The Influence of Epigenetic Modifications on Metabolic Changes in White Adipose Tissue and Liver and Their Potential Impact in Exercise.

Background: Epigenetic marks are responsive to a wide variety of environmental stimuli and serve as important mediators for gene transcription. A number of chromatin modifying enzymes orchestrate epigenetic responses to environmental stimuli, with a growing body of research examining how changes in metabolic substrates or co-factors alter epigenetic modifications. Scope of Review: Here, we provide a systematic review of existing evidence of metabolism-related epigenetic changes in white adipose tissue (WAT) and the liver and generate secondary hypotheses on how exercise may impact metabolism-related epigenetic marks in these tissues. Major Conclusions: Epigenetic changes contribute to the complex transcriptional responses associated with WAT lipolysis, hepatic de novo lipogenesis, and hepatic gluconeogenesis. While these metabolic responses may hypothetically be altered with acute and chronic exercise, direct testing is needed.

Heart Rate of Nursing Home Residents with Advanced Dementia and Persistent Vocalizations.

Persistent vocalizations (PVs) are a common behavioral symptom of dementia. There are currently no known studies examining physiological measurement in nursing home (NH) residents with dementia exhibiting PVs. Measures of heart rate (HR) could provide objective evidence of a person's response to a disruption in their internal or external environment. This was a two-case observational study involving NH residents with advanced dementia. HRs were collected via a sensor belt. We found a 39-45 bpm increase in HRs in both participants when comparing a day without PVs to a day exhibiting PVs. This is the first study to demonstrate a change in HR associated with PVs and potential evidence of stress in the person in response to either an internal or external stimuli.

Impact of parental exercise on epigenetic modifications inherited by offspring: A systematic review.

Performing regular exercise is associated with numerous health benefits including a reduction in all-cause mortality. The mechanisms associated with exercise-induced health improvements are wide ranging and benefit virtually every organ system in the body. Of significance, recent evidence has suggested that some of these protective benefits may also be passed to offspring through multiple generations via alterations in gamete presentation, changes to the in-utero and offspring rearing environments, and epigenetic modifications. The purpose of this review was to systematically examine the current literature for evidence of exercise-induced epigenetic modifications in offspring. A systematic search yielded four papers that met inclusion criteria. Parental exercise interventions were associated with differential DNA methylation patterns in offspring. These shifts in methylation patterns were consistent with concurrent changes in offspring mRNA levels, protein expression, and functional measures. Many of the observed changes were related to metabolic pathways. Hence, the evidence suggests that exercise-induced epigenetic changes can be observed in offspring and may play a pivotal role among the multifactorial intergenerational-health impact of exercise.

Myocardial apoptosis and mesenchymal stem cells with acute exercise.

Aerobic exercise confers many health benefits. However, numerous reports have shown that acute aerobic exercise can injure the heart. We tested the general hypothesis that acute moderate-intensity exercise in rodents induces cardiomyocyte damage and stimulates mesenchymal stem cells (MSCs) to increase paracrine-mediated protective effects on cardiomyocytes. A single session of treadmill running (13 m/min, 0% grade, for 45 min) in untrained C57BL/6 male mice (n = 18) increased cleaved poly ADP-ribose polymerase (PARP), a marker of apoptosis, in the myocardium 24 h postexercise. Microarray analysis of mouse myocardium identified 11 relevant apoptotic genes and several shifts in matrix remodeling transcripts over the postexercise window. Postexercise cardiomyocyte death was recapitulated in neonatal rat cardiomyocytes (NRCMs) by culturing cells in 2% plasma harvested from exercised rats. The increased cell death observed in exercise-treated NRCMs was attenuated by ß-adrenergic blockade, but not antioxidant treatment. MSC survival, proliferation, and chemotaxis showed no significant differences between sedentary and exercise plasma conditions, despite increased IL-6, TNF-α, IL-1ß, and IFN-γ secretions from MSCs treated with exercise plasma. NRCM survival was increased nearly 500% when cocultured with MSCs, but this effect was not altered under exercise plasma culture conditions. Our results suggest acute moderate-intensity aerobic treadmill running in exercise-naïve rodents induces temporal cardiomyocyte death due to plasma-borne factors, namely, catecholaminergic stress. Even though exercise conditions prompt an inflammatory response in MSCs, the exercise milieu does not alter the MSC-protective phenotype on cardiomyocytes.

Protease-activated receptor 4 deficiency offers cardioprotection after acute ischemia reperfusion injury.

