Protective Effect Of Aerobic Exercise Research Articles

Aerobic Exercise Protects against Cardiotoxin-Induced Skeletal Muscle Injury in a DDAH1-Dependent Manner.

Dimethylarginine dimethylaminohydrolase 1 (DDAH1) is a critical enzyme that regulates nitric oxide (NO) signaling through the degradation of asymmetric dimethylarginine (ADMA). Previous studies have revealed a link between the beneficial effects of aerobic exercise and the upregulation of DDAH1 in bones and hearts. We previously reported that skeletal muscle DDAH1 plays a protective role in cardiotoxin (CTX)-induced skeletal muscle injury and regeneration. To determine the effects of aerobic exercise on CTX-induced skeletal muscle injury and the role of DDAH1 in this process, wild-type (WT) mice and skeletal muscle-specific Ddah1-knockout (Ddah1MKO) mice were subjected to swimming training for 8 weeks and then injected with CTX. In WT mice, swimming training for 8 weeks significantly promoted skeletal muscle regeneration and attenuated inflammation, oxidative stress, and apoptosis in the gastrocnemius (GA) muscle after CTX injection. These phenomena were associated with increases in the protein expression of PAX7, myogenin, MEF2A, eNOS, SOD2, and peroxiredoxin 5 and decreases in iNOS expression in GA muscles. Swimming training also decreased serum ADMA levels and increased serum nitrate/nitrite (NOx) levels and skeletal muscle DDAH1 expression. Interestingly, swimming training in Ddah1MKO mice had no obvious effect on CTX-induced skeletal muscle injury or regeneration and did not repress the CTX-induced inflammatory response, superoxide generation, or apoptosis. In summary, our data suggest that DDAH1 is important for the protective effect of aerobic exercise on skeletal muscle injury and regeneration.

Integrating analysis of mRNA expression profiles indicates Sgk1 as a key mediator in muscle-brain crosstalk during resistance exercise

Abundant evidence has shown the protective effect of aerobic exercise on central neuronal system, however, research about resistance exercise remains limited. To evaluate the effect and potential molecular mechanisms of resistance exercise in improving cognition and mental health, three-month-old male C57BL/6J mice underwent resistance training for five weeks. Body parameters, cognitive performance and synaptic plasticity were then assessed. In both groups, total RNA from the frontal cortex, hippocampus and gastrocnemius was isolated and sequenced, GO term and KEGG analysis were performed to identify molecular mechanisms. The results from RNA sequencing were then verified by RT-PCR. Our data found that mice in training group showed reduced anxiety-like behavior and better spatial memory. Accordingly, resistance exercise specifically increased the number of thin spines without affecting the number of other kind of spines. mRNA sequence analysis showed that resistance exercise induced differential expression of hundreds of genes in the above three tissues. KEGG analysis indicated the FoxO signaling pathway the most significant changed pathway throughout the brain and muscle. GO terms analysis showed that Sgk1 was enriched in the three key cognition related BP, including long-term memory, learning or memory and memory, and the expression level of Sgk1 was positive related with cognitive performance in the water maze. In conclusion, resistance exercise improved the mental health, cognition and synaptic plasticity of mice. Integrating analysis of mRNA expression profiles in frontal cortex, hippocampus and muscle reveals Sgk1 as the key mediator in brain-muscle crosstalk.

Effects of aerobic exercise training on cerebral pulsatile hemodynamics in middle-aged adults with elevated blood pressure/stage 1 hypertension.

Mechanisms behind the protective effects of aerobic exercise on brain health remain elusive but may be vascular in origin and relate to cerebral pulsatility. This pilot study investigated the effects of 12-wk aerobic exercise training on cerebral pulsatility and its vascular contributors (large artery stiffness, characteristic impedance) in at-risk middle-aged adults. Twenty-eight inactive middle-aged adults with elevated blood pressure or stage 1 hypertension were assigned to either moderate/vigorous aerobic exercise training (AET) for 3 days/wk or no-exercise control (CON) group. Middle cerebral artery (MCA) pulsatility index (PI), large artery (i.e., aorta, carotid) stiffness, and characteristic impedance were assessed via Doppler and tonometry at baseline, 6, and 12 wk, whereas cardiorespiratory fitness (V̇o2peak) was assessed via incremental exercise test and cognitive function via computerized battery at baseline and 12 wk. V̇o2peak increased 6% in AET and decreased 4% in CON (P < 0.05). Proximal aortic compliance increased (P = 0.04, partial η2 = 0.14) and aortic characteristic impedance decreased (P = 0.02, partial η2 = 0.17) with AET but not CON. Cerebral pulsatility showed a medium-to-large effect size increase with AET, although not statistically significant (P = 0.07, partial η2 = 0.11) compared with CON. Working memory reaction time improved with AET but not CON (P = 0.02, partial η2 = 0.20). Our data suggest 12-wk AET elicited improvements in central vascular hemodynamics (e.g., proximal aortic compliance and characteristic impedance) along with apparent, paradoxical increases in cerebral pulsatile hemodynamics.NEW & NOTEWORTHY We identify differential central versus cerebrovascular responses to 12 wk of aerobic exercise training in middle-aged adults. Although proximal aortic compliance and characteristic impedance improved after 12 wk of exercise, cerebral pulsatility tended to unexpectedly increase. These data suggest short-term aerobic exercise training may lead to more immediate benefits in the central vasculature, whereas longer duration exercise training may be required for beneficial changes in pulsatility within the cerebrovasculature.

