RNA sequencing reveals the potential mechanism of exercise preconditioning for cerebral ischemia reperfusion injury in rats.

INTRODUCTION: Cerebral ischemia reperfusion injury (CIRI) often leads to deleterious complications after stroke patients receive reperfusion therapy. Exercise preconditioning (EP) has been reported to facilitate brain function recovery. We aim to explore the specific mechanism of EP in CIRI. METHODS: Sprague-Dawley rats were randomized into Sham, middle cerebral artery occlusion (MCAO), and EP groups (n = 11). The rats in the EP group received adaptive training for 3 days (10 m/min, 20 min/day, with a 0° incline) and formal training for 3 weeks (6 days/week, 25 m/min, 30 min/day, with a 0° incline). Then, rats underwent MCAO surgery to establish CIRI models. After 48 h, neurological deficits and cerebral infarction of the rats were measured. Neuronal death and apoptosis in the cerebral cortices were detected. Furthermore, RNA sequencing was conducted to investigate the specific mechanism of EP on CIRI, and qPCR and Western blotting were further applied to confirm RNA sequencing results. RESULTS: EP improved neurological deficit scores and reduced cerebral infarction in MCAO rats. Additionally, pre-ischemic exercise also alleviated neuronal death and apoptosis of the cerebral cortices in MCAO rats. Importantly, 17 differentially expressed genes (DEGs) were identified through RNA sequencing, and these DEGs were mainly enriched in the HIF-1 pathway, cellular senescence, proteoglycans in cancer, and so on. qPCR and Western blotting further confirmed that EP could suppress TIMP1, SOCS3, ANGPTL4, CDO1, and SERPINE1 expressions in MCAO rats. CONCLUSION: EP can improve CIRI in vivo, the mechanism may relate to TIMP1 expression and HIF-1 pathway, which provided novel targets for CIRI treatment.

The structure and function of FUN14 domain-containing protein 1 and its contribution to cardioprotection by mediating mitophagy.

Cardiovascular disease (CVD) is a serious public health risk, and prevention and treatment efforts are urgently needed. Effective preventive and therapeutic programs for cardiovascular disease are still lacking, as the causes of CVD are varied and may be the result of a multifactorial combination. Mitophagy is a form of cell-selective autophagy, and there is increasing evidence that mitophagy is involved in cardioprotective processes. Recently, many studies have shown that FUN14 domain-containing protein 1 (FUNDC1) levels and phosphorylation status are highly associated with many diseases, including heart disease. Here, we review the structure and functions of FUNDC1 and the path-ways of its mediated mitophagy, and show that mitophagy can be effectively activated by dephosphorylation of Ser13 and Tyr18 sites, phosphorylation of Ser17 site and ubiquitination of Lys119 site in FUNDC1. By effectively activating or inhibiting excessive mitophagy, the quality of mitochondria can be effectively controlled. The main reason is that, on the one hand, improper clearance of mitochondria and accumulation of damaged mitochondria are avoided, and on the other hand, excessive mitophagy causing apoptosis is avoided, both serving to protect the heart. In addition, we explore the possible mechanisms by which FUNDC1-mediated mitophagy is involved in exercise preconditioning (EP) for cardioprotection. Finally, we also point out unresolved issues in FUNDC1 and its mediated mitophagy and give directions where further research may be needed.

Resistance exercise preconditioning prevents disuse muscle atrophy by inhibiting apoptosis and protein degradation via SESN2 in C57BL/6J mice.

AIM: To compare the effects of different exercise preconditioning in the context of skeletal muscle atrophy and to investigate the potential involvement of Sestrin2 (SESN2), a stress-inducible protein that can be regulated by exercise, in exercise preconditioning on preventing disuse muscle atrophy. METHODS: Eight-week-old male C57BL/6J mice were randomly assigned to sedentary groups (SD), aerobic exercise groups (AE), resistance exercise groups (RE), and combined exercise groups (CE) with or without 7 days of immobilization. The duration of the exercise intervention was 10 weeks. The effects of different exercise preconditioning to prevent muscle atrophy were analyzed by evaluating skeletal muscle function and mass. Additionally, to investigate the potential underlying mechanism of exercise-induced protection of skeletal muscle, wild-type and SESN2--/-- mice were randomly divided into sedentary group and resistance exercise preconditioning group. C2C12 cells were treated with SESN2 adenoviruses and MK2206 (an AKT inhibitor) for 48 h to elucidate the underlined mechanism. RESULTS: RE was more effective in preserving skeletal muscle function, muscle mass and maintaining skeletal muscle protein homeostasis than AE and CE under immobilized condition. Importantly, exercise performance, muscle mass to body weight ratio, and the cross-sectional area of muscle fibers were significantly lower in SESN2-/- mice than wild-type mice after resistance exercise preconditioning. Mechanistically, the absence of SESN2 led to activation of the ubiquitin-proteasome system and induction of apoptosis. In vitro experiments showed that MK2206 treatment mitigated the regulatory effects of overexpression-SESN2 on protein hydrolysis and apoptosis. CONCLUSION: RE was more effective than AE or CE in preventing disuse muscle atrophy. SESN2 mediated the protective effects of resistance exercise preconditioning on skeletal muscle atrophy.

Exercise preconditioning inhibits doxorubicin-induced cardiotoxicity via YAP/STAT3 signaling.

