Exercise is an efficient strategy for myocardial protection against ischemia-reperfusion (IR) injury. Although endothelial nitric oxide synthase (eNOS) is phosphorylated and activated during exercise, its role in exercise-induced cardioprotection remains unknown. This study investigated whether modulation of eNOS activation during IR could participate in the exercise-induced cardioprotection against IR injury. Hearts isolated from sedentary or exercised rats (5 weeks training) were perfused with a Langendorff apparatus and IR performed in the presence or absence of NOS inhibitors [N-nitro-L-arginine methyl ester, L-NAME or N5-(1-iminoethyl)-L-ornithine, L-NIO] or tetrahydrobiopterin (BH₄). Exercise training protected hearts against IR injury and this effect was abolished by L-NAME or by L-NIO treatment, indicating that exercise-induced cardioprotection is eNOS dependent. However, a strong reduction of eNOS phosphorylation at Ser1177 (eNOS-PSer1177) and of eNOS coupling during early reperfusion was observed in hearts from exercised rats (which showed higher eNOS-PSer1177 and eNOS dimerization at baseline) in comparison to sedentary rats. Despite eNOS uncoupling, exercised hearts had more S-nitrosylated proteins after early reperfusion and also less nitro-oxidative stress, indexed by lower malondialdehyde content and protein nitrotyrosination compared to sedentary hearts. Moreover, in exercised hearts, stabilization of eNOS dimers by BH4 treatment increased nitro-oxidative stress and then abolished the exercise-induced cardioprotection, indicating that eNOS uncoupling during IR is required for exercise-induced myocardial cardioprotection. Based on these results, we hypothesize that in the hearts of exercised animals, eNOS uncoupling associated with the improved myocardial antioxidant capacity prevents excessive NO synthesis and limits the reaction between NO and O₂·- to form peroxynitrite (ONOO⁻), which is cytotoxic.

Aims To analyse the effects of different modalities of exercise training on heart rate variability (HRV) in individuals with metabolic syndrome (MetS). Methods and results Eighty MetS participants (aged 50-70 years) were housed and managed in an inpatient medical centre for 21 days, including weekends. Physical activity and food intake/diet were intensively monitored. Participants were randomly assigned into three training groups, differing only by intensity of exercise: moderate-endurance-moderate-resistance ( re), high-resistance-moderate-endurance ( Re), and moderate-resistance-high-endurance ( rE). HRV was recorded before and after the intervention by 24-hour Holter electrocardiogram. Although mean 24-hour heart rate decreased more in Re than re (-11.6 ± 1.6 vs. -4.8 ± 2.1%; P = 0.010), low frequency/high frequency decreased more in re than Re (-20.4 ± 5.5% vs. + 20.4 ± 9.1%; P = 0.002) and rE (-20.4 ± 5.5% vs. -0.3 ± 11.1%; P = 0.003). Very low frequency increased more in Re than re (+121.2 ± 35.7 vs. 42.9 ± 11.3%; P = 0.004). For all HRV parameters, rE ranged between re and Re values. Low frequency/high frequency changes were linked with visceral fat loss only in re (coefficient 5.9, 95% CI 1.9-10.0; P = 0.004). By day 21, HRV parameters of MetS groups (heart rate -8.6 ± 1.0%, standard deviation of R-R intervals + 34.0 ± 6.6%, total power + 63.3 ± 11.1%; P < 0.001) became closer to values of 50 aged-matched healthy controls. Conclusions A 3-week residential programme with intensive volumes of physical activity (15-20 hours per week) enhanced HRV in individuals with MetS. Participants with moderate intensity of training had greater improvements in sympathovagal balance, whereas those with high intensity in resistance training had greater decreases in heart rate and greater increases in very low frequency. Modality-specific relationships were observed between enhanced HRV and visceral fat loss. Clinical Trial Registration URL: http://www.clinicaltrials.gov . Unique identifier: NCT00917917.