Aerobic exercise mitigates high-fat diet-induced cardiac dysfunction, pyroptosis, and inflammation by inhibiting STING-NLRP3 signaling pathway.

Obesity has been identified as an independent risk factor for cardiovascular disease. Recent reports have highlighted the significance of stimulator of interferon genes (STING)-NOD-like receptor protein 3 (NLRP3) signaling pathway mediated pyroptosis, and inflammation in cardiovascular disease. Previous studies have demonstrated that exercise training effectively prevents cardiac pyroptosis and inflammation in high-fat diet (HFD)-fed mice. However, it is currently unknown whether exercise reduces pyroptosis and inflammation in obese hearts by targeting the STING-NLRP3 signaling pathway. We investigated the impact of an 8-week aerobic exercise regimen on cardiac function, pyroptosis, inflammation, and the STING-NLRP3 signaling pathway in HFD-induced obese mice. Additionally, to explore the underlying mechanism of STING in exercise-mediated cardioprotection, we administered intraperitoneal injections of the STING agonist diABZI to the mice. Furthermore, to investigate the role of the STING-NLRP3 signaling pathway in HFD-induced cardiac dysfunction, we administered adeno-associated virus 9 (AAV9) encoding shRNA targeting STING (shRNA-STING) via tail vein injection to knockdown STING expression specifically in mouse hearts. After one week of AAV9 injection, we intraperitoneally injected nigericin as an NLRP3 agonist. We first found that aerobic exercise effectively suppressed HFD-mediated upregulation of STING and NLRP3 in the hearts. Moreover, we demonstrated that the protective effect of aerobic exercise in HFD-induced cardiac dysfunction, pyroptosis, and inflammation was impaired by stimulating the STING pathway using diABZI. Additionally, activation of the NLRP3 with nigericin abolished the ameliorative effect of STING deficiency in HFD-induced cardiac dysfunction, pyroptosis, and inflammation. Based on these findings, we concluded that 8-week aerobic exercise alleviates HFD-induced cardiac dysfunction, pyroptosis, and inflammation by targeting STING-NLRP3 signaling pathway. Inhibition of STING-NLRP3 signaling pathway may serve as a promising therapeutic strategy against obesity-induced cardiomyopathy.

MCC950 Ameliorates Diabetic Muscle Atrophy in Mice by Inhibition of Pyroptosis and Its Synergistic Effect with Aerobic Exercise.

