Aerobic exercise alleviates skeletal muscle aging in male rats by inhibiting apoptosis via regulation of the Trx system.

Skeletal muscle aging in rats is a reduction in skeletal muscle mass caused by a decrease in the number or volume of skeletal muscle myofibers. Apoptosis has been recognized to play a key role in accelerating the process of skeletal muscle aging in rats. The thioredoxin (Trx) system is a widely expressed oxidoreductase system that controls the cellular reduction/oxidation state and has both potent anti-free radical damage and important pro-growth and apoptosis inhibitory functions. Previous studies have shown that exercise delays skeletal muscle aging. However, it is unclear whether exercise attenuates skeletal muscle aging via the Trx system. Therefore, the present study used the Trx system as an entry point to explore the effect of aerobic exercise to improve skeletal muscle aging in rats and its possible mechanisms, and to provide a theoretical basis for exercise to delay skeletal muscle aging in rats. It was shown that aerobic exercise in senescent rats resulted in increased gastrocnemius index, decreased body weight, increased endurance, decreased skeletal muscle cell apoptosis, increased activity and protein expression of the Trx system, and decreased expression of p38 and ASK1. Based on these findings, we conclude that 10 weeks of aerobic exercise may enhance the anti-apoptotic effect of Trx by up-regulating Trx and Trx reductase (TR) protein expression, which in turn increases Trx activity in rat skeletal muscle, and ultimately alleviates apoptosis in senescent skeletal muscle cells.

Endoplasmic reticulum stress mechanisms and exercise intervention in type 2 diabetes mellitus.

Type 2 diabetes mellitus (T2DM) is a metabolic disease primarily characterized by insulin resistance (IR) and insufficient insulin secretion. The unfolded protein response (UPR) overactivation induced by endoplasmic reticulum stress (ERS) appears to play a key role in this process, although the exact pathogenesis of T2DM is not fully understood. Studies have demonstrated that appropriate exercise can regulate ERS in the heart, liver, pancreas, skeletal muscle, and other body tissues leading to an improvement in diabetes and its complications. However, the exact mechanism remains unclear. By analyzing the relationship between ERS, T2DM pathology, and exercise intervention, this review concludes that exercise can increase insulin sensitivity, inhibit IR, promote insulin secretion and alleviate T2DM by regulating ERS. This paper specifically reviews the signaling pathways by which ERS induces diabetes, the mechanisms of exercise regulation of ERS in diabetes, and the varying effects of different types of exercise on diabetes improvement through ERS mechanisms. Physical exercise is an effective non-pharmacological intervention for T2DM. Thus, further exploration of how exercise regulates ERS in diabetes could refine "precision exercise medicine" for diabetes and identify new drug targets.

Resistance exercise upregulates Irisin expression and suppresses myocardial fibrosis following myocardial infarction via activating AMPK-Sirt1 and inactivating TGFß1-Smad2/3.

AIM: To reveal the contribution of Irisin in the beneficial effects of resistance exercise on myocardial fibrosis (MF) and cardiac function in the mice with myocardial infarction (MI). METHODS: The MI model was built by ligating the left anterior descending coronary artery in Fndc5 knockout mice (Fndc5-/-). Resistance exercise was started one week after surgery and continued for four weeks. In addition, H2O2, AICAR, recombinant human Irisin protein (rhIRISIN), and Sirt1 shRNA lentivirus (LV-Sirt1 shRNA) were used to intervene primary isolated cardiac fibroblasts (CFs). MF was observed through Masson staining, and apoptosis was assessed using TUNEL staining. MDA and T-SOD contents were detected by biochemical kits. The expression of proteins and genes was detected by Western blotting and RT-qPCR. RESULTS: Resistance exercise increased Fndc5 mRNA level, inhibited the activation of TGFß1-TGFßR2-Smad2/3 pathway, activated AMPK-Sirt1 pathway, reduced the levels of oxidative stress, apoptosis, and MF in the infarcted heart, and promoted cardiac function. However, Fndc5 knockout attenuated the protective effects of resistance exercise on the MI heart. Results of the in vitro experiments showed that AICAR and rhIRISIN intervention activated the AMPK-Sirt1 pathway and inactivated the TGFß1-Smad2/3 pathway, and promoted apoptosis in H2O2-treated CFs. Notably, these effects of rhIRISIN intervention, except for the TGFßR2 expression, were attenuated by LV-Sirt1 shRNA. CONCLUSION: Resistance exercise upregulates Fndc5 expression, activates AMPK-Sirt1 pathway, inhibits the activation of TGFß1-Smad2/3 pathway, attenuates MF, and promotes cardiac function after MI.