Doxorubicin (DOX) possesses strong anti-tumor effects but is limited by its irreversible cardiac toxicity. The relationship between exercise, a known enhancer of cardiovascular health, and DOX-induced cardiotoxicity has been a focus of recent research. Exercise has been suggested to mitigate DOX's cardiac harm by modulating the Yes-associated protein (YAP) and Signal transducer and activator of transcription 3 (STAT3) pathways, which are crucial in regulating cardiac cell functions and responses to damage. This study aimed to assess the protective role of exercise preconditioning against DOX-induced cardiac injury. We used Sprague-Dawley rats, divided into five groups (control, DOX, exercise preconditioning (EP), EP-DOX, and verteporfin + EP + DOX), to investigate the potential mechanisms. Our findings, including echocardiography, histological staining, Western blot, and q-PCR analysis, demonstrated that exercise preconditioning could alleviate DOX-induced cardiac dysfunction and structural damage. Notably, exercise preconditioning enhanced the nuclear localization and co-localization of YAP and STAT3. Our study suggests that exercise preconditioning may counteract DOX-induced cardiotoxicity by activating the YAP/STAT3 pathway, highlighting a potential therapeutic approach for reducing DOX's cardiac side effects.

Single and 7-day handgrip and squat exercise prevents endothelial ischemia-reperfusion injury in individuals with cardiovascular disease risk factors.

Whole body exercise provides protection against endothelial ischemia-reperfusion (IR) injury. In this crossover study, we examined the effects of 1) single bout of local exercise (handgrip, squats) on endothelial responses to IR, and 2) if 7 days of daily local exercise bolsters these effects in individuals with cardiovascular disease (CVD) risk factors. Fifteen participants (9 women, 58 ± 5 yr, ≥2 CVD risk factors) attended the laboratory for six visits. Subsequent to familiarization (visit 1), during visit 2 (control) brachial artery flow-mediated dilation (FMD) was measured before and after IR (15-min upper-arm ischemia, 15-min reperfusion). One week later, participants were randomized to 4 × 5-min unilateral handgrip (50% maximal voluntary contraction, 25 rpm) or squat exercises (15 rpm), followed by IR plus FMD measurements. Subsequently, home-based exercise was performed (6 days), followed by another visit to the laboratory for the IR protocol plus FMD measurements (18-24 h after the last exercise bout). After a 2-wk washout period, procedures were repeated with the alternative exercise mode. For a single exercise bout, we found a significant IR injury × exercise mode interaction (P < 0.01) but no main effect of injury (P = 0.08) or condition (P = 0.61). A lower post-IR FMD was evident after control (pre-IR: 4.3 ± 2.1% to post-IR: 2.9 ± 1.9%, P < 0.01) but not after handgrip (pre-IR: 3.8 ± 1.6% to post-IR: 3.4 ± 1.5%, P = 0.31) or squats (pre-IR: 3.9 ± 1.8% to post-IR: 4.0 ± 1.9%, P = 0.74). After 7 days of daily exercise, we found no change in FMD post-IR following handgrip (pre-IR: 4.3 ± 1.9% to post-IR: 4.7 ± 3.2%) or squats (pre-IR: 3.7 ± 2.1% to post-IR: 4.7 ± 3.0%, P > 0.05). Single bouts of dynamic, local exercise (handgrip, squats) provide remote protection against endothelial IR-induced injury in individuals with CVD risk factors, with 1-wk daily, home-based exercise preserving these effects for up to 24 h following the last exercise bout.NEW & NOTEWORTHY We show that single bouts of dynamic handgrip and squat exercise provide remote protection against endothelial ischemia-reperfusion (IR)-induced injury in individuals with cardiovascular disease (CVD) risk factors, with 1-wk daily, home-based exercise preserving these effects for up to 24 h following the last exercise bout.

Effects of different duration of exercise preconditioning on cerebral blood flow and microglia activation related proteins in rats with vascular dementia / 中国康复医学杂志

Objective:To explore the effects of different duration of exercise preconditioning on changes in cerebral blood flow and microglia activation related proteins in rats with vascular dementia. Method:Sixty SPF SD male rats were used to prepare vascular dementia rat models by permanent ligation of bilateral common carotid arteries.They were randomly divided into the model group,sham-operated group,ex-ercise preconditioning 4-week model group,exercise preconditioning 4-week sham-operated group,exercise pre-conditioning 2-week model group and exercise preconditioning 2-week sham-operated group,with 10 rats in each group.The exercise preconditioning 4-week rats received 30 minutes of moderate intensity non-weight-bear-ing swimming training 5 times a week for 4 weeks before modeling,while the exercise preconditioning 2-week rats received the same training for 2 weeks.Morris water maze was used to detect the spatial learning and memory ability of rats,laser speckle imaging technique was used to observe the changes of cerebral blood flow and the opening of collateral circulation of rats at different time point before and after the model-ing,and Western Blotting was used to detect the expression of TLR4 and Iba 1 protein in hippocampus. Result:Compared with the sham-operated group and the exercise preconditioning 2-week sham-operated group,the average escape latency time of rats in the exercise preconditioning 4-week sham-operated group,the model group,the exercise preconditioning 4-week model group and the exercise preconditioning 2-week model group was significantly prolonged(P＜0.05).Compared with the exercise preconditioning 4-week sham-operated group,the average escape latency time of rats in the model group and the exercise preconditioning 4-week model group was significantly prolonged(P＜0.05).Compared with the model group and exercise preconditioning 4-week model group,the average escape latency time of rats in exercise preconditioning 2-week model group was significantly decreased(P＜0.05).The simple effect of repetitive measurement deviation analysis suggested that the average cerebral blood flow before modeling,2h after modeling,3d after modeling and 7d after model-ing was statistically significant between the groups(P＜0.05).The simple effect of time factor on average cere-bral blood flow of the model group,the exercise preconditioning 4-week model group and the exercise precon-ditioning 2-week model group was statistically significant(P＜0.01).The opening of collateral circulation of rats in each group was observed.Compared with the model group,less reduction in microvessel diameter was ob-served in the exercise preconditioning 2-week model group(P＜0.05).Compared with the sham-operated group,the exercise preconditioning 4-week sham-operated group and the exercise preconditioning 2-week sham-operat-ed group,Ibal and TLR4 protein expressions in the model group were significantly increased(P＜0.01).Com-pared with the model group,Ibal and TLR4 protein expressions in the exercise preconditioning 2-week model group were decreased(P＜0.05). Conclusion:Moderate intensity exercise preconditioning for 2 weeks can improve the learning and memory abili-ty of vascular dementia rats,but exercise preconditioning for 4 weeks has no obvious effect on the improve-ment of learning and memory ability.The mechanism may be related to the improvement of cerebral blood flow status and the inhibition of microglia activation.

