Exercise training prevents obesity-associated disorders: Role of miRNA-208a and MED13.

Exercise training (ET) has been established as an important treatment for obesity, since it counteracts aberrant cardiac metabolism and weight gain; however, underlying mechanisms remain to be further determined. MicroRNAs (miRNAs) inhibit protein expression by base-pairing with the 3' UTRs of mRNA targets. MiRNA-208a is a cardiac-specific miRNA that regulates ß-MHC content and systemic energy homeostasis via MED13. We investigated whether ET regulates the cardiac miRNA-208a and its target MED13, reducing the weight gain and ß-MHC expression in obese Zucker rats (OZR). OZR (n = 11) and Lean (L, n = 10) male rats were assigned into 4 groups: OZR, trained OZR (OZRT), L and trained L (LT). Swimming ET consisted of 60 min of duration, 1x/day, 5x/week/10 weeks. MiRNA and gene expression were analyzed by real-time PCR and protein levels by western blot. Resting bradycardia was observed in trained groups. ET reduced weight gain, retroperitoneal fat weight and adipocyte cell size in OZRT compared with OZR group. Cardiac miRNA-208a levels increased 57% in OZR paralleled with a decrease of 39% in MED13 protein levels compared with L group. In contrast, ET corrected the cardiac miRNA-208a and MED13 levels in OZRT compared with L group. Furthermore, ET reduced the increased cardiac mass and normalized ß-MHC protein levels caused by obesity. These results suggest that ET can prevent weight gain and pathological cardiac hypertrophy via increased of cardiac MED13 by the regulation of miRNA-208a. Therefore, miRNA-208a can be used as potential therapeutic target for metabolic and cardiac disorders.

Obesity Downregulates MicroRNA-126 Inducing Capillary Rarefaction in Skeletal Muscle: Effects of Aerobic Exercise Training.

Background. We investigated the effects of exercise training (ET) on miR-126 levels and skeletal muscle angiogenesis in obese Zucker rats. Results. Zucker rats were randomly assigned to sedentary and swimming-trained groups: lean sedentary (LS) and trained (LTR); obese sedentary (OB) and trained (OBTR). The OB group displayed capillary rarefaction compared with the LS group. In contrast, ET increased the capillary/fiber ratio by 38% in the LTR group and normalized capillary rarefaction in the OBTR group. VEGF, PI3K, and eNOS levels were reduced in the skeletal muscle of the OB group. ET normalized VEGF, PI3K, and eNOS levels in OBTR, contributing to vascular network homeostasis. PI3KR2 inhibits PI3K, a key mediator of the VEGF signaling pathway. Obesity decreased miR-126 and increased PI3KR2 levels compared with the LS group. However, ET normalized miR-126 levels in the OBTR group versus the LS group and decreased expression of PI3KR2. Conclusion. Our findings show that obesity leads to skeletal muscle capillary rarefaction, which is regulated by decreased miR-126 levels and increased PI3KR2. Inversely, ET normalizes miR-126 levels and VEGF signaling and should be considered an important therapeutic strategy for vascular disorders.

Effects of aerobic exercise training on cardiac renin-angiotensin system in an obese Zucker rat strain.

OBJECTIVE: Obesity and renin angiotensin system (RAS) hyperactivity are profoundly involved in cardiovascular diseases, however aerobic exercise training (EXT) can prevent obesity and cardiac RAS activation. The study hypothesis was to investigate whether obesity and its association with EXT alter the systemic and cardiac RAS components in an obese Zucker rat strain. METHODS: THE RATS WERE DIVIDED INTO THE FOLLOWING GROUPS: Lean Zucker rats (LZR); lean Zucker rats plus EXT (LZR+EXT); obese Zucker rats (OZR) and obese Zucker rats plus EXT (OZR+EXT). EXT consisted of 10 weeks of 60-min swimming sessions, 5 days/week. At the end of the training protocol heart rate (HR), systolic blood pressure (SBP), cardiac hypertrophy (CH) and function, local and systemic components of RAS were evaluated. Also, systemic glucose, triglycerides, total cholesterol and its LDL and HDL fractions were measured. RESULTS: The resting HR decreased (∼12%) for both LZR+EXT and OZR+EXT. However, only the LZR+EXT reached significance (p<0.05), while a tendency was found for OZR versus OZR+EXT (p = 0.07). In addition, exercise reduced (57%) triglycerides and (61%) LDL in the OZR+EXT. The systemic angiotensin I-converting enzyme (ACE) activity did not differ regardless of obesity and EXT, however, the OZR and OZR+EXT showed (66%) and (42%), respectively, less angiotensin II (Ang II) plasma concentration when compared with LZR. Furthermore, the results showed that EXT in the OZR prevented increase in CH, cardiac ACE activity, Ang II and AT2 receptor caused by obesity. In addition, exercise augmented cardiac ACE2 in both training groups. CONCLUSION: Despite the unchanged ACE and lower systemic Ang II levels in obesity, the cardiac RAS was increased in OZR and EXT in obese Zucker rats reduced some of the cardiac RAS components and prevented obesity-related CH. These results show that EXT prevented the heart RAS hyperactivity and cardiac maladaptive morphological alterations in obese Zucker rats.