Diabetic muscle atrophy is an inflammation-related complication of type-2 diabetes mellitus (T2DM). Even though regular exercise prevents further deterioration of atrophic status, there is no effective mediator available for treatment and the underlying cellular mechanisms are less explored. In this study, we investigated the therapeutic potential of MCC950, a specific, small-molecule inhibitor of NLRP3, to treat pyroptosis and diabetic muscle atrophy in mice. Furthermore, we used MCC950 to intervene in the protective effects of aerobic exercise against muscle atrophy in diabetic mice. Blood and gastrocnemius muscle (GAS) samples were collected after 12 weeks of intervention and the atrophic state was assessed. We initially corroborated a diabetic muscle atrophy phenotype in db/db mice (D) by comparison with control m/m mice (W) by examining parameters such as fasting blood glucose (D vs. W: 24.47 ± 0.45 mmol L-1 vs. 4.26 ± 0.6 mmol L-1, p < 0.05), grip strength (D vs. W: 166.87 ± 15.19 g vs. 191.76 ± 14.13 g, p < 0.05), exercise time (D vs. W: 1082.38 ± 104.67 s vs. 1716 ± 168.55 s, p < 0.05) and exercise speed to exhaustion (D vs. W: 24.25 ± 2.12 m min-1 vs. 34.75 ± 2.66 m min-1, p < 0.05), GAS wet weight (D vs. W: 0.07 ± 0.01 g vs. 0.13 ± 0.01 g, p < 0.05), the ratio of GAS wet weight to body weight (D vs. W: 0.18 ± 0.01% vs. 0.54 ± 0.02%, p < 0.05), and muscle fiber cross-sectional area (FCSA) (D vs. W: 1875 ± 368.19 µm2 vs. 2747.83 ± 406.44 µm2, p < 0.05). We found that both MCC950 (10 mg kg-1) treatment and exercise improved the atrophic parameters that had deteriorated in the db/db mice, inhibited serum inflammatory markers and significantly attenuated pyroptosis in atrophic GAS. In addition, a combined MCC950 treatment with exercise (DEI) exhibited a further improvement in glucose uptake capacity and muscle performance. This combined treatment also improved the FCSA of GAS muscle indicated by Laminin immunofluorescence compared to the group with the inhibitor treatment alone (DI) (DEI vs. DI: 2597 ± 310.97 vs. 1974.67 ± 326.15 µm2, p < 0.05) or exercise only (DE) (DEI vs. DE: 2597 ± 310.97 vs. 2006.33 ± 263.468 µm2, p < 0.05). Intriguingly, the combination of MCC950 treatment and exercise significantly reduced NLRP3-mediated inflammatory factors such as cleaved-Caspase-1, GSDMD-N and prevented apoptosis and pyroptosis in atrophic GAS. These findings for the first time demonstrate that targeting NLRP3-mediated pyroptosis with MCC950 improves diabetic muscle homeostasis and muscle function. We also report that inhibiting pyroptosis by MCC950 can enhance the beneficial effects of aerobic exercise on diabetic muscle atrophy. Since T2DM and muscle atrophy are age-related diseases, the young mice used in the current study do not seem to fully reflect the characteristics of diabetic muscle atrophy. Considering the fragile nature of db/db mice and for the complete implementation of the exercise intervention, we used relatively young db/db mice and the atrophic state in the mice was thoroughly confirmed. Taken together, the current study comprehensively investigated the therapeutic effect of NLRP3-mediated pyroptosis inhibited by MCC950 on diabetic muscle mass, strength and exercise performance, as well as the synergistic effects of MCC950 and exercise intervention, therefore providing a novel strategy for the treatment of the disease.

Aerobic Exercise in Male Mice Prevents Ventilator-Induced Lung Injury by Inhibiting Mitochondrial Damage from sirt1 Dysregulation.

Ventilator-induced lung injury (VILI) is a common complication of mechanical ventilation under general anesthesia. Regular aerobic exercise before surgery improves postoperative recovery and reduces postoperative pulmonary complications, but the mechanism driving this protective effect is unclear. To determine how aerobic exercise prevents VILI, we investigated the effects of exercise and mechanical ventilation on the lungs of male mice and the effects of AMPK stimulation (simulating exercise) and cyclic stretching on human lung microvascular endothelial cells (HLMVEC). Sirtuin 1 (Sirt1) knockdown male mice were generated to explore the regulating mechanisms of sirt1 on mitochondrial function in male mice after mechanical ventilation was explored. Western blot, flow cytometry, live cell imaging, and mitochondrial function evaluations were used to determine the protective effects of aerobic exercise in preventing mitochondrial damage in VILI. Mitochondrial function and cell junctions were destroyed by mechanical ventilation in male mice or cyclic stretching in HLMVEC, a model of VILI. However, mitochondrial function and cell junction dysfunction were improved by exercise before mechanical ventilation (male mice) or treatment with AMPK before cyclic stretching (HLMVEC). p66shc, a marker of oxidative stress, was increased, and PINK1, a marker of mitochondrial autophagy, was decreased by mechanical ventilation or cyclic stretching. Sirt1 knockdown increased p66shc and decreased PINK1. Increased sirt1 expression was observed in the exercise and exercise + ventilation groups, suggesting that sirt1 inhibits mitochondrial damage in VILI. Mechanical ventilation induces mitochondrial damage in lung cells and leads to VILI. Regular aerobic exercise before ventilation may prevent VILI by improving mitochondrial function.