Effects of exercise preconditioning on VEGF/VEGFR2/Dock6 signaling pathway in ischemic brain tissue of rats with cerebral ischemia reperfusion injury / 中国康复医学杂志

Objective:To investigate the effect of exercise preconditioning on angiogenesis in ischemic brain tissue in rats with cerebral ischemia-reperfusion injury in the view of VEGF/VEGFR2/dock6 signaling pathway. Method:SD male rats were divided into sham group,model group and exercise preconditioning group by ran-dom number table method,with 18 rats in each group.The sham operation group and the model group were not given any treatment,while the exercise preconditioning group was given adaptive running training for 3 days at a speed of 10 m/min,once a day for 20 minutes each time.After the adaptive training,the exercise preconditioning group was given formal running training for 3 weeks,continuous training for 6 days a week,rest for 1 day,electric treadmill slope of 0°,speed of 15m/min,30min/d.Model group and exercise precondi-tioning group were modified to prepare the middle cerebal artery occlusion(MACO)models by Koizumi thread method,while sham operation group only given skin cutting without thread insertion.Zea longa score and modi-fied neurological severity score(mNSS)were used to score neurological deficit in rats,the relative infarct size of the brain was detected by TTC staining,the morphological changes of the ischemic cerebral cortex was ob-served by HE staining,the expression of CD31 in ischemic cerebral cortex was detected by immunohistochemis-try and the expressions of VEGFA,VEGFR2,Dock6 in ischemic cerebral cortex were detected by western blot. Result:①Zea-Longa scoring:after awaking from anesthetizati,compared with the sham group,the Zea-Longa scores of the other two groups were increased(P＜0.01),and there was no statistical significance in the Zea-Lon-ga scores between the two groups.At 72 hours after reperfusion,compared with the sham group,the Zea-Longa score of the rats in the model group was significantly increased(P＜0.01);compared with the model group,the Zea-Longa score of the rats in the exercise preconditioning group was significantly decreased(P＜0.05).②mNSS scoring:At 72 hours after reperfusion,compared with the sham group,the mNSS score of the rats in the mod-el group was significantly increased(P＜0.01);compared with the model group,the mNSS score of the rats in the exercise preconditioning group was significantly decreased(P＜0.05).③TTC staining:Compared with the sham group,the cerebral infarction volume in the model group was increased(P＜0.01),and compared with the mod-el group,the cerebral infarction volume in the exercise preconditioning group was decreased(P＜0.05).④ HE staining:Compared with the sham group,the model group rats appeared significant pathological changes in the cerebral cortex on the ischemic side.Compared with the model group,the pathological changes of the cerebral cortex on the ischemic side of the rats in the exercise preconditioning group were alleviated.⑤ Immunohisto-chemistry of CD31:Compared with the sham group,the expression of CD31 in the ischemic cerebral cortex of the model group was significantly increased(P＜0.05).The expression of CD31 in the ischemic cerebral cortex of the exercise preconditioning group was further increased(P＜0.05).⑥Western blot of VEGF,VEGFR2 and Dock6:Compared with the sham group,the expressions of VEGF(P＜0.05),VEGFR2(P＜0.05)and Dock6(P＜0.01)in the ischemic cerebral cortex of the model group were significantly increased;compared with the model group,the expressions of VEGF(P＜0.05),VEGFR2(P＜0.05)and Dock6(P＜0.01)in the ischemic cerebral cor-tex of the exercise preconditioning group were further increased. Conclusion:Exercise preconditioning can effectively promote angiogenesis after cerebral ischemia and reduce cerebral ischemia-reperfusion injury,which may be related to the activation of VEGF/VEGFR2/Dock6 signaling pathway.