The objective of this study was to evaluate the effects of high-intensity resistance and endurance exercise on body composition and plasma leptin and ghrelin concentrations in overweight individuals. One hundred participants were randomly assigned to 3 exercise interventions: high-resistance–low-aerobic exercise (Re), low-resistance–high-aerobic exercise (rE), low-resistance–low-aerobic exercise (re). Interventions began with 3 weeks of residential supervision (phase 1) after which participants had to manage the physical activity programs individually (phase 2). Body composition and plasma variables were measured at baseline and after phase 1 as well as after 3, 6, and 12 months. Significant decreases in body weight and fat were observed after phase 1 (p < 0.001) and continued at a lower rate for up to 3 months and then remained stable for the rest of the protocol. Once a body weight plateau was reached, body fat loss after the Re and rE conditions exceeded the fat loss observed in the re condition by 1.5–2 kg (p < 0.05). Leptin was significantly decreased after day 21 and month 3 (p < 0.001) and remained stable for the rest of the study. Ghrelin was significantly increased after day 21 and month 3 (p < 0.001) and returned to a level comparable to baseline between month 6 and 12 when body weight and fat had reached a plateau. In conclusion, this study reinforces the idea that an increase in exercise intensity may accentuate body fat loss before the occurrence of a body weight plateau. Resistance to further fat loss was accompanied by a decrease in plasma leptin and an increase in plasma ghrelin.

Prolonged strenuous exercise (PSE) induces transient left ventricular (LV) dysfunction. Previous studies suggest that β-adrenergic pathway desensitization could be involved in this phenomenon, but it remains to be confirmed. Moreover, other underlying mechanisms involving oxidative stress have been recently proposed. The present study aimed to evaluate the involvement of both the β-adrenergic pathway and NADPH oxidase (Nox) enzyme-induced oxidative stress in myocardial dysfunction in rats following PSE. Rats were divided into 4 groups: controls (Ctrl), 4-h exercised on treadmill (PSE), and 2 groups in which Nox enzyme was inhibited with apocynin treatment (Ctrl APO and PSE APO, respectively). We evaluated cardiac function in vivo and ex vivo during basal conditions and isoproterenol stress. GSH/GSSG ratio, cardiac troponin I (cTnI) release, and lipid peroxidation (MDA) were evaluated. PSE induced a decrease in LV developed pressure, intrinsic myocardial contractility, and relaxation associated with an increase in plasma cTnI release. Our in vivo and ex vivo results demonstrated no differences in myocardial response to isoproterenol and of effective dose 50 between control and PSE rats. Interestingly, the LV dysfunction was reversed by apocynin treatment. Moreover, apocynin prevented cellular oxidation [GSH/GSSG ratio: PSE APO rats vs. PSE rats in arbitrary units (au): 1.98 ± 0.07 vs. 1.35 ± 0.10; P < 0.001]. However, no differences in MDA were observed between groups. These data suggest that myocardial dysfunction observed after PSE was not due to β-adrenergic receptor desensitization but could be due to a signaling oxidative stress from the Nox enzyme.

ObjectivesTo demonstrate that lifestyle modifications will reduce the cost of routine medications in individuals with type 2 diabetes (T2D), through a mechanism involving glycaemic control.DesignA within-trial cost-medication analysis with a 1-year time horizon.SettingControlled environment within the spa resort of Chatel-Guyon, France.ParticipantsTwenty-nine participants (aged 50–70 years) with T2D.InterventionsA 1-year follow-up intervention, beginning with a 3-week residential programme combining high exercise volume (15–20 hours/week), restrictive diet (−500 kcal/day) and education. Participants continued their routine medication, independently managed by their general practitioner.Main outcome measuresNumber of medications, number of pills, cost of medications and health-related outcomes.ResultsTwenty-six participants completed the 1-year intervention. At 1 year, 14 patients out of 26 (54%) stopped/decreased their medications whereas only 5 (19%) increased or introduced new drugs (χ2=6.3, p=0.02). The number of pills per day decreased by 1.3±0.3 at 12 months (p<0.001). The annual cost of medications for T2D were lower at 1 year (€135.1±43.9) versus baseline (€212.6±35.8) (p=0.03). The regression coefficients on costs of routine medication were 0.507 (95% CI 0.056 to 0.959, p=0.027) for HbA1c and 0.156 (95% CI −0.010 to 0.322, p=0.06) for blood glucose levels. Diabetics patients with HbA1c >6.5% in the highest (last) quartile doubled their routine medication costs (66% vs 33%, p=0.037).ConclusionsIndividuals with T2D reduced routine medication costs following a long-term lifestyle intervention that started with a 3-week residential programme. Combining high exercise volume, restrictive diet and education effectively supported the health of T2D. The main factor explaining reduced medication costs was better glycaemic control, independent of weight changes. Despite limitations precluding generalisability, cost-effective results of reduced medication should contribute to the evidence base required to promote lifestyle interventions for individuals with T2D.Trial registration numberNCT00917917; Post-results.

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