Evaluation of the effects of mild aerobic exercise and Losartan treatment on aortic endothelial function in a mouse model of Marfan syndrome

Marfan Syndrome (MFS) is an autosomal dominant disorder in a family of connective tissue disorders. It is well established that vascular complications in MFS is associated with endothelial dysfunction, leading to a whole host of phenotypic abnormalities. A predominant clinical concern is the development of aortic aneurysm with possible subsequent dissection and rupture.In the present study, we have utilized the ex‐vivo isometric myograph technique to examine the reactivity of isolated aortic segments from control and MFS mice in the presence or absence of different in‐vivo treatments and pharmacological agents. More specifically, we assessed the impact of mild aerobic exercise on endothelial function, aortic root growth, and aortic wall elasticity in a well‐established mouse model of MFS‐associated aortic aneurysm with special focus on nitric oxide production. Nitric oxide, as frequently demonstrated in the literature, plays a crucial role in maintaining normal vascular structure and function. In the current study, we examine the potential effects of mild aerobic exercise in the absence or presence of a potent general inhibitor of nitric oxide synthase (NOS), N5‐[imino(nitroamino)methyl]‐L‐ornithine, methyl ester, monohydrochloride (L‐NAME) on aortic contraction and endothelium‐mediated vasorelaxation in 6‐month‐old MFS mice carrying Fbn1 mutation and age‐ and sex‐matched C57BL/6J wildtype (WT) controls (male and females).At 4‐6 weeks of age, MFS mice were subjected to daily treadmill exercise (at 55% of VO2max, 8m/min, 30min/day, 5days/week) and/or drug treatment for a duration of 5 months. At 6 months of age, 2mm descending aortic rings were collected and mounted onto a small chamber myograph in order to measure the vascular reactivity in response to different vasoconstricting and vasodilating agents.Our study shows marked reduction in the phenylephrine (PE)‐induced contraction [50 µmol] and aortic wall rupture point in MFS mice aorta as compared to healthy controls. Treatment with either aerobic exercise or Losartan, an angiotensin II type 1 receptor blocker (ARB), rescued rupture point closer to WT control, but led to further decrease in PE contraction compared to MFS sedentary mice, mainly due to further increase in NO production within the aortic wall. In addition, direct inhibition of NO production via L‐Name, a nitric oxide synthase (NOS) inhibitor, effectively reduced PE‐induced contraction in MFS mice aorta that were subjected to exercise or Losartan treatment, further confirming that both exercise and Losartan treatment cause an increase in NO production.This study highlights the importance of endothelial function in improving the function and structure of aortic wall during the progression of aortic aneurysm in MFS mice and establish the notion that the protective effects of aerobic exercise and Losartan treatments are potentially through improving endothelium‐mediated nitric oxide production.

Aerobic exercise and eugenol supplementation ameliorated liver injury induced by chlorpyrifos via modulation acetylcholinesterase activation and antioxidant defense.

The primary metabolize of chlorpyrifos (CPF) is in the liver tissue, which it can cause oxidative damage and apoptosis in liver cells. The use of exercise with antioxidant supplements could have a protective effects in the liver tissue especially by improve mitochondria function. The aim of the present study was to investigate the protective effect of aerobic exercise and eugenol (Eu) supplementation on destructive effects of CPF in liver tissue. Sixty-four adult male albino rats were randomly divided into eight groups (eight rats in each group). Four experimental groups received intraperitoneal injection of either 3.0 mg/kg body weight CPF in dimethyl sulfoxide for six consecutive weeks. Aerobic exercise was performed 5 days per week over 4 weeks for exercise groups. Finally, the animals were sacrificed for the histomorphometric analysis and biochemical measurement in the liver tissue. The result of this study show that consumption of CPF alone, caused collagen deposition, increased apoptosis, tumor necrosis factor α, malondialdehyde, and decreased catalase, superoxide dismutase, acetylcholinesterase (AChE) compared to control and exercise groups (healthy groups) in liver tissue (P ˂ .05). Prescription of exercises and Eu supplements in CPF consumer groups, neutralized this destructive effects of CPF. However, concomitant administration of Eu with exercise had better effects on liver tissue (P ˂ .05). It seems that consumption of Eu with aerobic exercise have a protective role in tissue destruction, inflammatory damage by improving antioxidant defense and modulating AChE activity in hepatocytes.

Protective Effect of Aerobic Exercise on the Nasal Mucosa of Rats Against the Histopathologic Changes in Cigarette Smoke Exposure.