The effects of exercise preconditioning on angiogenesis and protein expression after cerebral ischemia and reperfusion / 中华物理医学与康复杂志

Objective:To observe any effect of exercise preconditioning on the levels of hypoxia-inducible factor-1α (HIF-1α) and vascular endothelial growth factor (VEGF) in the brain tissue of rats after induced cerebral ischemia and reperfusion, and how it might promote angiogenesis.Methods:Thirty-six male Sprague-Dawley rats were randomly divided into a sham-operation group, a model group and an exercise preconditioning group, each of 12. After adaptive running training for 3 days, the exercise preconditioning group ran daily for 30 minutes at 15m/min for 14 days, while the other two groups did not exercise. Middle cerebral artery occlusion and reperfusion were then induced in the model and exercise preconditioning groups using the modified Zea-Longa suture method. Rats in the sham-operation group were only cut open to expose the right carotid artery. Right after the modeling, and again 24 hours later neurological deficit was evaluated using the Zea-Longa score and modified neurological severity scoring (mNSS). Infarct sizes were measured using 2, 3, 5-triphenyl tetrazolium chloride staining. Any morphological changes were noted using hematoxylin and eosin (HE) staining, and the expression of CD31 protein, hypoxia-inducible factor-1α and vascular endothelial growth factor in the ischemic cerebral cortex were quantified immunohistochemically.Results:Right after the modelling, compared with the sham-operation group, the average Zea-Longa scores of the model and exercise groups had increased significantly, but were not significantly different from each other. Twenty-four hours later the average Zea-Longa score, mNSS score and relative cerebral infarction area of the model group had increased significantly compared with the sham-operation group, while the exercise preconditioning group′s averages had decreased significantly. The HE staining showed that compared with the sham-operation group, pathological changes such as loose tissue, reduced number of nerve cells, nucleolysis, and vacuolization of the cerebral cortex on the ischemic side were found in the model group. Compared with the model group, the pathological changes in the exercise preconditioning group were less serious. The levels of CD31 protein, HIF-1α and VEGF in the ischemic cerebral cortexes of the model group had by then increased significantly. But compared with the model group, those levels had increased more in the exercise preconditioning group.Conclusion:Exercise preconditioning can effectively promote angiogenesis after cerebral ischemia and reduce chronic injury. That may be related to the activation of the HIF-1α and/or VEGF signaling pathways.

Role of endothelial nitric oxide synthase in exercise preconditioning-induced improvement of myocardial ischemia-reperfusion injury / 中国组织工程研究

BACKGROUND:Exercise is an effective strategy to prevent and treat various cardiovascular diseases and protect the heart from ischemia-reperfusion injury.Its mechanism of action needs to be studied in depth. OBJECTIVE:To observe the effect of aerobic exercise preconditioning on myocardial ischemia-reperfusion injury and to explore the effect of endothelial nitric oxide synthase(eNOS)activation(including coupling and phosphorylation). METHODS:Eighty adult Wistar rats were randomly divided into sedentary(n=40)and exercise(n=40)groups.The rats in the exercise group were subjected to aerobic exercise for 8 weeks while those in the sedentary group were quietly fed and caged.After 8 weeks of intervention,three experiments were performed.(1)Experiment 1:After the last training,cardiac function,cardiac nitric oxide metabolite content and cardiac eNOS,phosphorylated eNOS-S1177,eNOS dimer and eNOS monomer protein expression levels were detected.(2)Experiment 2:Rats were divided into sedentary control group,exercise control group,sedentary+eNOS inhibitor group,exercise+eNOS inhibitor group,all of which were subjected to an in vitro myocardial ischemia-reperfusion injury experiment.eNOS inhibitor was continuously infused into the sedentary+eNOS inhibitor group and exercise+eNOS inhibitor group 10 minutes before reperfusion,and cardiac function and myocardial infarction area were detected 3 hours after reperfusion.(3)Experiment 3:Rats were divided into sedentary control group,exercise control group,sedentary+eNOS coupler group and exercise+eNOS coupler group,all of which were subjected to an in vitro myocardial ischemia-reperfusion injury experiment.The rats in the sedentary+eNOS coupler group and exercise+eNOS coupler group were treated with eNOS coupler.Myocardial infarct area,cardiac nitric oxide metabolite content,cardiac protein expression of eNOS,phosphorylated eNOS-S1177,eNOS dimer,eNOS monomer and 3-nitrotyrosine were detected 3 hours after reperfusion.The phosphorylated eNOS-S1177/eNOS ratio reflected the phosphorylated/dephosphorylated level of eNOS and eNOS dimer/monomer ratio reflected eNOS coupling/uncoupling level. RESULTS AND CONCLUSION:Experiment 1:Compared with the sedentary group,the exercise group had increased cardiac output and left ventricular ejection fraction(P<0.05),increased nitrite and S-nitrosothiol contents(P<0.05),upregulated phosphorylated eNOS-S1177,eNOS protein expression and phosphorylated eNOS-S1177/eNOS ratio(P<0.05),eNOS dimer protein expression and eNOS dimer/monomer ratios were elevated(P<0.05).Experiment 2:Compared with the sedentary control group,left ventricular development pressure increased(P<0.05)and myocardial infarct area decreased(P<0.05)in the exercise control group.Compared with the exercise control group,left ventricular development pressure decreased(P<0.05)and myocardial infarct area increased(P<0.05)in the exercise+eNOS inhibitor group.Experiment 3:Compared with the sedentary control group,the exercise control group had increased left ventricular developmental pressure(P<0.05),decreased myocardial infarct area(P<0.05),decreased phosphorylated eNOS-S1177/eNOS ratio(P<0.05),decreased eNOS dimer/monomer ratio(P<0.05),increased S-nitrosothiol content(P<0.05),and decreased 3-nitrotyrosine protein expression(P<0.05).Compared with the exercise control group,the exercise+eNOS coupler group had decreased left ventricular developmental pressure(P<0.05),increased myocardial infarct area(P<0.05),increased phosphorylated eNOS-S1177/eNOS ratio(P<0.05),increased eNOS dimer/monomer ratio(P<0.05),and elevated 3-nitro tyrosine protein expression(P<0.05).To conclude,aerobic exercise preconditioning could induce cardioprotection,which is related to uncoupling and dephosphorylation of eNOS during cardiac ischemia-reperfusion,thereby inhibiting the excessive production of nitric oxide and reducing nitro-oxidative stress.

