Decreased SIRT3 in aged human mesenchymal stromal/stem cells increases cellular susceptibility to oxidative stress

Sirtuin3 (SIRT3) is an important member of the sirtuin family of protein deacetylases that is localized to mitochondria and linked to lifespan extension in organisms ranging from yeast to humans. As aged cells have less regenerative capacity and are more susceptible to oxidative stress, we investigated the effect of ageing on SIRT3 levels and its correlation with antioxidant enzyme activities. Here, we show that severe oxidative stress reduces SIRT3 levels in young human mesenchymal stromal/stem cells (hMSCs). Overexpression of SIRT3 improved hMSCs resistance to the detrimental effects of oxidative stress. By activating manganese superoxide dismutase (MnSOD) and catalase (CAT), SIRT3 protects hMSCs from apoptosis under stress. SIRT3 expression, levels of MnSOD and CAT, as well as cell survival showed little difference in old versus young hMSCs under normal growth conditions, whereas older cells had a significantly reduced capacity to withstand oxidative stress compared to their younger counterparts. Expression of the short 28 kD SIRT3 isoform was higher, while the long 44 kD isoform expression was lower in young myocardial tissues compared with older ones. These results suggest that the active short isoform of SIRT3 protects hMSCs from oxidative injury by increasing the expression and activity of antioxidant enzymes. The expression of this short isoform decreases in cardiac tissue during ageing, leading to a reduced capacity for the heart to withstand oxidative stress.     

Alterations in mitochondrial dynamics with age‐related Sirtuin1/Sirtuin3 deficiency impair cardiomyocyte contractility

Sirtuin1 (SIRT1) and Sirtuin3 (SIRT3) protects cardiac function against ischemia/reperfusion (I/R) injury. Mitochondria are critical in response to myocardial I/R injury as disturbance of mitochondrial dynamics contributes to cardiac dysfunction. It is hypothesized that SIRT1 and SIRT3 are critical components to maintaining mitochondria homeostasis especially mitochondrial dynamics to exert cardioprotective actions under I/R stress. The results demonstrated that deficiency of SIRT1 and SIRT3 in aged (24–26 months) mice hearts led to the exacerbated cardiac dysfunction in terms of cardiac systolic dysfunction, cardiomyocytes contractile defection, and abnormal cardiomyocyte calcium flux during I/R stress. Moreover, the deletion of SIRT1 or SIRT3 in young (4–6 months) mice hearts impair cardiomyocyte contractility and shows aging‐like cardiac dysfunction upon I/R stress, indicating the crucial role of SIRT1 and SIRT3 in protecting myocardial contractility from I/R injury. The biochemical and seahorse analysis showed that the deficiency of SIRT1/SIRT3 leads to the inactivation of AMPK and alterations in mitochondrial oxidative phosphorylation (OXPHOS) that causes impaired mitochondrial respiration in response to I/R stress. Furthermore, the remodeling of the mitochondria network goes together with hypoxic stress, and mitochondria undergo the processes of fusion with the increasing elongated branches during hypoxia. The transmission electron microscope data showed that cardiac SIRT1/SIRT3 deficiency in aging alters mitochondrial morphology characterized by the impairment of mitochondria fusion under I/R stress. Thus, the age‐related deficiency of SIRT1/SIRT3 in the heart affects mitochondrial dynamics and respiration function that resulting in the impaired contractile function of cardiomyocytes in response to I/R.     

Bakuchiol attenuates myocardial ischemia reperfusion injury by maintaining mitochondrial function: the role of silent information regulator 1