Smoking is a public health problem that has been proven to have adverse effects on human health. Aerobic exercise has positive effects on the human body, especially on the respiratory system. The aim of this experimental animal model study was to determine whether regular aerobic exercise has a protective effect against the harmful effects of cigarette smoke on the nasal mucosa of rats. A total of 24 male Wistar albino rats were randomly separated into 3 groups of 8: group 1 (cigarette smoking), group 2 (cigarette smoking and exercise), and group 3 (control group). At the end of the experiment period, histopathological (light and electron microscopy) and immunohistochemical (GSTA 1, CYP1A1, and CYP2E1) evaluations were made of the nasal mucosa of the animals. Goblet cell loss and basal membrane thickening were significantly lower in group 2 and group 3 compared to group 1. In the electron microscope evaluation, the inflammatory expressions of the goblet cells were observed in a very small area in group 2. In group 1, these were distributed over large areas between the mucosal cells. There was seen to be significant swelling of the mitochondria in group 1 compared to the other groups. No statistically significant difference was determined between the groups with respect to GSTA1, CYP2E1, and CYP1A1 scores (P > .05). The results of this study showed that regular aerobic exercise has a protective effect against the harmful effects of smoking on the nasal mucosa of rats.

Investigating the protective effect of aerobic exercise on oxidative stress and histological damages of testicular tissue associated with chlorpyrifos in male rats.

The current study aimed to investigate the protective effects of moderate aerobic exercise against chlorpyrifos (CPF)-induced testes dysfunction. In excremental study, 48 adult male albino rats were randomly allocated into 16 groups of 3 rats each. Twelve experimental groups received intraperitoneal injection (5days a week) of either 1.0 or 3.0mg/kg body weight CPF in DMSO for 2, 4 or 6 consecutive weeks. Seven of these experimental groups were subjected to run at moderate exercise intensity for 5days per week over 2weeks, whereas the other groups were not. Two groups (sham groups) were administered to the equal volume of vehicle (DMSO) for 4 or 6 consecutive weeks. The remaining two groups comprised the control groups including a sedentary and an exercise-trained control group. Exercise training leads to a markedly increase in testicular superoxide dismutase (SOD) activity in CPF-exposed rats compared with corresponding sedentary animals (p<.05). Lipid peroxidation level was found to be significantly decreased in the testis of exercised animals that had been exposed to CPF (p<.05). Our results suggest that aerobic exercise can alleviate the oxidative stress induced by sub-acute CPF exposure in testis. Exercise training could barely mitigate CPF-induced testicular damages in rats.

Therapeutic Approaches in Mitochondrial Dysfunction, Inflammation, and Autophagy in Uremic Cachexia: Role of Aerobic Exercise.

Chronic kidney disease (CKD) causes several systemic changes, including muscular homeostasis, and eventually results in muscle atrophy. CKD-induced muscle atrophy is highly prevalent, and exercise is well known to enhance muscle function in these cases, although the exact mechanism remains unclear. Here, we aim to assess whether the protective effect of aerobic exercise in 5/6 nephrectomized (CKD) mice is associated with mitochondrial dysfunction, autophagy, or inflammation. C57BL/6J mice were randomly allocated into 3 different experimental groups: Sham, CKD, and CKD+aerobic exercise (CKD+AE). Renal function was assessed via serum creatinine and urea levels, and histological PAS and Masson staining were performed. Muscle wasting was determined based on grip strength, cross-sectional area (CSA), and MyHC protein expression. We also measured mitochondrial dysfunction in mice by assessing mtDNA, ROS, ATP production, and mitochondrial configuration. Autophagy was determined via assessments for Atg7, LC3, and SQSTM1 on western blotting. Inflammation was identified via proinflammatory cytokines and NLRP3 inflammasome components using real-time PCR and western blotting. We found that CKD mice exhibited higher BUN and creatinine levels and more severe glomerulosclerosis in the glomeruli and renal tubulointerstitial fibrosis, relative to the Sham group; all these effects were relieved by aerobic exercise. Moreover, grip strength, CSA, and MyHC protein expression were improved after 8 weeks of aerobic exercise. Furthermore, aerobic exercise significantly decreased MDA levels, increased SOD2 activity and ATP production, and improved mitochondrial configuration, relative to the CKD group. In addition, aerobic exercise downregulated the overexpression of proinflammatory cytokines and NLRP3 inflammasome components and balanced the mitochondrial biogenesis and autophagy-lysosomal system. Thus, we observed that aerobic exercise may ameliorate CKD-induced muscle wasting by improving mitochondrial dysfunction, inflammation, and autophagy-lysosomal system in uremic cachexia.

Protective effect of aerobic exercise on the vocal folds against cigarette smoke exposure.