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.

Irisin and ALCAT1 mediated aerobic exercise-alleviated oxidative stress and apoptosis in skeletal muscle of mice with myocardial infarction.

Skeletal muscle in patients with heart failure (HF) exhibits altered structure, function and metabolism. Myocardial infarction (MI) is the most common cause of HF. Oxidative stress and cell apoptosis are involved in the pathophysiology of MI/HF-induced skeletal muscle atrophy. It is well recognized that aerobic exercise (AE) could prevent skeletal muscle atrophy after MI, but the underlying mechanism and molecular targets are still not fully clarified. In this study, Fndc5-/- and Alcat1-/- mice were used to establish the MI model and subjected to six weeks of moderate-intensity AE. C2C12 cells were treated with H2O2 and recombinant human Irisin (rhIrisin), or transduced with a lentiviral vector to mediate the overexpression of ALCAT1 (LV-Alcat1). Results showed that MI reduced Irisin expression and antioxidant capacity of skeletal muscle, increased ALCAT1 expression, induced protein degradation and cell apoptosis, which were partly reversed by AE; Knockout of Fndc5 further aggravated MI-induced oxidative stress and cell apoptosis in skeletal muscle, and partly weakened the beneficial effects of AE. In contrast, knockout of Alcat1 reduced MI-induced oxidative stress and cell apoptosis and strengthened the beneficial effects of AE. rhIrisin and AICAR intervention inhibited ALCAT1 expression, oxidative stress and cell apoptosis, which induced by H2O2 or LV-Alcat1 in C2C12 cells. These findings reveal that AE could alleviate the levels of oxidative stress and apoptosis in skeletal muscle following MI, partly via up-regulating Irisin and inhibiting ALCAT1 expression.

Effects of Moderate-Intensity Continuous Training and High-Intensity Interval Training on Testicular Oxidative Stress, Apoptosis and m6A Methylation in Obese Male Mice.

Exercise is an effective way to improve reproductive function in obese males. Oxidative stress and apoptosis are important pathological factors of obesity-related male infertility. Accumulating studies have demonstrated that N6-methyladenosine (m6A) methylation is associated with obesity and testicular reproductive function. Our study aimed to investigate and compare the effect of 8 weeks of moderate-intensity continuous training (MICT) and high-intensity interval training (HIIT) on testicular oxidative stress, apoptosis and m6A methylation in obese male mice. Male C57BL/6 mice were randomly allocated into the four groups: normal diet (ND) group, high-fat diet (HFD) group, high-fat diet with moderate-intensity continuous training (HFD-MICT) group and high-fat diet with high-intensity interval training (HFD-HIIT) group. Mice in the HFD-MICT and HFD-HIIT groups were subjected to 8 weeks of MICT or HIIT treadmill protocols after 12 weeks of HFD feeding. We found that MICT and HIIT increased the protein expression of Nrf2, HO-1 and NQO-1 in the testes of obese mice, and HIIT increased it more than MICT. The Bax/Bcl-2 ratio, Cleaved Caspase-3 protein expression and TUNEL-positive cells were consistently up-regulated in the testes of obese mice, but MICT and HIIT restrained these HFD-induced effects. In addition, HFDs increased m6A levels and the gene expression of METTL3, YTHDF2 and FTO in the testes, but these effects were reversed by MICT and HIIT. However, HIIT was more effective than MICT in reducing m6A methylation in the testes of obese mice. These results demonstrate that both MICT and HIIT protected against HFD-induced oxidative stress, apoptosis and m6A methylation in testicular tissues; as a result, testicular morphological and functional impairment improved. In particular, HIIT was more beneficial than MICT in increasing the mRNA expression of steroidogenic enzymes and testicular antioxidant capacity and decreasing m6A methylation in the testes of HFD-fed mice.

Emerging Roles and Mechanism of m6A Methylation in Cardiometabolic Diseases.