Ischemia reperfusion (IR) injury (IRI) is associated with poor prognoses in the settings of both cardiac surgery and ischemic heart disease and causes mitochondrial oxidative stress and cell death. Silent information regulator 1 (SIRT1), a member of the histone deacetylase family, exerts anti-IRI effects. Bakuchiol (BAK), an analog of resveratrol and a monoterpene phenol isolated from the seeds of Psoralea corylifolia (Leguminosae), protects tissues from injury. This study was designed to investigate the protective effects of BAK treatment in the setting of myocardial IRI and to elucidate the potential mechanism of those effects. Prior to induction of IR, isolated rat hearts or cardiomyocytes were exposed to BAK in either the absence or presence of the SIRT1 inhibitors Sirtinol and SIRT1 siRNA. BAK exerted cardioprotective effects, as evidenced by the improvements noted in cardiac function following ischemia, attenuated myocardial apoptosis, and changes in several biochemical parameters (including increases in the level of the anti-apoptotic protein Bcl2, decreases in the level of the pro-apoptotic protein Bax, and decreases in the cleaved Caspase 3 level). However, Sirtinol and SIRT1 siRNA each blocked BAK-induced cardioprotection by inhibiting SIRT1 signaling. Additionally, BAK significantly increased the activities of mitochondrial succinate dehydrogenase, cytochrome c oxidase, and mitochondrial superoxide dismutase and decreased the production of malondialdehyde. These findings suggested that BAK significantly attenuated IR-induced mitochondrial oxidative damage. However, Sirtinol and SIRT1 siRNA abolished BAK-dependent mitochondrial function. In summary, our results demonstrate that BAK treatment attenuates IRI by attenuating IR-induced mitochondrial oxidative damage via the activation of SIRT1/PGC-1α signaling.     

Hesperetin protects against cardiac remodelling induced by pressure overload in mice

Cardiac remodelling is a major determinant of heart failure (HF) and is characterised by cardiac hypertrophy, fibrosis, oxidative stress and myocytes apoptosis. Hesperetin, which belongs to the flavonoid subgroup of citrus flavonoids, is the main flavonoid in oranges and possesses multiple pharmacological properties. However, its role in cardiac remodelling remains unknown. We determined the effect of hesperetin on cardiac hypertrophy, fibrosis and heart function using an aortic banding (AB) mouse. Male, 8–10-week-old, wild-type C57 mice with or without oral hesperetin administration were subjected to AB or a sham operation. Our data demonstrated that hesperetin protected against cardiac hypertrophy, fibrosis and dysfunction induced by AB, as assessed by heart weigh/body weight, lung weight/body weight, heart weight/tibia length, echocardiographic and haemodynamic parameters, histological analysis, and gene expression of hypertrophic and fibrotic markers. Also, hesperetin attenuated oxidative stress and myocytes apoptosis induced by AB. The inhibitory effect of hesperetin on cardiac remodelling was mediated by blocking PKCα/βII-AKT, JNK and TGFβ1-Smad signalling pathways. In conclusion, we found that the orange flavonoid hesperetin protected against cardiac remodelling induced by pressure overload via inhibiting cardiac hypertrophy, fibrosis, oxidative stress and myocytes apoptosis. These findings suggest a potential therapeutic drug for cardiac remodelling and HF.     

烟酰胺核糖抑制db/db小鼠糖尿病心肌病的作用及机制研究

目的:探讨烟酰胺核糖(NR)对2型糖尿病小鼠心肌病的治疗作用及其机制。方法:2型糖尿病模型db/db鼠和及其严格对照小鼠db/+小鼠,将小鼠分为Con (db/+)组,DM (db/db)组,DM+NR组。采用超声测小鼠心脏功能,western-blot及免疫组化测SIRT1表达含量,DHE染色、MDA含量和MnSOD活性检测反映氧化应激水平。结果:与对照组相比,db/db小鼠心脏功能显著下降(LVEF:42.3±7.2vs 73.7±10.2, P0.01;LVFS:22.1±4.2vs 42.7±6.9, P0.01),SIRT1表达量显著下调(P0.01)。NR喂养提高SIRT1表达量(P0.01),并有效改善db/db小鼠心脏功能(LVEF:53.1±8.1vs 42.3±7.2, P0.01;LVFS:33.4±6.9vs 22.1±4.2, P0.01)。同时,NR喂养显著降低了db/db小鼠心肌组织的凋亡水平和氧化应激水平(P0.05)。结论:NR有效改善了db/db小鼠的心功能障碍,降低了db/db小鼠的心肌凋亡水平和氧化应激水平,这些作用的发挥可能与NR增加SIRT1的表达量有关。     

Resveratrol‐enhanced autophagic flux ameliorates myocardial oxidative stress injury in diabetic mice

