ketone body oxidation. The findings suggest that female mice have a higher endurance exercise capacity and a greater ability to mobilize and utilize fatty acids for energy.