Cardiometabolic diseases (CMDs) are currently the leading cause of death and disability worldwide, and their underlying regulatory mechanisms remain largely unknown. N6-methyladenosine (m6A) methylation, the most common and abundant epigenetic modification of eukaryotic mRNA, is regulated by m6A methyltransferase, demethylase, and the m6A binding protein, which affect the transcription, cleavage, translation, and degradation of target mRNA. m6A methylation plays a vital role in the physiological and pathological processes of CMDs. In this review, we summarize the role played by m6A methylation in CMDs, including obesity, hypertension, pulmonary hypertension, ischemic heart disease, myocardial hypertrophy, heart failure, and atherosclerosis. We also describe mechanisms that potentially involve the participation of m6A methylation, such as those driving calcium homeostasis, circadian rhythm, lipid metabolism, autophagy, macrophage response, and inflammation. m6A methylation and its regulators are expected to be targets for the treatment of CMDs.

Intermittent Fasting Improves High-Fat Diet-Induced Obesity Cardiomyopathy via Alleviating Lipid Deposition and Apoptosis and Decreasing m6A Methylation in the Heart.

Intermittent fasting (IF) plays an essential role in improving lipid metabolism disorders caused by metabolic cardiomyopathy. Growing evidence revealed that N6-methyladenosine (m6A) RNA methylation is related to obesity and lipid metabolic. Our study aimed to assess the beneficial effects of IF on lipid deposition, apoptosis, and m6A methylation in high-fat diet (HFD)-induced obesity cardiomyopathy. Male C57BL/6J mice were fed a normal diet (ND) or HFD ad libitum for 13 weeks, after which time a subgroup of HFD mice were subjected to IF for 24 h and fed HFD in the other day for 8 weeks. We found that IF intervention significantly improved cardiac functional and structural impairment and serum lipid metabolic disorder induced by HFD. Furthermore, IF intervention decreased the mRNA levels of the fatty acid uptake genes of FABP1, FATP1, and CD36 and the fatty acid synthesis genes of SREBF1, FAS, and ACCα and increased the mRNA levels of the fatty acid catabolism genes of ATGL, HSL, LAL, and LPL in cardiac tissueof HFD-induced obese mice. TUNEL-positive cells, Bax/Bcl-2 ratio, and Cleaved Caspase-3 protein expression in HFD-induced obese mice hearts was down-regulated by IF intervention. In addition, IF intervention decreased the m6A methylation levels and METTL3 expression and increased FTO expression in HFD-induced obesity cardiomyopathy. In conclusion, our findings demonstrate that IF attenuated cardiac lipid deposition and apoptosis, as well as improved cardiac functional and structural impairment in HFD-induced obesity cardiomyopathy, by a mechanism associated with decreased m6A RNA methylation levels.

Effect of Different Exercise Methods on Non-Alcoholic Fatty Liver Disease: A Meta-Analysis and Meta-Regression.

Exercise could alleviate non-alcoholic fatty liver disease (NAFLD), but it was not clear which exercise methods could effectively treat NAFLD. The purpose of this systematic review and meta-analysis was to evaluate the effects of different exercise patterns on eight indicators in patients with NAFLD. We searched PubMed, Scopus, Web of Science, China National Knowledge Infrastructure, and the Wanfang Data from its inception to 30 June 2020. This review includes all randomized controlled trials (RCT) that assessed and compared the effects of different exercise on eight indicator parameters in patients with NAFLD. The results indicate that aerobic exercises could significantly improve the eight indicators in patients with NAFLD including triglycerides (TG, weighted mean difference (WMD) = -0.53, 95%CI: -0.68~-0.39, Z = 7.37, p < 0.01), total cholesterol (TC, WMD = -0.39, 95%CI: -0.55~-0.23, Z = 4.76, p < 0.01), low density lipoprotein (LDL, WMD = -0.47, 95%CI: -0.68~-0.26, Z = 4.33, p < 0.01), high density lipoprotein (HDL, WMD = 0.12, 95%CI: 0.05~0.18, Z = 3.56, p < 0.01), alanine aminotransferase (ALT, WMD = -6.14, 95%CI: -10.99~-1.29, Z = 2.48, p < 0.05), aspartate aminotransferase (AST, WMD = -5.73, 95%CI: -9.08~-2.38, Z = 3.36, p < 0.01), and body mass index (BMI, WMD = -0.85, 95%CI: -1.19~-0.51, Z = 4.92, p < 0.01). Resistance exercises could significantly reduce the levels of TG (WMD = -0.56, 95%CI: -0.85~-0.28, Z = 3.86, p < 0.01) and AST (WMD = -2.58, 95%CI: -4.79~-0.36, Z = 2.28, p < 0.05) in the patients. High-intensity interval training could significantly improve the level of ALT (WMD = -6.20, 95%CI: -9.34~-3.06, Z = 3.87, p < 0.01) in patients with NAFLD. These three exercise methods had different effects on the eight indexes of NAFLD in our present meta-analysis, providing some reference for the establishment of exercise prescription for patients with NAFLD.