Autophagic dysfunction is observed in diabetes mellitus. Resveratrol has a beneficial effect on diabetic cardiomyopathy. Whether the resveratrol‐induced improvement in cardiac function in diabetes is via regulating autophagy remains unclear. We investigated the mechanisms underlying resveratrol‐mediated protection against heart failure in diabetic mice, with a focus on the role of sirtuin 1 (SIRT1) in regulating autophagic flux. Diabetic cardiomyopathy in mice was induced by streptozotocin (STZ). Long‐term resveratrol treatment improved cardiac function, ameliorated oxidative injury and reduced apoptosis in the diabetic mouse heart. Western blot analysis revealed that resveratrol decreased p62 protein expression and promoted SIRT1 activity and Rab7 expression. Inhibiting autophagic flux with bafilomycin A1 increased diabetic mouse mortality and attenuated resveratrol‐induced down‐regulation of p62, but not SIRT1 activity or Rab7 expression in diabetic mouse hearts. In cultured H9C2 cells, redundant or overactive H₂O₂ increased p62 and cleaved caspase 3 expression as well as acetylated forkhead box protein O1 (FOXO1) and inhibited SIRT1 expression. Sirtinol, SIRT1 and Rab7 siRNA impaired the resveratrol amelioration of dysfunctional autophagic flux and reduced apoptosis under oxidative conditions. Furthermore, resveratrol enhanced FOXO1 DNA binding at the Rab7 promoter region through a SIRT1‐dependent pathway. These results highlight the role of the SIRT1/FOXO1/Rab7 axis in the effect of resveratrol on autophagic flux in vivo and in vitro, which suggests a therapeutic strategy for diabetic cardiomyopathy.     

ICS II protects against cardiac hypertrophy by regulating metabolic remodelling,not by inhibiting autophagy

Cardiac hypertrophy is characterized by a shift in metabolic substrate utilization. Therefore, the regulation of ketone body uptake and metabolism may have beneficial effects on heart injuries that induce cardiac remodelling. In this study, we investigated whether icariside II (ICS II) protects against cardiac hypertrophy in mice and cardiomyocytes. To create cardiac hypertrophy animal and cell models, mice were subjected to transverse aortic constriction (TAC), and embryonic rat cardiomyocytes (H9C2) were stimulated with angiotensin II, a neurohumoral stressor. Both the in vivo and in vitro results suggest that ICS II treatment ameliorated pressure overload–induced cardiac hypertrophy and preserved heart function. In addition, apoptosis and oxidative stress were reduced in the presence of ICS II. Moreover, ICS II inhibited excess autophagy in TAC-induced hearts and angiotensin II–stimulated cardiomyocytes. Mechanistically, we found that ICS II administration regulated SIRT3 expression in cardiac remodelling. SIRT3 activation increased ketone body transportation and utilization. Collectively, our data show that ICS II attenuated cardiac hypertrophy by modulating ketone body and fatty acid metabolism, and that this was likely due to the activation of the SIRT3-AMPK pathway. ICS II treatment may provide a new therapeutic strategy for improving myocardial metabolism in cardiac hypertrophy and heart failure.     

CaMKII inhibitor KN‐93 impaired angiogenesis and aggravated cardiac remodelling and heart failure via inhibiting NOX2/mtROS/p‐VEGFR2 and STAT3 pathways

Persistent cardiac Ca²⁺/calmodulin‐dependent Kinase II (CaMKII) activation was considered to promote heart failure (HF) development, some studies believed that CaMKII was a target for therapy of HF. However, CaMKII was an important mediator for the ischaemia‐induced coronary angiogenesis, and new evidence confirmed that angiogenesis inhibited cardiac remodelling and improved heart function, and some conditions which impaired angiogenesis aggravated ventricular remodelling. This study aimed to investigate the roles and the underlying mechanisms of CaMKII inhibitor in cardiac remodelling. First, we induced cardiac remodelling rat model by ISO, pre‐treated by CaMKII inhibitor KN‐93, evaluated heart function by echocardiography measurements, and performed HE staining, Masson staining, Tunel staining, Western blot and RT‐PCR to test cardiac remodelling and myocardial microvessel density; we also observed ultrastructure of cardiac tissue with transmission electron microscope. Second, we cultured HUVECs, pre‐treated by ISO and KN‐93, detected cell proliferation, migration, tubule formation and apoptosis, and carried out Western blot to determine the expression of NOX2, NOX4, VEGF, VEGFR2, p‐VEGFR2 and STAT3; mtROS level was also measured. In vivo, we found KN‐93 severely reduced myocardial microvessel density, caused apoptosis of vascular endothelial cells, enhanced cardiac hypertrophy, myocardial apoptosis, collagen deposition, aggravated the deterioration of myocardial ultrastructure and heart function. In vitro, KN‐93 inhibited HUVECs proliferation, migration and tubule formation, and promoted apoptosis of HUVECs. The expression of NOX2, NOX4, p‐VEGFR2 and STAT3 were down‐regulated by KN‐93; mtROS level was severely reduced by KN‐93. We concluded that KN‐93 impaired angiogenesis and aggravated cardiac remodelling and heart failure via inhibiting NOX2/mtROS/p‐VEGFR2 and STAT3 pathways.     

