The consequences of extremely intense long-term exercise for brain health remain unknown. We studied the effects of strenuous exercise on brain structure and function, its dose-response relationship, and mechanisms in a rat model of endurance training.Five-week-old male Wistar rats were assigned to moderate (MOD) or intense (INT) exercise or a sedentary (SED) group for 16 weeks. MOD rats showed the highest motivation and learning capacity in operant conditioning experiments; SED and INT presented similar results. In vivo MRI demonstrated enhanced global and regional connectivity efficiency and clustering as well as a higher cerebral blood flow (CBF) in MOD but not INT rats compared with SED. In the cortex, downregulation of oxidative phosphorylation complex IV and AMPK activation denoted mitochondrial dysfunction in INT rats. An imbalance in cortical antioxidant capacity was found between MOD and INT rats. The MOD group showed the lowest hippocampal brain-derived neurotrophic factor levels. The mRNA and protein levels of inflammatory markers were similar in all groups. In conclusion, strenuous long-term exercise yields a lesser improvement in This is an open access article under the terms of the Creative Commons Attribution-NonCommercial License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited and is not used for commercial purposes.

Most cells release extracellular vesicles (EVs) that can be detected circulating in blood. We and others have shown that the microRNA contents of these vesicles induce transcriptomic changes in acceptor cells, contributing to the adjustment of metabolic homeostasis in response to environmental demands. Here, we explore the potential for modulating obesity- and exercise-derived EV-microRNAs to treat the metabolic dysfunction associated with obesity in mice. Treatment with EV-miRNAs alleviated glucose intolerance and insulin resistance in obese mice to an extent similar to that of high-intensity interval training, although only exercise improved cardiorespiratory fitness and decreased body weight. Mechanistically, EV-miRNAs decreased fatty acid and cholesterol biosynthesis pathways in the liver, reducing hepatic steatosis and increasing insulin sensitivity, resulting in decreased glycemia and triglyceridemia. Our data suggest that manipulation of EV-miRNAs may be a viable strategy to alleviate metabolic dysfunction in obese and diabetic patients who are unable to exercise, although actual physical activity is needed to improve cardiorespiratory fitness.

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Introduction Compelling evidence supports that regular moderate exercise has a positive impact on cardiovascular disease (CVD) incidence and prognosis [1]. Nevertheless, emerging clinician and experimental data in healthy individuals suggests that long-term, high-intensity endurance exercise might increase vascular stiffness and enhance coronary calcification [2,3]. In patients with CV risk factors, it has been hypothesized that the beneficial effects of strenuous exercise on risk factors could outweigh its deleterious effects, but this remains unproven [4]. Purpose To analyze how increasing doses of exercise impinge on the vascular system in a murine model of aged rats with metabolic syndrome and kidney disease. Methods Seven-week-old male Zucker obese rats, a metabolic syndrome model, were subjected to left nephrectomy. At 26 weeks of age, rats were assigned to a sedentary (SED), moderate intensity (MOD, 15 cm/s, 40 min/day), or high intensity (INT, 25 cm/s, 60 min/day) group, and trained 5 days/week for 10 weeks. An echocardiogram and a glucose tolerance test were performed 24 hours after the last training bout. At sacrifice, vascular reactivity was assayed in the descending thoracic aorta, and EC50 calculated for every experiment. Expression of oxidant and antioxidant mRNA markers was analyzed in thoracic perivascular adipose tissue (tPVAT). Cytokines levels (TNFα, IL10, IL6, Selectin, ICAM1 and Adiponectin) were analyzed in plasma samples. Results Rats in the INT group had a significantly lower body weight (10.99±0.35 g/mm vs 12.23±0.58 g/mm) and a higher heart weight (32.44±0.72 mg/mm vs 31.28±0.78 mg/mm), indexed by tibia length, than the SED group. Both MOD and INT exercise improved glucose tolerance compared with SED (Fig 1a). On echocardiography, INT rats presented with LV septum hypertrophy and dilation, mildly reduced ejection fraction and fractional shortening compared with SED. Aortic diameter was also increased in the INT group (3.62±0.11 mm vs 3.25±0.13 mm). In vascular reactivity assays, the MOD group showed improved endothelial function, indicated by a larger carbachol-induced relaxation than SED and INT (Fig. 1b). However, MOD and INT were no longer different after adding the antioxidant Tempol (Fig1c). No differences were found in tunica media fibrosis amongst the groups (19.12±0.45%; 26.97±2.52%; 25.98±2.14%). In tPVAT, the mRNA expression of prooxidants (NOX2, p47) was higher, and antioxidant markers (SOD2, GCH1) was lower in the INT group than MOD and SED (Fig. 2). TNFα levels were higher in plasma of INT rats than SED. Conclusion In a rodent model, both intense and moderate exercise improved the CV risk profile, but only moderate training improved vascular function. Oxidative stress may, at least partially, account for the lack of benefits of intensive exercise. Our results suggest that the deleterious effects of strenuous physical activity could persist even in individuals with CV risk factor. Funding Acknowledgement Type of funding sources: Public grant(s) – National budget only. Main funding source(s): Fondo de Investigaciόn Sanitaria (FIS), Instituto de Salud Carlos III