Protease-activated receptor (PAR)4 is a low affinity thrombin receptor with less understood function relative to PAR1. PAR4 is involved in platelet activation and hemostasis, but its specific actions on myocyte growth and cardiac function remain unknown. This study examined the role of PAR4 deficiency on cardioprotection after myocardial ischemia-reperfusion (IR) injury in mice. When challenged by in vivo or ex vivo IR, PAR4 knockout (KO) mice exhibited increased tolerance to injury, which was manifest as reduced infarct size and a more robust functional recovery compared to wild-type mice. PAR4 KO mice also showed reduced cardiomyocyte apoptosis and putative signaling shifts in survival pathways in response to IR. Inhibition of PAR4 expression in isolated cardiomyocytes by shRNA offered protection against thrombin and PAR4-agonist peptide-induced apoptosis, while overexpression of wild-type PAR4 significantly enhanced the susceptibility of cardiomyocytes to apoptosis, even under low thrombin concentrations. Further studies implicate Src- and epidermal growth factor receptor-dependent activation of JNK on the proapoptotic effect of PAR4 in cardiomyocytes. These findings reveal a pivotal role for PAR4 as a regulator of cardiomyocyte survival and point to PAR4 inhibition as a therapeutic target offering cardioprotection after acute IR injury.

Acute aerobic exercise increases exogenously infused bone marrow cell retention in the heart.

Stem cell therapy for myocardial infarction (MI) has been shown to improve cardiac function and reduce infarct size. Exercise training, in the form of cardiac rehabilitation, is an essential part of patient care post-MI. Hence, we tested the effects of acute and chronic aerobic exercise on stem cell retention and cardiac remodeling post-MI. Small epicardial MI's were induced in 12-month-old C57BL/6 mice via cryoinjury. Two weeks post-MI, vehicle infusion (N = 4) or GFP(+) bone marrow-derived cells (BMC) were injected (tail vein I.V.) immediately after acute exercise (N = 14) or sedentary conditions (N = 14). A subset of mice continued a 5-week intervention of chronic treadmill exercise (10-13 m/min; 45 min/day; 4 days/week; N = 7) or remained sedentary (N = 6). Exercise tolerance was assessed using a graded exercise test, and cardiac function was assessed with echocardiography. Acute exercise increased GFP(+) BMC retention in the infarcted zone of the heart by 30% versus sedentary (P < 0.05). This was not associated with alterations in myocardial function or gene expression of key cell adhesion molecules. Animals treated with chronic exercise increased exercise capacity (P < 0.05) and cardiac mass (P < 0.05) without change in left ventricular ejection fraction (LVEF), infarct size, or regional wall thickness (P = NS) compared with sedentary. While BMC's alone did not affect exercise capacity, they increased LVEF (P < 0.05) and Ki67(+) nuclei number in the border zone of the heart (P < 0.05), which was potentiated with chronic exercise training (P < 0.05). We conclude that acute exercise increases BMC retention in infarcted hearts and chronic training increases exogenous BMC-mediated effects on stimulating the cardiomyocyte cell cycle. These preclinical results suggest that exercise may help to optimize stem cell therapeutics following MI.

Moderate-intensity treadmill exercise training decreases murine cardiomyocyte cross-sectional area.

The aim of this study was to examine the impact of moderate-intensity treadmill exercise on the structure and function of the murine heart and its associated impact on Akt-AMPK-mTOR signaling. A secondary aim was to test whether the exercise phenotype was altered following a cardiotoxic bolus dose of doxorubicin (DOX). Two-month-old C57Bl/6J female mice remained sedentary (SED, n = 12) or were progressively trained with treadmill running for 2 months up to 18 m/min; 60 min/day, 5 days/weeks (EX, n = 11) or EX + DOX (15 mg/kg/dose) (EX + DOX, n = 6). Following treadmill training, mice underwent graded exercise tolerance testing and echocardiography. Training improved graded exercise tolerance by 68 ± 5% relative to SED, and this effect was not altered with bolus DOX. There were no changes in relative heart size with EX or EX + DOX versus SED. Regional posterior wall thickening was improved in EX and abrogated in EX + DOX. EX had a reduced cardiomyocyte cross-sectional area (CSA) relative to SED, and CSA was further attenuated with DOX. Following EX, AMPK-associated phosphorylation of ULK1(ser317) tended to be lower relative to SED. Akt-associated phosphorylation of TSC2(thr1462) and mTOR(ser2448) were also decreased relative to SED. We observed an increase in AMPK activity with DOX that was not translated to downstream AMPK phosphorylation sites. We conclude that 2 months of moderate treadmill exercise training improves regional cardiac function and exercise capacity, but does not induce relative physiologic hypertrophy in female mice. Differential responses in Akt-AMPK-mTOR signaling may mediate the observed phenotype.