Laryngeal pathologies due to cigarette smoking vary among individuals, whereas some smokers remain disease free. These differences can be explained by multiple factors among individuals. In this context, an animal study was designed to determine if there is any protective effect of aerobic exercise against the detrimental effects of cigarette smoke on laryngeal tissues. A total of 24 male Wistar albino rats were divided into three groups of eight animals each: control (no smoke exposure), smoking (smoke exposure), and exercise (smoke exposure and exercise) groups. Histopathological (light and electron microscopy) and immunohistochemical (GSTA1, CYP1A1, CYP2E1) evaluations of the vocal folds were performed at the end of experimental period. Exercise group revealed statistically significant decrease in edema (p = 0.03) and inflammatory cell infiltration (p = 0.02) compared to smoking group. In electron microscopic evaluation; cytoplasmic vacuoles were also present in exercise group, but were smaller than smoking group. Edema and swollen mitochondria were also less prominent in exercise group. Condensed chromatin material in the periphery of nucleus was observed only in few cells in exercise group, and observed in more cells in smoking group. GSTA1 expression was higher (p = 0.047) and CYP1A1 expression was lower (p = 0.01) in exercise group than smoking group. Our results indicate that aerobic exercise has a protective role on the larynx against the damaging effect of cigarette smoke. Smokers who exercise regularly may be at a lower risk of cigarette smoke-related laryngeal diseases, as compared with those who do not exercise.

Ten years younger: Practice of chronic aerobic exercise improves attention and spatial memory functions in ageing.

Aerobic exercise is associated with changes in brain morphology and improvement of cognitive functions. Physical activity may be especially important after age 60 when cognitive decline is more pronounced. In this paper, the effect of chronic practice of aerobic sports was studied in old adults by assessing their executive and mnesic functions, supported by frontal and temporal brain structures. Two groups were formed according to their age (60-69 and 70-79 years-old) including sportsmen (n = 23) and sedentary men (n = 24). Spatial memory and efficiency of attentional networks were measured, as well as general intelligence. Results showed that sportsmen outperformed sedentary participants in many of the tests employed. Thus their alerting, orienting and executive networks worked more effectively in the ANT-I task for executive functions, and they were more accurate in the spatial memory task, displaying a better spatial orientation. Scores in other neuropsychological tasks followed the same tendency. These data support the protective effect of aerobic exercise on cognitive functions.

Age-related effect of aerobic exercise training on antioxidant and oxidative markers in the liver challenged by doxorubicin in rats

The aims of the current study were to investigate the oxidant and antioxidant status of liver tissue challenged by doxorubicin and to examine the possible protective effects of aerobic exercise on doxorubicin-induced oxidative stress. Seventy-two rats were divided into three age groups (Young, Adult, and Elderly) with three treatment subgroups consisting of eight rats per age group: doxorubicin, aerobic exercise + doxorubicin, and aerobic exercise + saline. The experimental groups performed regular treadmill running for 3 weeks. Doxorubicin was administered by i.p. injection at a dosage of 20 mg kg−1 while the aerobic exercise + saline group received saline of a comparable volume. Heat shock protein 70, malondialdehyde, glutathione peroxidase, and protein carbonyl were determined from the liver homogenates following the intervention period. Treatment with doxorubicin induced hepatotoxicity in all groups with lower values of oxidative stress in young compared with the older groups. The inclusion of aerobic exercise training significantly increased heat shock protein 70 and antioxidant enzyme levels (glutathione peroxidase) whereas it decreased oxidative stress biomarkers (malondialdehyde and protein carbonyl) for all age groups. These results suggest that aerobic exercise training may be a potential, non-drug strategy to modulate doxorubicin-induced hepatotoxicity through its positive impact on antioxidant levels and oxidative stress biomarkers.

The protective effect of aerobic exercise on breast cancer by TGFβ protein and Smad-3 and MMP2 gene in female mice.

The protective effect of aerobic exercise on breast cancer by TGFβ protein and Smad-3 and MMP2 gene in female mice.

Aerobic exercise protects against pressure overload-induced cardiac dysfunction and hypertrophy via β3-AR-nNOS-NO activation.