Aerobic exercise preconditioning improves therapeutic effect of bone marrow mesenchymal stem cells on acute myocardial infarction / 中国组织工程研究

BACKGROUND:Stem cell therapy is an alternative treatment strategy for restoring damaged myocardial tissue after acute myocardial infarction.Exercise preconditioning can induce endogenous cardioprotective effects in the body.However,the efficacy and mechanism of the combined application are still unclear. OBJECTIVE:To explore the effect and possible mechanism of exercise preconditioning combined with bone marrow mesenchymal stem cells on the therapeutic effect in rats with acute myocardial infarction. METHODS:Seventy male SD rats were randomly divided into sham operation group,model group,stem cell therapy group,exercise preconditioning group,and combined intervention group.Rats in the exercise preconditioning group and combined intervention group underwent 8-week aerobic exercise on the treadmill before modeling.The animal model of acute myocardial infarction was made by ligating the anterior descending coronary artery.The stem cell therapy group and the combined intervention group were injected with bone marrow mesenchymal stem cells(1×109 L-1,1 mL)through the tail vein the next day after modeling.After 4 weeks of treatment,the exercise performance was evaluated by a graded treadmill exercise test.The cardiac structure and function were detected by echocardiography.The left ventricle was isolated.2,3,5-Triphenyltetrazolium chloride staining was used to evaluate myocardial infarct size.Masson staining was used to obtain collagen volume fraction.CD31 immunohistochemical staining was used to detect myocardial capillary density.TUNEL staining was used to detect myocardial cell apoptosis.Immunoblotting was used to detect protein expression levels of stromal cell-derived factor 1,CXC chemokine receptor protein 4,tumor necrosis factor-α,interleukin-10,and vascular endothelial growth factor. RESULTS AND CONCLUSION:(1)Intervention efficacy:Compared with the sham operation group,exercise performance,left ventricular ejection fraction,left ventricular fractional shortening,and CD31 positive cell rate decreased(P<0.05);myocardial infarct size,collagen volume fraction,and myocardial apoptotic rate increased(P<0.05)in the model group.Compared with the model group,exercise performance was not statistically significant(P>0.05)in the stem cell therapy group,and the exercise performance improved(P<0.05)in the exercise preconditioning and combined intervention groups;left ventricular ejection fraction,left ventricular fractional shortening,and CD31 positive cell rate increased(P<0.05),and the myocardial infarct size,collagen volume fraction,and cardiomyocyte apoptosis rate decreased(P<0.05)in the stem cell therapy,exercise preconditioning,and combined intervention groups.Compared with the stem cell therapy group,exercise performance,left ventricular ejection fraction,left ventricular shortening fraction,and CD31 positive cell rate increased(P<0.05),myocardial infarct size,collagen volume fraction,and myocardial cell apoptosis rate decreased(P<0.05)in the combined intervention group.(2)Protein expression:Compared with the sham operation group,the expression of tumor necrosis factor-α increased(P<0.05),while interleukin-10 and vascular endothelial growth factor expression decreased(P<0.05)in the model group.Compared with the model group,the expression of CXC chemokine receptor protein 4 increased(P<0.05)in the stem cell therapy group and combined intervention group,and the expression of tumor necrosis factor-α decreased(P<0.05)while interleukin-10 and vascular endothelial growth factor increased(P<0.05)in the stem cell therapy group,exercise preconditioning group,and combined intervention group.Compared with the stem cell therapy group,the expression of tumor necrosis factor-α decreased(P<0.05),while CXC chemokine receptor protein 4,interleukin-10,and vascular endothelial growth factor increased(P<0.05)in the combined intervention group.To conclude,exercise preconditioning can enhance the therapeutic effect of bone marrow mesenchymal stem cells in rats with acute myocardial infarction,which can inhibit cardiac remodeling,improve cardiac function,and delay the progress of heart failure.Its mechanism is related to the promotion of stem cell homing,inhibition of inflammatory response,and promotion of angiogenesis.

Exercise preconditioning promotes myocardial GLUT4 translocation and induces autophagy to alleviate exhaustive exercise-induced myocardial injury in rats.

Exercise preconditioning (EP) is a line of scientific inquiry into the short-term biochemical mediators of cardioprotection in the heart. This study examined the involvement of autophagy induced by energy metabolism in myocardial remodelling by EP and myocardial protection. A total of 120 healthy male Sprague Dawley (SD) rats were randomly divided into six groups. Plasma cTnI, HBFP staining and electrocardiographic indicators were examined in the context of myocardial ischemic/hypoxic injury and protection. Western blotting and fluorescence double labelling were used to investigate the relationship between energy metabolism and autophagy in EP-resistant myocardial injury caused by exhaustive exercise. Compared with those in the C group, the levels of myocardial ischemic/hypoxic injury were significantly increased in the EE group. Compared with those in the EE group, the levels of myocardial ischemic/hypoxic injury were significantly decreased in the EEP + EE and LEP + EE groups. Compared with that in the EE group, the level of GLUT4 in the sarcolemma was significantly increased, and the colocalization of GLUT4 with the sarcolemma was significantly increased in the EEP + EE and LEP + EE groups (P < 0.05). LC3-II and LC3-II/LC3-I levels of the EEP + EE group were significantly elevated compared with those in the EE group (P < 0.05). The levels of p62 were significantly decreased in the EEP + EE and LEP + EE groups compared with the EE group (P < 0.05). EP promotes GLUT4 translocation and induced autophagy to alleviate exhaustive exercise-induced myocardial ischemic/hypoxic injury.