Aerobic exercise alleviates oxidative stress-induced apoptosis in kidneys of myocardial infarction mice by inhibiting ALCAT1 and activating FNDC5/Irisin signaling pathway.

Aerobic exercise involves in ameliorating kidney injury, but the underlying mechanisms are not fully clarified. In this study, we elucidated the potential mechanisms of aerobic exercise in ameliorating kidney injury following myocardial infarction (MI). In vivo, wildtype and alcat1 knockout mice were used to establish the MI model, and subjected to six-week moderate-intensity aerobic exercise. In vitro, Normal Rat Kidney (NRK) cells treated with H2O2 and recombinant human Irisin (rhIrisin) were used for exploring potential mechanisms. Our results showed that Irisin expression was up-regulated by aerobic exercise in kidneys after MI, while ALCAT1 was reduced. In alcat1 knockout mice, we found that ALCAT1 involved in the progressions of oxidative stress and apoptosis in impaired kidney tissues of MI mice, but aerobic exercise reversed these changes. Furthermore, in vitro, we observed that Irisin inhibited both H2O2-treatment or overexpression of alcat1-induced oxidative stress and apoptosis in NRK cells, partially via AMPK-Sirt1-PGC-1α pathway. These findings reveal that aerobic exercise participates in alleviating the levels of oxidative stress and apoptosis in impaired kidney tissues following MI, partially via activating FNDC5/Irisin-AMPK-Sirt1-PGC-1α signaling pathway and inhibiting ALCAT1 expression.

Up-regulation of Thioredoxin 1 by aerobic exercise training attenuates endoplasmic reticulum stress and cardiomyocyte apoptosis following myocardial infarction.

Exercise training (ET) has been reported to reduce oxidative stress and endoplasmic reticulum (ER) stress in the heart following myocardial infarction (MI). Thioredoxin 1 (Trx1) plays a protective role in the infarcted heart. However, whether Trx1 regulates ER stress of the infarcted heart and participates in ET-induced cardiac protective effects are still not well known. In this work, H9c2 cells were treated with hydrogen peroxide (H2O2) and recombinant human Trx1 protein (TXN), meanwhile, adult male C57B6L mice were used to establish the MI model, and subjected to a six-week aerobic exercise training (AET) with or without the injection of Trx1 inhibitor, PX-12. Results showed that H2O2 significantly increased reactive oxygen species (ROS) level and the expression of TXNIP, CHOP and cleaved caspase12, induced cell apoptosis; TXN intervention reduced ROS level and the expression of CHOP and cleaved caspase12, and inhibited cell apoptosis in H2O2-treated H9c2 cells. Furthermore, AET up-regulated endogenous Trx1 protein expression and down-regulated TXNIP expression, restored ROS level and the expression of ER stress-related proteins, inhibited cell apoptosis as well as improved cardiac fibrosis and heart function in mice after MI. PX-12 partly inhibited the AET-induced beneficial effects in the infarcted heart. This study demonstrates that Trx1 attenuates ER stress-induced cell apoptosis, and AET reduces MI-induced ROS overproduction, ER stress and cell apoptosis partly through up-regulating of Trx1 expression in mice with MI.

Effect of proximal contact strength on the three-dimensional displacements of implant-supported cantilever fixed partial dentures under axial loading.