Effects of acute angiotensin II on ischemia reperfusion injury following myocardial infarction.

Myocardial infarction (MI) induces cardiac remodeling. This may increase the susceptibility of the infarcted heart to subsequent ischemic events. While chronic angiotensin II blockade is cardioprotective post-MI, the acute effects of angiotensin II in ischemia-reperfusion injury (IR) remains unclear. In the present study, we tested whether angiotensin II administration altered recovery of left ventricular (LV) function to IR in hearts from sham and MI rats. Echocardiography, LV pressure-volume relationships, and IR performance were established in subsets of sham (N = 27) and MI hearts (N = 41). IR was conducted in red-cell-perfused Langendorff hearts (60 minutes of low-flow ischemia; 30 minutes of reperfusion) during vehicle or angiotensin II infusions (10(-7) M). MI hearts were dilated and had reduced fractional shortening and blunted systolic elastance (p < 0.05). Despite systolic dysfunction in MI, functional recovery to IR was similar to sham. Angiotensin II significantly worsened IR performance in sham (p < 0.05), but not MI. The effect of angiotensin II on in vitro cardiomyocyte survival under various pH conditions was also tested. Acidosis increased cardiomyocyte death and angiotensin II potentiated this effect. We conclude that IR performance is similar between sham and MI hearts and that MI hearts are resistant to angiotensin II-induced cardiac dysfunction in response to IR.

Concomitant low-dose doxorubicin treatment and exercise.

Cardiotoxicity is a side effect for cancer patients treated with doxorubicin (DOX). We tested the hypothesis that low-intensity aerobic exercise concomitant with DOX treatment would offset DOX-induced cardiotoxicity while also improving the therapeutic efficacy of DOX on tumor progression. B16F10 melanoma cells (3 × 10(5)) were injected subcutaneously into the scruff of 6- to 8-wk-old male C57BL/6 mice (n = 48). A 4 mg/kg cumulative dose of DOX was administered over 2 wk, and exercise (EX) consisted of treadmill walking (10 m/min, 45 min/day, 5 days/wk, 2 wk). Four experimental groups were tested: 1) sedentary (SED) + vehicle, 2) SED + DOX, 3) EX + vehicle, and 4) EX + DOX. Tumor volume was attenuated in DOX and lowest in EX + DOX. DOX-treated animals had less gain in body weight, reduced heart weights (HW), smaller HW-to-body weight ratios, and shorter tibial lengths by the end of the protocol; and exercise did not reverse the cardiotoxic effects of DOX. Despite decreased left ventricular (LV) mass with DOX, cardiomyocyte cross-sectional area, ß-myosin heavy chain gene expression, and whole heart systolic (fractional shortening) and diastolic (E/A ratio) function were similar among groups. DOX also resulted in increased LV fibrosis with lower LV end diastolic volume and stroke volume. Myocardial protein kinase B activity was increased with both DOX and EX treatments, and tuberous sclerosis 2 (TSC2) abundance was reduced with EX. Downstream phosphorylation of TSC2 and mammalian target of rapamycin were similar across groups. We conclude that exercise increases the efficacy of DOX in inhibiting tumor growth without mitigating subclinical DOX-induced cardiotoxicity in a murine model of melanoma.

The effects of exercise on cardiovascular outcomes before, during, and after treatment for breast cancer.

Asymptomatic cardiotoxicity following breast cancer treatment is a significant issue for many patients, as these patients typically face an increased risk of cardiovascular disease (CVD). Exercise has well established benefits to improve and maintain cardiovascular function across patients with and without CVD. However, there is a dearth of information on the effects of exercise on cardiovascular outcomes in breast cancer patients. While pre-clinical studies support the use of exercise in mitigating cardiotoxicity, only one human study has specifically investigated cardiac function following an exercise intervention during chemotherapy treatment. No significant differences were observed between groups, which highlights the unidentified role of exercise in altering the risk of cardiotoxicity in breast cancer patients. Issues such as establishing the optimal timing, type, and intensity of an exercise program before, during, or after oncologic treatment for breast cancer are unclear. CVD risk and incidence increase in breast cancer survivors post therapy, and CVD is the number one killer of women in the United States. Thus, there is an increasing need to define the efficacy of exercise as a non-pharmacologic intervention in this growing population.