Handgrip exercise in patients scheduled for cardiac surgery to attenuate troponin release: a feasibility study.

Cardiac surgery, including surgical aortic valve repair (SAVR) and coronary artery bypass grafting (CABG), are associated with ischemia-reperfusion (I/R) injury. Single bouts of exercise, including handgrip exercise, may protect against I/R injury. This study explored 1) the feasibility of daily handgrip exercise in the week before SAVR and/or CABG and 2) its impact on cardiac I/R injury, measured as postoperative cardiac troponin-T (cTnT) release. Sixty-five patients undergoing elective SAVR and/or CABG were randomized to handgrip exercise + usual care (intervention, n = 33) or usual care alone (control, n = 32). Handgrip exercise consisted of daily 4 × 5-min handgrip exercise (30% maximal voluntary contraction) for 2-7 days before cardiac surgery. Feasibility was assessed using validated questionnaires. Postoperative cTnT release was assessed at 0, 6, 12, 18, and 24 h [primary outcome area under the curve (cTnTAUC)]. Most patients (93%) adhered to handgrip exercise and 77% was satisfied with this intervention. Handgrip exercise was associated with lower cTnTAUC (402,943 ± 225,206 vs. 473,300 ± 232,682 ng · min/L), which is suggestive of a medium effect size (Cohen's d 0.31), and lower cTnTpeak (313 [190-623] vs. 379 [254-699] ng/L) compared with controls. We found that preoperative handgrip exercise is safe and feasible for patients scheduled for SAVR and/or CABG and is associated with a medium effect size to reduce postoperative cardiac I/R injury. This warrants future studies to assess the potential clinical impact of exercise protocols before cardiac surgery.NEW & NOTEWORTHY Daily handgrip exercise in the week before elective cardiac surgery is safe and feasible. Handgrip exercise is associated with a medium effect size for less troponin-T release. Future larger-sized studies are warranted to explore the impact of (handgrip) exercise prior to cardiac surgery on clinical outcomes and direct patient benefits.

Effects of Exercise Preconditioning on Doxorubicin-Induced Liver and Kidney Toxicity in Male and Female Rats.

Doxorubicin (DOX) is a highly effective chemotherapy agent prescribed for cancer treatment. However, the clinical use of DOX is limited due to off-target toxicity in healthy tissues. In this regard, hepatic and renal metabolic clearance results in DOX accumulation within these organ systems. Within the liver and kidneys, DOX causes inflammation and oxidative stress, which promotes cytotoxic cellular signaling. While there is currently no standard of care to treat DOX hepatic- and nephrotoxicity, endurance exercise preconditioning may be an effective intervention to prevent elevations in liver alanine transaminase (ALT) and aspartate aminotransferase (AST) and to improve kidney creatinine clearance. To determine whether exercise preconditioning is sufficient to reduce liver and kidney toxicity resulting from acute exposure to DOX chemotherapy treatment, male and female Sprague-Dawley rats remained sedentary or were exercise trained prior to saline or DOX exposure. Our findings demonstrate that DOX treatment elevated AST and AST/ALT in male rats, with no effects of exercise preconditioning to prevent these increases. We also showed increased plasma markers of renin-angiotensin-aldosterone system (RAAS) activation and urine markers of proteinuria and proximal tubule damage, with male rats revealing greater differences compared to females. Exercise preconditioning showed improved urine creatinine clearance and reduced cystatin c in males, while females had reduced plasma angiotensin II (AngII) levels. Our results demonstrate both tissue- and sex-specific responses related to the effects of exercise preconditioning and DOX treatment on markers of liver and kidney toxicity.

Exercise preconditioning attenuates cerebral ischemia-induced neuronal apoptosis, Th17/Treg imbalance, and inflammation in rats by inhibiting the JAK2/STAT3 pathway.

BACKGROUND: Exercise preconditioning (EP) is essential for preventing ischemic stroke. Recent studies have shown that EP exerts neuroprotective effects in the cerebral ischemia-reperfusion injury model. Nonetheless, there have been few reports on the relationship between EP and the Th17/Treg balance. Moreover, it is unclear whether the JAK2/STAT3 pathway is responsible for the neuroprotective effect of EP. Therefore, we aimed to explore the impact of EP, other than the anti-inflammatory and antiapoptotic functions, on the Th17/Treg balance via the JAK2/STAT3 pathway in a middle cerebral artery occlusion (MCAO)-induced model. RESULTS: Fifty rats were randomly allocated into five groups, including the sham group (n = 10), EP+sham group (n = 10), MCAO group (n = 10), EP+MCAO group (n = 10), and EP+MCAO+JAK2/STAT3 pathway agonist (coumermycin A1, CA1) group (n = 10). The results indicated that EP alleviated neurological deficits, reduced infarct volume, and ameliorated neuronal apoptosis induced by MCAO. Additionally, the MCAO-induced Th17/Treg imbalance could be rectified by EP. The decreased levels of IL-10 and Foxp3 and increased IL-17 and RORα in the MCAO group were reversed by EP treatment. Regarding inflammation, EP reduced the concentrations of IL-6 and IL-17 and elevated those of IL-10 and TGF-ß. The neuroprotective effects of EP were accompanied by decreased phosphorylation of JAK2 and STAT3. Furthermore, CA1 pretreatment diminished all the beneficial effects of EP partially. CONCLUSION: Our findings suggest that EP contributes to attenuating neuronal apoptosis, Th17/Treg imbalance, and inflammation induced by MCAO via inhibiting the JAK2/STAT3 pathway, indicating its therapeutic potential in ischemic stroke.