Treinamento físico aeróbio previne à hipertrofia cardíaca patológica e melhora a função diastólica em ratos Zucker obesos / Aerobic exercise training revert pathologic cardiac hypertrophy and improves the diastolic function in obese Zucker rats

A obesidade é uma patologia diretamente relacionada com o desenvolvimento de doenças cardiovasculares. Por outro lado, o treinamento físico aeróbio atenua o desenvolvimento da obesidade e promove benefícios cardíacos em obesos. Dessa forma, nosso objetivo foi investigar se a obesidade altera a função cardíaca e se sua associação com o treinamento físico aeróbio promove melhora na função cardíaca em ratos Zucker obesos. Os ratos Zucker foram divididos da seguinte forma: grupo magro (GM), grupo obeso (GO), grupo magro treinado (GMTR) e grupo obeso treinado (GOTR). O protocolo de treinamento aeróbio de natação foi realizado por um período de 10 semanas com cinco sessões semanais de 60 minutos de duração. A frequência cardíaca de repouso, a pressão arterial sistólica, a hipertrofia e função cardíaca foram avaliadas no final do período de treinamento físico. Ambos os grupos treinados apresentaram uma queda de 12 por cento da frequência cardíaca de repouso, quando comparado com seus respectivos controles. Ainda, nossos resultados demonstraram que o treinamento aeróbio reduziu o aumento da massa cardíaca em 13 por cento e melhorou a função diastólica na obesidade em 43 por cento. Em conclusão, nossos dados demonstraram que o treinamento físico aeróbio reverteu os prejuízos cardíacos causados pela obesidade.

Obesity is profoundly involved in cardiovascular diseases. On the other hand, aerobic exercise training (EXT) attenuates obesity and promotes cardiac benefits in obese individuals. Therefore, the aim of this study was to investigate if obesity alters the cardiac function and whether its association with exercise training can improve cardiac function in an obese Zucker rat strain. The rats were divided in the following groups: Lean Zucker rats (LZR); lean Zucker rats plus exercise training (LZR+EXT); obese Zucker rat (OZR) and obese Zucker rat plus exercise training (OZR+EXT). EXT consisted of 10 weeks swimming sessions of 60 min, 5 days/week. At the end of the training protocol we evaluated heart rate (HR), systolic blood pressure (SBP), cardiac hypertrophy (CH) and function. The trained groups LZR+EXT and OZR+EXT showed a 12 percent lower resting HR when compared with theirs respective controls. In addition, our results showed that exercise training reduced the cardiac mass by 13 percent and improved the diastolic function by 43 percent in the obese trained group when compared with the obese untrained. In conclusion, aerobic exercise training reverts the cardiac injuries in obese Zucker rats.

Exercício de força ativa a via AKT/mTor pelo receptor de angiotensina II tipo I no músculo cardíaco de ratos / Activation of AKT-mTor signaling pathways by angiotensin II receptor type 1 after a session of strength exercise in cardiac muscle of rats

O receptor de angiotensina II tipo I (AT1) tem uma importante participação no desenvolvimento da hipertrofia cardíaca. Em um trabalho publicado anteriormente, por nosso grupo, demonstramos que o bloqueio do receptor AT1 durante o treinamento de força inibiu a hipertrofia cardíaca em ratos. Por isso, o objetivo deste trabalho foi estudar a participação do receptor AT1 na ativação de vias de sinalização intracelular relacionadas com o aumento da síntese de proteína em ratos submetidos a uma sessão de exercício de força. Para isso, realizamos um experimento com seis grupos de animais (n = 6; cada): controle (Con), exercitado e sacrificado cinco minutos após o exercício (Exe 5), exercitado e sacrificado 30 minutos após o exercício (Exe 30), controle tratado com losartan (Con Los), tratado com losartan, exercitado e sacrificado cinco minutos após o exercício (Exe 5 Los), tratado com losartan, exercitado e sacrificado 30 minutos após o exercício (Exe 30 Los). Os resultados mostram que no grupo Exe 5 e Exe 30 ocorreu um aumento de 63 por cento (P < 0,05) e 62 por cento (P < 0,05), respectivamente, na fosforilação da proteína AKT comparado com o grupo controle. Enquanto a fosforilação da mTor foi aumentada 65 por cento (P < 0,05) somente no grupo Exe 30 comparado com o grupo controle, sendo estes efeitos bloqueados pelo uso do losartan nos grupos Exe 5 Los e Exe 30 Los. Portanto, esses resultados, juntamente com nossos resultados prévios, demonstram que o receptor AT1 tem participação na ativação da AKT e mTOR após uma sessão de exercício de força.

The angiotensin II type I (AT1) receptor has an important participation in the development of cardiac hypertrophy. Previously, we have shown that AT1 receptor participates in the cardiac hypertrophy induced by resistance training in rats. Here, we studied the involvement of AT1 receptor in the activation of intracellular signaling pathways related to the concentric HC in rats submitted to a session of strength exercise. Male Wistar rats were divided into 6 groups (n= 6 each): control (Con); exercised and killed 5 minutes after exercise (Exe 5); exercised and killed 30 minutes after exercise (Exe 30); control treated with Losartan (Con Los); treated with Losartan, exercised and killed 5 minutes after the exercise (Exe Los 5); treated with Losartan, exercised and killed 30 minutes after training (Exe Los 30). The results show that phosphorylation activity of AKT in group Exe 5 and Exe 30 increased 63 percent (P < 0.05) and 62 percent (P < 0.05), respectively, compared with Con. Whereas the phosphorylation of mTOR was increased 65 percent (P < 0.05), compared to Con, only in the group Exe 30. Furthermore, these effects were blocked by losartan treatment in groups Exe Los 5 and Exe Los 30. These results, together with ours previous data shows that the AT1 receptor has an role in the activation of AKT and mTOR pathway after a session of strength exercise.