Step-count promotion through a school-based intervention.

The purpose was to determine the effects of a school-based pedometer intervention (SBPI) on daily accrued steps, academic performance, attendance, tardiness, and fitness performance in middle school students. Students from one, public middle school were assigned to a control (n = 46) or a 6-week SBPI (n = 46). Both groups recorded daily accrued pedometer steps. Grade point average (GPA), tardiness, absenteeism, and physical fitness scores were assessed. While baseline daily accrued step-counts were similar (p = NS), SBPI significantly increased daily accrued step-counts versus control (p < 0.05). During the study interval, academic performance increased in both groups, while SBPI had reduced tardiness (p < 0.05) and a tendency for reduced absenteeism (p = 0.06) postintervention. Shuttle and mile run performance decreased from pre- to postintervention in both groups. These data suggest that SBPI can increase physical activity levels and decrease tardiness in middle school students, without translating into short-term improvements in academic or physical fitness performance.

Cardiovascular effects and enjoyment of exercise gaming in older adults.

The purpose of this study was to quantify the cardiovascular responses and enjoyment of one trial of electronic exercise gaming (EG) (Nintendo(®) Wii(™) Tennis) in healthy, older adults (mean age = 81 [SD = 4 years]). Findings indicate that 15 minutes of EG moderately increased heart rate (p < 0.001), blood pressure (p < 0.001), and perceived exertion (p < 0.0001) compared to resting levels. This corresponded to achieving 64% of age-predicted maximum heart rate. No differences were observed for the cardiovascular responses to EG between genders, but participants taking beta-blocker drugs showed an attenuated response (p < 0.05). All participants completed EG tennis without excessive fatigue, with 86% of participants enjoying the experience. There were only a few cases of EG-related arrhythmias (n = 2) and post-exercise muscle soreness (n = 3). These results suggest that Nintendo Wii Tennis EG technology represents an enjoyable, moderate intensity physical activity for healthy, older adults.

Physical activity and body mass perception.

PURPOSE: To evaluate ethnic perceptual variations in body mass index (BMI) and accrued physical activity. Women (n = 204) from the eastern United States were stratified into the following ethnic groups: White women (WW; n = 97), Black women (BW n = 62) and Others (Hispanic and Asian women, n = 45). Participants completed questionnaires and physiologic variables were determined. BW had increased weight, BMI, waist circumference, and body fat percentage vs. WW (p < .05). Body mass was higher in BW vs. Others (p < .05). There were no differences for perception of BMI or body dissatisfaction. BW were the only group in which perception of BMI was lower than measured BMI. BW engaged in 50% less domestic and total physical activity than WW and Others. Physical activity was not correlated to perception of BMI. CONCLUSION: Perception of BMI was similar across ethnic groups and not correlated to physical activity levels in young women.

Acute exercise exacerbates ischemia-induced diastolic rigor in hypertensive myocardium.

Previous studies have shown that acute exercise preconditions the myocardium from ischemic injury. The purpose of this study was to test whether acute exercise protects the hypertensive myocardium from ischemia-induced diastolic rigor, and to compare the response between normotensive and uncompensated hypertensive hearts. Hearts harvested from female Wistar-Kyoto (WKY; n = 24) and spontaneously hypertensive rats (SHR; n = 27) (age:10-12 weeks) were exposed to ischemia (Langendorff isovolumic preparation; 22 minutes of no flow ischemia and studied following prior conditions of: 1) no exercise (WKY-CON, n=8; SHR-CON, n=8); 2) ischemia initiated one hour post-acute exercise (WKY-1HR, n = 8; SHR-1HR, n = 11); and 3) ischemia initiated 24 hours post-acute exercise (WKY-24HR; n = 8; SHR-24HR, n = 8). Acute exercise consisted of one bout of treadmill running at 25 m/min for 60 minutes. Heart weight was similar between WKY and SHR despite elevated in vivo resting systolic blood pressure and rate pressure product in SHR (P<0.05). During normoxic perfusion, left ventricular (LV) Langendorff performance was similar between WKY and SHR over the post-exercise time course. However, during ischemia, LV diastolic rigor was less in WKY vs. SHR (P<0.05). Acute exercise augmented ischemia-induced LV dysfunction one hour post-exercise in SHR (P<0.05), with gradual recovery by 24 hours post-exercise. These data suggest that acute exercise promotes ischemic diastolic rigor in SHR, even prior to the development of cardiac hypertrophy.