Alleviation of ischemic brain injury by exercise preconditioning is associated with modulation of autophagy and mitochondrial dynamics in cerebral cortex of female aged mice.

Evidence from clinical studies and preclinical studies supports that exercise preconditioning can not only reduce the risk of stroke but also improve brain tissue and functional outcome after stroke. It has been demonstrated that autophagy and mitochondrial dynamics are involved in ischemic stroke. However, it is still unclear whether exercise preconditioning-induced neuroprotection against stroke is associated with modulation of autophagy and mitochondrial dynamics. Although age and sex interactively affect ischemic stroke risk, incidence, and outcome, studies based on young male animals are most often used to explore the role of exercise preconditioning in the prevention of ischemic stroke. In the current study, we examined whether exercise preconditioning could modulate autophagy and mitochondrial dynamics in a brain ischemia and reperfusion (I/R) model of female aged mice. The results showed that exercise preconditioning reduced infarct volume and improved neurological deficits. Additionally, increased levels of autophagy-related proteins LC3-II/LC3-I, LC3-II, p62, Atg7, and mitophagy-related proteins Bnip3L and Parkin, as well as increased levels of mitochondrial fusion modulator Mfn2 and mitochondrial fission modulator Drp1 in the ischemic cortex of female aged mice at 12 h after I/R were present. Our results could contribute to a better understanding of exercise preconditioning-induced neuroprotection against ischemic stroke for the elderly.

Impact of handgrip exercise and ischemic preconditioning on local and remote protection against endothelial reperfusion injury in young men.

Ischemic preconditioning (IPC), cyclical bouts of nonlethal ischemia, provides immediate protection against ischemic injury, which is evident both locally and remotely. Given the similarities in protective effects of exercise with ischemic preconditioning, we examined whether handgrip exercise also offers protection against endothelial ischemia-reperfusion (IR) injury and whether this protection is equally present in the local (exercised) and remote (contralateral, nonexercised) arm. Fifteen healthy males (age, 24 ± 3 yr; body mass index, 25 ± 2 kg/m2) attended the laboratory on three occasions. Bilateral brachial artery flow-mediated dilation (FMD) was examined at rest and after a temporary IR injury in the upper arm. Before the IR injury, in the dominant (local) arm, participants performed (randomized, counterbalanced): 1) 4 × 5 min unilateral handgrip exercise (50% maximal voluntary contraction), 2) 4 × 5 min unilateral IPC (220 mmHg), or 3) 4 × 5 min rest (control). Data were analyzed using repeated-measures general linear models. Allometrically scaled FMD declined after IR in the control condition (4.6 ± 1.3% to 2.2 ± 1.7%, P < 0.001), as well as following handgrip exercise (4.6 ± 1.6% to 3.4 ± 1.9%, P = 0.01), however, was significantly attenuated with IPC (4.5 ± 1.4% to 3.8 ± 3.5%, P = 0.14). There were no differences between the local and remote arm. Our findings reinforce the established protective effects of IPC in young, healthy males and also highlight a novel strategy to protect against IR injury with handgrip exercise, which warrants further study.

Effects of Exercise Preconditioning on the Inflammatory Response of Rats after Ischemic Stroke through Exosome-mediated miR-146a / 中国运动医学杂志