Aerobic exercise confers sustainable protection against cardiac hypertrophy and heart failure (HF). Nitric oxide synthase (NOS) and nitric oxide (NO) are known to play an important role in exercise-mediated cardioprotection, but the mechanism of NOS/NO stimulation during exercise remains unclear. The aim of this study is to determine the role of β3-adrenergic receptors (β3-ARs), NOS activation, and NO metabolites (nitrite and nitrosothiols) in the sustained cardioprotective effects of aerobic exercise. An HF model was constructed by transverse aortic constriction (TAC). Animals were treated with either moderate aerobic exercise by swimming for 9 weeks and/or the β3-AR-specific inhibitor SR59230A at 0.1 mg/kg/hour one day after TAC operation. Myocardial fibrosis, myocyte size, plasma catecholamine (CA) level, cardiac function and geometry were assessed using Masson’s trichrome staining, FITC-labeled wheat germ agglutinin staining, enzyme-linked immuno sorbent assay (ELISA) and echocardiography, respectively. Western blot analysis was performed to elucidate the expression of target proteins. The concentration of myocardial NO production was evaluated using the nitrate reductase method. Myocardial oxidative stress was assessed by detecting the concentration of myocardial super oxidative dismutase (SOD), malonyldialdehyde (MDA), and reactive oxygen species (ROS). Aerobic exercise training improved dilated left ventricular function and partially attenuated the degree of cardiac hypertrophy and fibrosis in TAC mice. Moreover, the increased expression of β3-AR, activation of neuronal NOS (nNOS), and production of NO were detected after aerobic exercise training in TAC mice. However, selective inhibition of β3-AR by SR59230A abolished the upregulation and activation of nNOS induced NO production. Furthermore, aerobic exercise training decreased the myocardial ROS and MDA contents and increased myocardial levels of SOD; both effects were partially attenuated by SR59230A. Our study suggested that aerobic exercise training could improve cardiac systolic function and alleviate LV chamber dilation, cardiac fibrosis and hypertrophy in HF mice. The mechanism responsible for the protective effects of aerobic exercise is associated with the activation of the β3-AR-nNOS-NO pathway.

Chronic Aerobic Exercise Decreases Lectin-Like Low Density Lipoprotein (LOX-1) Receptor Expression in Heart of Diabetic Rat.

Background:Overexpression of lectin-like low density lipoprotein (LOX-1) receptor plays an important role in hyperglycemia-induced vascular complications such as atherosclerosis. Based on the beneficial effects of exercise on preventing cardiovascular complications of diabetes, we aimed to examine the protective effects of aerobic exercise on expression of LOX-1 receptor and production of free radicals in the heart of diabetic rats. Methods:Four groups of rats were used: (n = 5 per group): sedentary normal, trained normal, sedentary diabetes and trained diabetes. Diabetes was induced by a single intraperitoneal injection of streptozotocin (50 mg/kg). The exercise protocol was consisted of swimming 30 min/day, 5 days/week for eight weeks. Plasma glucose was evaluated at initiation, weeks 4 and 8 of experiment. At the end of experiment, rats were sacrificed and the heart was removed for determination of nitrate, malondialdehyde, and LOX-1 gene expression. Results:In normal non-diabetic rats, the blood glucose level was <150 mg/dl; however, the induction of diabetes resulted in levels more than >400 mg/dl. Gene expression of LOX-1 was increased in the heart of diabetic rats. Exercise reduced the gene expression of this protein in diabetic states without reducing the blood glucose. Finally, swimming exercise decreased the malondialdehyde and nitrate levels in heart tissue both in control and diabetic rats. Conclusion:Swimming exercise reduces heart expression of the LOX-1 receptor in accompany with reduction of free radicals production. Since these parameters are important in generation of diabetic complications, swimming exercise is a good candidate for reducing these complications.

Chronic effects of aerobic exercise on gene expression of LOX-1 receptor in the heart of rats fed with high fat diet.

Lectin-like low density lipoprotein receptor (LOX-1) has pivot role in vascular complications, which is upregulated in numerous pathological conditions. Since exercise has beneficial effects in prevention of hyperlipidemic complications, present study examined protective effects of aerobic exercise through reduction of LOX-1 expression in heart during dyslipidemia. Four groups of rats were used (N=25): Normal, Normal and exercise, High fat and High fat and exercise. High fat diet (HFD) was made by adding 10% animal oil, 2% cholesterol and 0.5% colic acid to standard rodent chow. Exercise protocol consisted of swimming 1 hr/day, and 5 days/week for 8 weeks. Plasma lipids were evaluated at the end of experiment, 48 hr after final session of exercise. At the end, rats were sacrificed and heart was removed for determination of malondialdehyde (MDA) content, and LOX-1 expression. HFD meaningfully changed lipid profile (>50%), but chronic exercise had no significant effects on lipid profile. LOX-1 expression was significantly increased in heart of rats fed with HFD, while swimming exercise considerably reduced gene expression of LOX-1. MDA content was significantly enhanced in rats fed with HFD (4.37±0.6 nmol/mg, P<0.01) compared to normal group (1.56±0.48 nmol/mg), whereas swimming exercise decreased MDA level of heart in rats fed with HFD (2.28±0.32, P<0.01). Findings indicated that swimming exercise is able to diminish heart expression of LOX-1 receptor concomitant reduction of oxidative stress. Since these parameters are involved in generation of dyslipidemic complications, swimming exercise is a good candidate to reduce these complications.