OBJECTIVE: This study investigated the effect of proximal contact strength on the three-dimensional displacements of cantilever fixed partial denture (CFPD) under vertically concentrated loading with digital laser speckle (DLS) technique. METHODS: Fresh mandible of beagle dog was used to establish the implant-supported CFPD for specimen. DLS technique was employed for measuring the three-dimensional displacement of the prosthesis under vertically concentrated loading ranging from 200 to 3000 g. The effect of the contact tightness on the displacement of CFPD was investigated by means of changing the contact tightness. RESULTS: When an axial concentrated loading was exerted on the pontic of the implant-supported CFPD, the displacement of the CFPD was the greatest. The displacement of the prosthesis decreased with the increase of contact strength. When the contact strength was 0, 0.95, and 3.25 N, the displacement of the buccolingual direction was smaller than that of the mesiodistal direction but greater than that of the occlusogingival direction. When the force on the contact area was 6.50 N, the mesiodistal displacement of the prosthesis was the biggest while the buccolingual displacement was the smallest. CONCLUSIONS: The implant-supported CFPD is an effective therapy for fully or partially edentulous patients. The restoration of the contact area and the selection of the appropriate contact strength can reduce the displacement of the CFPD, and get a better stress distribution. The most appropriate force value is 3.25 N in this study.

[Measuring three-dimensional displacement of tooth-supported rigid fixed bridge under oblique concentrated loading using digital laser speckle photography].

OBJECTIVE: To measure three-dimensional displacements of rigid fixed bridge under oblique concentrated loading and to analyze the effect of displacement on the stability of abutment teeth. METHODS: Right mandible of Beagle dog was used to establish the tooth-supported rigid fixed bridge. Digital laser speckle photography was employed to measure the three-dimensional displacements of the prosthesis under oblique concentrated loading ranging from 200 g to 3000 g. RESULTS: The displacements of prosthesis increased as the load increased. When the load was on the abutment, the buccolingual displacement of the abutment under loading was the biggest but no more than 100 microm. This was followed by mesiodistal and occlusallingual displacements. With slighter loadings, the buccolingual displacements of non-loaded abutment were greater than the mesiodistal displacements. However, as the loading increased greater mesiodistal displacements on non-loaded abutment were found compared to buccolingual displacements. When the bridge was loaded, the biggest displacements of the prosthesis were always shown on the buccolingual direction, followed by the mesiodistal direction and the occlusallingual direction. The displacements with loaded bridge were smaller than those when the load was applied on abutment. CONCLUSION: The displacements of rigid fixed bridge change with different loading positions. This has implications on the design of prosthesis. Lateral force should be minimized and early occlusion contact should be avoided, especially on the feeble abutment. This study has developed a new method for measuring bit shift of teeth.

[Study on the digital laser speckle technique of three-dimensional displacement of cantilever fixed partial denture under oblique loading].

The purpose of this study was to investigate the three-dimensional displacement of the cantilever fixed partial denture (CFPD) under an oblique loading. One Beagle dog was used in this experiment. The CFPD, which used the second premolar and the first molar as abutments and the second molar as pontic, was made in vitro fresh mandible of the Beagle dog, and the digital laser speckle (DLS) technique was employed to measure the three-dimensional displacement of the CFPD under the oblique loading for the first time. We found that when an oblique loading was exerted on the pontic, the displacement of CFPD was the greatest, and the displacement of the abutment near the pontic was smaller than that of the pontic but greater than that of the abutment far from the pontic. We also found that when an oblique loading was exerted on the abutment, the displacement of the directly loaded abutment was greater than that of the other abutment and the pontic. Under the oblique loading, the displacement increased with increasing of load. The experiment demonstrated that it would be advisable for the clinicians to avoid oblique loading, especially the oblique loading of the pontic when using the CPDF. The DLS technique may be one kind of methods for measuring the three-dimensional displacements of the small and irregular objects.

[Analysis of the effect of contact strength on three-dimensional displacement of an implant-supported fixed bridge under axial-concentrated load using digital laser speckle photography].

The purpose of this study was to investigate the effect of four kinds of different contact strength on the three-dimensional displacement of an implant-supported fixed bridge using digital laser speckle photography method. An in vitro model of beagle mandible with an implant-supported fixed bridge in its right premolar region was developed. The bridge was Au-Pt metal-ceramic. The contact was recovered to four different tightnesses, named 0, 1, 2, and 3. Different axial concentrated static load was applied to abutments and bridge respectively. The three-dimensional displacement of the implant-supported fixed bridge was measured using digital laser speckle photographic method. The results demonstrated that the influence of contact tightness was mainly on the mesio-distal and buccal lingual parts. When the contact tightness reached number 3, the regularity of displacement distribution was changed. The present study proved that digital laser speckle photography was an effective method of measuring the micro-displacement. One of the criterions of contact recovering decreased the implant displacement effectively without changing the regularity of displacement distribution.