Physically active lifestyle has huge implications for the health and well-being of people of all ages. However, excessive training can lead to severe cardiovascular events such as heart fibrosis and arrhythmia. In addition, strenuous exercise may impair brain plasticity. Here we investigate the presence of any deleterious effects induced by chronic high-intensity exercise, although not reaching exhaustion. We analyzed cardiovascular, cognitive, and cerebral molecular changes in young adult male mice submitted to treadmill running for eight weeks at moderate or high-intensity regimens compared to sedentary mice. Exercised mice showed decreased weight gain, which was significant for the high-intensity group. Exercised mice showed cardiac hypertrophy but with no signs of hemodynamic overload. No morphological changes in the descending aorta were observed, either. High-intensity training induced a decrease in heart rate and an increase in motor skills. However, it did not impair recognition or spatial memory, and, accordingly, the expression of hippocampal and cerebral cortical neuroplasticity markers was maintained. Interestingly, proteasome enzymatic activity increased in the cerebral cortex of all trained mice, and catalase expression was significantly increased in the high-intensity group; both first-line mechanisms contribute to maintaining redox homeostasis. Therefore, physical exercise at an intensity that induces adaptive cardiovascular changes parallels increases in antioxidant defenses to prevent brain damage.

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Although the benefits of moderate exercise in patients at high cardiovascular risk are well established, the effects of strenuous exercise remain unknown. We aimed to study the impact of strenuous exercise in a very high cardiovascular risk model. Nephrectomized aged Zucker obese rats were trained at a moderate (MOD) or high (INT) intensity or were kept sedentary (SED) for 10 weeks. Subsequently, echocardiography and ex vivo vascular reactivity assays were performed, and blood, aortas, perivascular adipose tissue (PVAT), and left ventricles (LVs) were harvested. An improved risk profile consisting of decreased body weight and improved response to a glucose tolerance test was noted in the trained groups. Vascular reactivity experiments in the descending thoracic aorta demonstrated increased endothelial NO release in the MOD group but not in the INT group, compared with SED; the free radical scavenger TEMPOL improved endothelial function in INT rats to a similar level as MOD. An imbalance in the expression of oxidative stress-related genes toward a pro-oxidant environment was observed in the PVAT of INT rats. In the heart, INT training promoted eccentric hypertrophy and a mild reduction in ejection fraction. Obesity was associated with LV fibrosis and a transition toward β-myosin heavy chain and the N2Ba titin isoform. Exercise reverted the myosin imbalance, but only MOD reduced the predominance of the N2Ba titin isoform. In conclusion, moderate exercise yields the most intense cardiovascular benefits in a high-cardiovascular-risk animal model, while intense training partially reverts them.