Cardiac remodeling and function following exercise and angiotensin II receptor antagonism.

The purpose of this study was to test the impact of chronic exercise training combined with selective angiotensin II receptor (AT1) antagonism on systolic blood pressure (SBP) and the left-ventricular pressure-volume relationship in normotensive, non-infarcted rat hearts. Wistar rats (N = 19) were randomly assigned to either a sedentary control group (N = 8) or an exercise-trained group (N = 11). Losartan was administered to individually caged rats via the drinking water (10 mg/kg/d). Exercise training consisted of running on a motorized driven treadmill for 6 weeks at 30 m/min, 60 min/day, 5 days/week. Tail cuff SBP was measured weekly. Left ventricular performance was assessed in an ex vivo Langendorff isovolumic mode. One week of losartan treatment significantly reduced SBP in both groups by 13% relative to baseline (P < 0.05). SBP was lower in exercise-trained animals versus sedentary animals in the later weeks of the protocol (P < 0.05) Body weight was significantly lower in exercise-trained animals versus sedentary animals, but heart weight, heart to body weight ratio, atrial weight, and absolute left ventricular mass and length were similar between groups. The LV systolic pressure-volume relationship (PV) and systolic elastance were significantly greater in exercise-trained animals versus sedentary controls (P < 0.05). The left ventricular end-diastolic PV and diastolic stiffness were similar between exercise-trained and sedentary animals. These data suggest that chronic aerobic exercise training can improve the Starling response in the presence of AT1 receptor blockade without altering absolute cardiac size.

Exercise training improves systolic function in hypertensive myocardium.

The general purpose of this study was to test the effect of exercise training on the left ventricular (LV) pressure-volume relationship (LV/PV) and apoptotic signaling markers in normotensive and hypertensive hearts. Four-month-old female normotensive Wistar-Kyoto rats (WKY; n = 37) and spontaneously hypertensive rats (SHR; n = 38) were assigned to a sedentary (WKY-SED, n = 21; SHR-SED, n = 19) or treadmill-trained (WKY-TRD, n = 16; SHR-TRD, n = 19) group (∼60% Vo(2 peak), 60 min/day, 5 days/wk, 12 wk). Ex vivo LV/PV were established in isovolumic Langendorff-perfused hearts, and LV levels of Akt, phosphorylated Akt (Akt(Pi)), Bad, phosphorylated Bad (Bad(Pi)) c-IAP, x-IAP, calcineurin, and caspases 3, 8, and 9 were measured. Heart-to-body weight ratio was increased in SHR vs. WKY (P < 0.05), concomitant with increased calcineurin mRNA (P < 0.05). There was a rightward shift in the LV/PV (P < 0.05) and a reduction in systolic elastance (E(s)) in SHR vs. WKY. Exercise training corrected E(s) in SHR (P < 0.05) but had no effect on the LV/PV in WKY. Caspase 3 was increased in SHR-SED relative to WKY-SED, while Bad(Pi,) c-IAP, and x-IAP were significantly lower in SHR relative to WKY (P < 0.05). Exercise training increased Bad(Pi) in both WKY and SHR but did not alter caspase 9 activity in either group. While caspase 3 activity was increased with training in WKY (P < 0.05), it was unchanged with training in SHR. We conclude that moderate levels of regular aerobic exercise attenuate systolic dysfunction early in the compensatory phase of hypertrophy, and that a differential phenotypical response to moderate-intensity exercise exists between WKY and SHR.

Cardiac ß-adrenergic responsiveness with exercise.