Isosteviol sodium protects the cardiomyocyte response associated with the SIRT1/PGC‐1α pathway

Cardiomyocyte dysfunction is attributed to excess oxidative damage, but the molecular pathways involved in this process have not been completely elucidated. Evidence indicates that isosteviol sodium (STVNa) has cardioprotective effects. We therefore aimed to identify the effect of STVNa on cardiomyocytes, as well as the potential mechanisms involved in this process. We established two myocardial hypertrophy models by treating H9c2 cells with high glucose (HG) and isoprenaline (ISO). Our results showed that STVNa reduced H9c2 mitochondrial damage by attenuating oxidative damage and altering the morphology of mitochondria. The results also indicated that STVNa had a positive effect on HG‐ and ISO‐induced damages via mitochondrial biogenesis. The protective effects of STVNa on cardiomyocytes were associated with the regulation of the SIRT1/PGC‐1α signalling pathway. Importantly, the effects of STVNa involved different methods of regulation in the two models, which was confirmed by experiments using an inhibitor and activator of SIRT1. Together, the results provide the basis for using STVNa as a therapy for the prevention of cardiomyocyte dysfunctions.     

松果菊苷对多柔比星心脏毒性保护作用及机制研究

目的:观察松果菊苷(ECH)能否减轻多柔比星(DOX)心脏毒性并初步阐明其作用机制。方法:通过单次腹腔注射大剂量多柔比星(15 mg/kg)建立急性心脏毒性小鼠模型,DOX处理后每日通过腹腔注射ECH(50 mg/kg/day)。实验分组如下:正常组(Control组);单纯松果菊苷处理组(ECH组);多柔比星处理组(DOX组);多柔比星+松果菊苷处理组(DOX+ECH组)。给药5天后检测左心室功能、心肌组织病理改变、氧化应激和心肌凋亡情况。结果:与Control组相比,DOX组小鼠心脏收缩和舒张功能明显减弱,心肌细胞出现空泡变性,心肌MDA含量、凋亡率以及促凋亡蛋白Bax和cleaved Caspase-3表达明显增加,而抑制凋亡蛋白Bcl-2表达量、SOD与GSH-Px活性明显下降。与DOX组相比,松果菊苷能明显改善心脏功能,缓解心肌空泡变性,降低MDA含量、凋亡率以及Bax和cleaved Caspase-3表达量,而提高Bcl-2表达量、SOD与GSH-Px活性(均P 0.05)。结论:松果菊苷可以通过抑制心肌组织氧化应激损伤和凋亡缓解多柔比星诱导的急性心脏毒性。     

SIRT6 mediated histone H3K9ac deacetylation involves myocardial remodelling through regulating myocardial energy metabolism in TAC mice

Pathological myocardial remodelling is the initial factor of chronic heart failure (CHF) and is induced by multiple factors. We previously demonstrated that histone acetylation is involved in CHF in transverse aortic constriction (TAC) mice, a model for pressure overload-induced heart failure. In this study, we investigated whether the histone deacetylase Sirtuin 6 (SIRT6), which mediates deacetylation of histone 3 acetylated at lysine 9 (H3K9ac), is involved pathological myocardial remodelling by regulating myocardial energy metabolism and explored the underlying mechanisms. We generated a TAC mouse model by partial thoracic aortic banding. TAC mice were injected with the SIRT6 agonist MDL-800 at a dose of 65 mg/kg for 8 weeks. At 4, 8 and 12 weeks after TAC, the level of H3K9ac increased gradually, while the expression of SIRT6 and vascular endothelial growth factor A (VEGFA) decreased gradually. MDL-800 reversed the effects of SIRT6 on H3K9ac in TAC mice and promoted the expression of VEGFA in the hearts of TAC mice. MDL-800 also attenuated mitochondria damage and improved mitochondrial respiratory function through upregulating SIRT6 in the hearts of TAC mice. These results revealed a novel mechanism in which SIRT6-mediated H3K9ac level is involved pathological myocardial remodelling in TAC mice through regulating myocardial energy metabolism. These findings may assist in the development of novel methods for preventing and treating pathological myocardial remodelling.     