The Value of Exercise Training for Prevention and Complementary Treatment of Brain Aging and Neurodegeneration

It is widely documented that sedentarism is a risk factor for most common age-related chronic diseases. Regarding brain’s health, there is increasing evidence of the beneficial effects of aerobic physical exercise on synapse and general brain function, at both young and old ages and in both healthy and pathological states [1]. Indeed, in adult animals, physical training has been shown to enhance performance in learning and memory tasks [2-4], increase neuronalproliferation [5-7], and affect neuronal structure and the functionality ofcellular mechanisms associated with learning processes [8,9]. In addition, several studies using transgenic mouse models of Alzheimer’s disease (AD) have demonstrated the protective effects of aerobic exercise against neurodegeneration [10,11]. Although transcriptional responsiveness varies over the lifetime, many brain genes still seem to be responsive to exercise in old animals and in animal models for neurodegenerative diseases [12-14]. In mice, brain gene expression is sensitive to physical exercise, particularly in the hippocampus [15-19]. These findings are particularly relevant because the hippocampus is especially susceptible to dysfunctional and degenerative processes during aging or in Alzheimer’s disease, plays a key role in learning and memory processes and is involved in the regulation of mood and antidepressant responses [20-22]. Using the senescence-accelerated SAMP8 mouse a non-transgenic model for studying aspects of progressive cognitive decline and Alzheimer’s disease (AD) we have recently shown that exercise training during adulthood (6 months of voluntary training on a running wheel, 3 alternate days per week) prevented or delayed processes associated with aging [23]. Upon completion of the long-term intervention, SAMP8 mice were at the final stage of their lives (their median life is 9.7 months [24]), however they were still voluntarily running and showed improvement in several aging traits compared with the sedentary controls. We found that the exercise intervention ameliorated their skin color, decreased body tremor, increased hippocampal vascularization and modulated the expression of the brain derived neurotrophic factor (Bdnf) gene as well as several extracellular matrix gene alterations in the hippocampus. Recent data have described that epigenetic modifications seem to be involved in the peripheral and central effects of physical exercise [25]. Notably, we have recently observed epigenetic changes in specific microRNA (miRNA) and histone acetylation levels in the hippocampus of senescent SAMP8 mice in response to 8 weeks of voluntary wheel running (Cosin-Tomas et al., unpublished data). In sum, there is a growing body of research showing the neurophysiological aging-protective responses elicited by exercise training. Moreover, a still limited but fascinating field has begun to describe the epigenetic impact of physical exercise in peripheral tissues and in the brain. Unveiling the exercise-responsive mechanisms of chromatin regulation and their pathophysiological implications may lead to the development of new preventive and/or therapeutic interventions for age-related disorders, including neurodegenerative conditions.

Effect of Aerobic Exercise on miRNA-TLR4 Signaling in Atherosclerosis

Toll-like receptor 4 (TLR4)-tumor necrosis factor receptor 6 (TRAF6) signaling is activated in atherosclerosis (AS), inducing inflammatory mediators. Because miR-146a, a TLR4 microRNA (miRNA), can regulate TLR4 signaling during inflammatory responses, this study investigated the effects of aerobic exercise on TLR4-targeted miRNAs in AS. Apolipoprotein E-null mice fed a high-fat diet for 12 weeks were separated into 3 groups: (i) no treatment (AS), (ii) statin treatment (AD), or (iii) aerobic exercise (AE). Plaques and foam cells were observed in the untreated control and statin groups, respectively, but not in the AE group. Reduced angiotensin II (Ang II) and endothelin 1 (ET1) levels were observed in the AE group. Both treatment groups significantly altered the expression of inflammatory cytokine expression and reduced vascular TLR4 levels. Increased miR-146a and miR-126 and reduced miR-155 levels were observed in both treatment groups (all, P<0.001). miR-146a interacted with the 3' untranslated region of the TRAF6 gene, reducing its expression. Thus, aerobic exercise and statins may induce miR-146a expression, thereby reducing vascular TRAF and TLR4 signaling and vascular inflammatory injury in AS. Further analysis of this pathway may provide insight into the protective effects of aerobic exercise on vascular disease as well as new therapeutic targets.