Objective To explore the effect of exercise preconditioning on inflammatory response in ischemic stroke brain tissue which mediated by miR-146a in extracellular vesicles in rats with middle cerebral artery oc-clusion(MCAO),and its mechanism.Methods Sixty 6-week-old male Sprague-Dawley rats were randomly divid-ed into a non-exercise group and an exercise group.The non-exercise group was further divided into a sham-operation control group(C,n=15)and an MCAO model group(M,n=15),while the exercise group was further di-vided into an exercise only group(E,n=15)and an exercise plus MCAO model group(EM,n=15).Rats in the E and EM groups underwent 8 weeks of treadmill exercise,6 days per week,30 minutes per day.Then rats in the M and EM groups received MCAO to induce ischemic stroke,while the C and E groups underwent a sham surgery.Twenty-four hours after the surgery,neurobehavioral tests were performed.Plasma was collected to ex-tract extracellular vesicles,and brain tissue was collected to measure the volume of cerebral infarction by using the triphenyl tetrazolium chloride(TTC)staining.Moreover,the Nissl staining was conducted to observe neuronal and Nissl body.Mean while,the content of miR-146a in plasma extracellular vesicles and brain tissue was mea-sured by using the quantitative polymerase chain reaction(qPCR),and the expression of TNF receptor associat-ed factor 6(TRAF6),nuclear factor kappa-B(NF-κB)and tumor necrosis factor-α(TNF-α)in brain tissues were determined using Western blotting.The targeting relationship between miR-146a and TRAF6 was detected by using the dual luciferase reporter gene assay.Results(1)The neurological behavioral scores of the EM and M groups were higher than those of the C group(P<0.01 and P<0.01),with that of the EM group lower than the M group(P<0.01).(2)TTC staining showed that the infarct volume of the EM and M groups was larger than that of the other two groups(P<0.01 and P<0.01),with that of the EM group smaller than the M group(P<0.01).(3)Nissl staining results showed that the neuronal arrangement was loose,the number of neurons re-duced,and the Nissl bodies were lightly stained and decreased in the M group compared with the C and E groups.Moreover,compared with the M group,the number of neurons and Nissl bodies increased in the EM group.(4)The qPCR analysis showed that the expression of miR-146a in the plasma-derived exosomes and brain tissues of the EM and M groups decreased compared with the C group(P<0.05 and P<0.01),with that of the EM group higher than the M group(P<0.05).(5)According to Western blotting,compared with the C group,the expression levels of TRAF6,NF-κB,and TNF-α proteins increased significantly(P<0.05 and P<0.01),with that of group EM signfiicantly lower than group M(P<0.05 and P<0.05).(6)Dual-luciferase report-er gene assay showed that miR-146a had a specific binding site with TRAF6.Conclusion Eight weeks of exer-cise preconditioning reduces the infarct area and the extent of brain damage,which may be mediated by miR-146a via exosomes,increasing the expression of miR-146a in brain tissue,targeting TRAF6,negatively regulat-ing TRAF6/NF-κB,and reducing the expression of TNF-α,thus alleviating the inflammatory response in brain tissue and exerting a protective effect on ischemic brain injury.

Physical activity, cardiorespiratory fitness, and cardiovascular health: A clinical practice statement of the ASPC Part I: Bioenergetics, contemporary physical activity recommendations, benefits, risks, extreme exercise regimens, potential maladaptations.

Regular moderate-to-vigorous physical activity (PA) and increased levels of cardiorespiratory fitness (CRF) or aerobic capacity are widely promoted as cardioprotective measures in the primary and secondary prevention of atherosclerotic cardiovascular (CV) disease (CVD). Nevertheless, physical inactivity and sedentary behaviors remain a worldwide concern. The continuing coronavirus (COVID-19) pandemic has been especially devastating to patients with known or occult CVD since sitting time and recreational PA have been reported to increase and decrease by 28% and 33%, respectively. Herein, in this first of a 2-part series, we discuss foundational factors in exercise programming, with specific reference to energy metabolism, contemporary PA recommendations, the dose-response relationship of exercise as medicine, the benefits of regular exercise training, including the exercise preconditioning cardioprotective phenotype, as well as the CV risks of PA. Finally, we discuss the 'extreme exercise hypothesis,' specifically the potential maladaptations resulting from high-volume, high-intensity training programs, including accelerated coronary artery calcification and incident atrial fibrillation. The latter is commonly depicted by a reverse J-shaped or U-shaped curve. On the other hand, longevity data argue against this relationship, as elite endurance athletes live 3-6 years longer than the general population.

Compositions and Functions of Mitochondria-Associated Endoplasmic Reticulum Membranes and Their Contribution to Cardioprotection by Exercise Preconditioning.

Mitochondria-associated endoplasmic reticulum membranes (MAMs) are important components of intracellular signaling and contribute to the regulation of intracellular Ca2+/lipid homeostasis, mitochondrial dynamics, autophagy/mitophagy, apoptosis, and inflammation. Multiple studies have shown that proteins located on MAMs mediate cardioprotection. Exercise preconditioning (EP) has been shown to protect the myocardium from adverse stimuli, but these mechanisms are still being explored. Recently, a growing body of evidence points to MAMs, suggesting that exercise or EP may be involved in cardioprotection by modulating proteins on MAMs and subsequently affecting MAMs. In this review, we summarize the latest findings on MAMs, analyzing the structure and function of MAMs and the role of MAM-related proteins in cardioprotection. We focused on the possible mechanisms by which exercise or EP can modulate the involvement of MAMs in cardioprotection. We found that EP may affect MAMs by regulating changes in MFN2, MFN1, AMPK, FUNDC1, BECN1, VDAC1, GRP75, IP3R, CYPD, GSK3ß, AKT, NLRP3, GRP78, and LC3, thus playing a cardioprotective role. We also provided direction for future studies that may be of interest so that more in-depth studies can be conducted to elucidate the relationship between EP and cardioprotection.

Insight Into the Mechanism of Exercise Preconditioning in Ischemic Stroke.

Exercise preconditioning has attracted extensive attention to induce endogenous neuroprotection and has become the hotspot in neurotherapy. The training exercise is given multiple times before cerebral ischemia, effectively inducing ischemic tolerance and alleviating secondary brain damage post-stroke. Compared with other preconditioning methods, the main advantages of exercise include easy clinical operation and being readily accepted by patients. However, the specific mechanism behind exercise preconditioning to ameliorate brain injury is complex. It involves multi-pathway and multi-target regulation, including regulation of inflammatory response, oxidative stress, apoptosis inhibition, and neurogenesis promotion. The current review summarizes the recent studies on the mechanism of neuroprotection induced by exercise, providing the theoretical basis of applying exercise therapy to prevent and treat ischemic stroke. In addition, we highlight the various limitations and future challenges of translational medicine from fundamental study to clinical application.