Left ventricular performance is enhanced with chronic exercise training. Alterations in cardiomyocyte ß-adrenergic responsiveness (BAR) may, in part, mediate this response. In this study, cardiac BAR and the expression of some key cardiac hypertrophic signaling molecules following 3 months of treadmill training were examined. Four-month old, female, Wistar Kyoto (WKY) rats were randomly assigned into either a sedentary (WKY-SED, n = 15) or an exercise-trained (WKY-TRD, n = 11) group. All rats were maintained on a 12-h light/dark cycle, and fed ad libitum. Exercise training consisted of motorized treadmill training at 25 m/min, 0% grade, 60 continuous minutes, 5 days/week for a period of 12 weeks. RT-PCR was used to establish basal cardiac calcineurin A, ANP, and AKT mRNA expression. In vitro cardiac BAR responsiveness was determined in Langendorff, isolated hearts. Following baseline, isoproterenol (ISO) was incrementally infused at concentrations ranging from 1 × 10(-10) to 1 × 10(-7) mol/L. There were no group differences for heart weight, heart to body weight ratio, calcineurin A, ANP, or AKT mRNA levels between WKY-SED and WKY-TRD. WKY-TRD showed enhanced cardiac BAR relative to WKY-SED (at ISO 1 × 10(-7) mol/L; P < 0.05). Moderate intensity treadmill exercise improved cardiac BAR responsiveness to a high concentration of isoproterenol. This adaptation was independent of training-induced alterations in cardiac hypertrophy or hypertrophic marker expression.

Resistance training improves vasoreactivity in end-stage heart failure patients on inotropic support.

PURPOSE: Peripheral vascular abnormalities contribute to compromised functional status in heart failure (HF) patients. The purpose of the present study was to test whether the intervention of moderate-intensity, resistance training could improve peripheral vascular responsiveness, that is, flow-mediated dilation (FMD) in HF. METHODS: Baseline brachial artery FMD analysis (2 minutes of cuff occlusion and 5 minutes of reperfusion) was measured in HF patients on intravenous inotropic support (n = 9) awaiting cardiac transplantation. Unilateral, upper-body resistance exercises (moderate intensity, combination of isometric and isotonic exercises at 60%-80% of maximum) were performed 3 d/wk for 4 weeks. Follow-up FMD analysis was conducted after training. Central hemodynamics were defined via right-side-heart catheterization. RESULTS: At baseline prior to training, HF patients elicited a significant hyperemic response 10 seconds following cuff occlusion (mean increase in blood flow: 194 ± 44 mL/min, P < .05). Despite this significant hyperemic response, HF patients demonstrated a mild, but paradoxical vasoconstriction of nearly 3% at 1-minute after cuff release. Four weeks of resistance training corrected the paradoxical vasoconstriction observed at baseline and resulted in vasodilatation (a positive increase in brachial artery diameter of 0.04 ± 0.04 mm, at 1 minute after cuff release; P < .05). Conversely, in a subset of 3 HF patients, studies in the untrained contralateral arm revealed no change in the FMD response. CONCLUSION: Moderate-intensity upper-body resistance training improved brachial artery FMD in end-stage HF patients on inotropic support. The reversal of the paradoxical vasoconstrictive response to reactive hyperemia following 4 weeks of training may be secondary to local improvements in vascular endothelial function rather than a quantitative change in the reactive hyperemic stimulus.

Neonatal exendin-4 leads to protection from reperfusion injury and reduced rates of oxidative phosphorylation in the adult rat heart.

PURPOSE: Glucagon like peptide-1 (7-36) amide (GLP-1) is an incretin hormone with multiple salutary cardiovascular effects. A short course of the GLP-1 analogue Exendin-4 (Ex-4) in the neonatal period prevents the development of mitochondrial dysfunction and oxidative stress in a rat prone to obesity and diabetes. We sought to evaluate whether neonatal Ex-4 can exert the same effect in the normal rat heart, as well as whether Ex-4 could affect susceptibility to cardiac reperfusion injury. METHODS: After birth, Sprague Dawley rat pups were given either Ex-4 (1 nmole/kg body weight) or vehicle (1% BSA in 0.9% saline) subcutaneously for 6 days. Animals were studied at juvenile (4-6 weeks) and adult (8-9 months) ages. Using the Langendorff isolated perfused heart, cardiovascular function was assessed at baseline and following ischemia-reperfusion. Mitochondria were isolated from fresh heart tissue, and oxidative phosphorylation and calcium sequestration were analyzed. TBARS, MnSOD activity, and non-enzymatic anti-oxidant capacity were measured to assess the degree of oxidative stress present in the two groups. RESULTS: Both at the juvenile and adult age, Ex-4 treated rats demonstrated improved recovery from an ischemic insult. Rates of oxidative phosphorylation were globally reduced in adult, but not juvenile Ex-4 treated animals. Furthermore, mitochondria isolated from adult Ex-4 treated rats sequestered less calcium before undergoing the mitochondrial permeability transition. Oxidative stress did not differ between groups at any time point. CONCLUSION: A short course of Exendin-4 in the neonatal period leads to protection from ischemic injury and a preconditioned mitochondrial phenotype in the adult rat.