Emerging role of SIRT3 in endothelial metabolism,angiogenesis, and cardiovascular disease

Sirtuin 3 (SIRT3) a mitochondrial enzyme that plays an important role in energy homeostasis, cardiac remodeling, and heart failure (HF). The expression of SIRT3 declines with advanced age, cardiovascular, and metabolic diseases. Accumulating evidence suggests that SIRT3 plays a critical role in protecting the heart from cardiac hypertrophy, cardiac dysfunction associated with HF, and in the protection of cardiac cells from stress-mediated cell death. Clinical studies have demonstrated that HF with preserved ejection fraction (HFpEF) in patients present with abnormalities in coronary microcirculation related to endothelial dysfunction and coronary microvascular rarefaction. Although SIRT3-mediated regulation of mitochondrial homeostasis and heart function has been intensively investigated, the effect of SIRT3 on endothelial cell (EC) glycolytic metabolism and microvascular function has not been well studied. ECs utilize glycolysis for generating ATP rather than oxidative phosphorylation to maintain their normal functions and promote angiogenesis and EC–cardiomyocyte interactions. Emerging evidence indicates that SIRT3 is involved in the regulation of endothelial metabolism and angiogenesis and thus affects the development of cardiovascular diseases associated with aging. This review will discuss the current knowledge of SIRT3 and its functional role on endothelial metabolism, cardiac function, and cardiovascular diseases.     

Resveratrol prevents doxorubicin cardiotoxicity through mitochondrial stabilization and the Sirt1 pathway

Doxorubicin (DOX) is one of the most effective chemotherapeutic drugs; however, its incidence of cardiotoxicity compromises its therapeutic index. DOX-induced heart failure is thought to be caused by reduction/oxidation cycling of DOX to generate oxidative stress and cardiomyocyte cell death. Resveratrol (RV), a stilbene found in red wine, has been reported to play a cardioprotective role in diseases associated with oxidative stress. The objective of this study was to test the ability of RV to protect against DOX-induced cardiomyocyte death. We hypothesized that RV protects cardiomyocytes from DOX-induced oxidative stress and subsequent cell death through changes in mitochondrial function. DOX induced a rapid increase in reactive oxygen species (ROS) production in cardiac cell mitochondria, which was inhibited by pretreatment with RV, most likely owing to an increase in MnSOD activity. This effect of RV caused additional polarization of the mitochondria in the absence and presence of DOX to increase mitochondrial function. RV pretreatment also prevented DOX-induced cardiomyocyte death. The protective ability of RV against DOX was abolished when Sirt1 was inhibited by nicotinamide. Our data suggest that RV protects against DOX-induced oxidative stress through changes in mitochondrial function, specifically the Sirt1 pathway leading to cardiac cell survival.     

Fuziline alleviates isoproterenol‐induced myocardial injury by inhibiting ROS‐triggered endoplasmic reticulum stress via PERK/eIF2α/ATF4/Chop pathway

Fuziline, an aminoalcohol‐diterpenoid alkaloid derived from Aconiti lateralis radix preparata, has been reported to have a cardioprotective activity in vitro. However, the potential mechanism of fuziline on myocardial protection remains unknown. In this study, we aimed to explore the efficacy and mechanism of fuziline on isoproterenol (ISO)‐induced myocardial injury in vitro and in vivo. As a result, fuziline effectively increased cell viability and alleviated ISO‐induced apoptosis. Meanwhile, fuziline significantly decreased the production of ROS, maintained mitochondrial membrane potential (MMP) and blocked the release of cytochrome C, suggesting that fuziline could play the cardioprotective role through restoring the mitochondrial function. Fuziline also could suppress ISO‐induced endoplasmic reticulum (ER) stress via the PERK/eIF2α/ATF4/Chop pathway. In addition, using ROS scavenger NAC could decrease ISO‐induced apoptosis and block ISO‐induced ER stress, while PERK inhibitor GSK2606414 did not reduce the production of ROS, indicating that excess production of ROS induced by ISO triggered ER stress. And fuziline protected against ISO‐induced myocardial injury by inhibiting ROS‐triggered ER stress. Furthermore, fuziline effectively improved cardiac function on ISO‐induced myocardial injury in rats. Western blot analysis also showed that fuziline reduced ER stress‐induced apoptosis in vivo. Above these results demonstrated that fuziline could reduce ISO‐induced myocardial injury in vitro and in vivo by inhibiting ROS‐triggered ER stress via the PERK/eIF2α/ATF4/Chop pathway.     

Vagal nerve stimulation improves mitochondrial dynamics via an M3 receptor/CaMKKβ/AMPK pathway in isoproterenol‐induced myocardial ischaemia

Mitochondrial dynamics—fission and fusion—are associated with ischaemic heart disease (IHD). This study explored the protective effect of vagal nerve stimulation (VNS) against isoproterenol (ISO)‐induced myocardial ischaemia in a rat model and tested whether VNS plays a role in preventing disorders of mitochondrial dynamics and function. Isoproterenol not only caused cardiac injury but also increased the expression of mitochondrial fission proteins [dynamin‐related peptide1 (Drp1) and mitochondrial fission protein1 (Fis‐1)) and decreased the expression of fusion proteins (optic atrophy‐1 (OPA1) and mitofusins1/2 (Mfn1/2)], thereby disrupting mitochondrial dynamics and leading to increase in mitochondrial fragments. Interestingly, VNS restored mitochondrial dynamics through regulation of Drp1, Fis‐1, OPA1 and Mfn1/2; enhanced ATP content and mitochondrial membrane potential; reduced mitochondrial permeability transition pore (MPTP) opening; and improved mitochondrial ultrastructure and size. Furthermore, VNS reduced the size of the myocardial infarction and ameliorated cardiomyocyte apoptosis and cardiac dysfunction induced by ISO. Moreover, VNS activated AMP‐activated protein kinase (AMPK), which was accompanied by phosphorylation of Ca²⁺/calmodulin‐dependent protein kinase kinase β (CaMKKβ) during myocardial ischaemia. Treatment with subtype‐3 of muscarinic acetylcholine receptor (M₃R) antagonist 4‐diphenylacetoxy‐N‐methylpiperidine methiodide or AMPK inhibitor Compound C abolished the protective effects of VNS on mitochondrial dynamics and function, suggesting that M₃R/CaMKKβ/AMPK signalling are involved in mediating beneficial effects of VNS. This study demonstrates that VNS modulates mitochondrial dynamics and improves mitochondrial function, possibly through the M₃R/CaMKKβ/AMPK pathway, to attenuate ISO‐induced cardiac damage in rats. Targeting mitochondrial dynamics may provide a novel therapeutic strategy in IHD.     

Postinfarction exercise training alleviates cardiac dysfunction and adverse remodeling via mitochondrial biogenesis and SIRT1/PGC-1α/PI3K/Akt signaling

Exercise training mitigates cardiac pathological remodeling and dysfunction caused by myocardial infarction (MI), but its underlying cellular and molecular mechanisms remain elusive. Our present study in an in vivo rat model of MI determined the impact of post-MI exercise training on myocardial fibrosis, mitochondrial biogenesis, antioxidant capacity, and ventricular function. Adult male rats were randomized into: (a) Sedentary control group; (b) 4-week treadmill exercise training group; (c) Sham surgery group; (d) MI group with permanent ligation of left anterior descending coronary artery and kept sedentary during post-MI period; and (e) post-MI 4-week exercise training group. Results indicated that exercise training significantly improved post-MI left ventricular function and reduced markers of cardiac fibrosis. Exercise training also significantly attenuated MI-induced mitochondrial damage and oxidative stress, which were associated with enhanced antioxidant enzyme expression and/or activity and total antioxidant capacity in the heart. Interestingly, the adaptive activation of the SIRT1/PGC-1α/PI3K/Akt signaling following MI was further enhanced by post-MI exercise training, which is likely responsible for exercise-induced cardioprotection and mitochondrial biogenesis. In conclusion, this study has provided novel evidence on the activation of SIRT1/PGC-1α/PI3K/Akt pathway, which may mediate exercise-induced cardioprotection through reduction of cardiac fibrosis and oxidative stress, as well as improvement of mitochondrial integrity and biogenesis in post-MI myocardium.