Exercise Training Reduces Insulin Resistance and Upregulates the mTOR/p70S6k Pathway in Cardiac Muscle of Diet-Induced Obesity Rats

Obesity and insulin resistance are rapidly expanding public health problems. These disturbances are related to many diseases, including heart pathology. Acting through the Akt/mTOR pathway, insulin has numerous and important physiological functions, such as the induction of growth and survival of many cell types and cardiac hypertrophy. However, obesity and insulin resistance can alter mTOR/p70S6k. Exercise training is known to induce this pathway, but never in the heart of diet-induced obesity subjects. To evaluate the effect of exercise training on mTOR/p70S6k in the heart of obese Wistar rats, we analyzed the effects of 12 weeks of swimming on obese rats, induced by a high-fat diet. Exercise training reduced epididymal fat, fasting serum insulin and plasma glucose disappearance. Western blot analyses showed that exercise training increased the ability of insulin to phosphorylate intracellular molecules such as Akt (2.3-fold) and Foxo1 (1.7-fold). Moreover, reduced activities and expressions of proteins, induced by the high-fat diet in rats, such as phospho-JNK (1.9-fold), NF-kB (1.6-fold) and PTP-1B (1.5-fold), were observed. Finally, exercise training increased the activities of the transduction pathways of insulin-dependent protein synthesis, as shown by increases in Raptor phosphorylation (1.7-fold), p70S6k phosphorylation (1.9-fold), and 4E-BP1 phosphorylation (1.4-fold) and a reduction in atrogin-1 expression (2.1-fold). Results demonstrate a pivotal regulatory role of exercise training on the Akt/ mTOR pathway, in turn, promoting protein synthesis and antagonizing protein degradation. J. Cell. Physiol. 226: 666-674, 2011. (C) 2010 Wiley-Liss, Inc.

Brainstem oxytocinergic modulation of heart rate control in rats: effects of hypertension and exercise training

Oxytocinergic brainstem projections participate in the autonomic control of the circulation. We investigated the effects of hypertension and training on cardiovascular parameters after oxytocin (OT) receptor blockade within the nucleus tractus solitarii (NTS) and NTS OT and OT receptor expression. Male spontaneously hypertensive rats (SHR) and Wistar-Kyoto (WKY) rats were trained (55% of maximal exercise capacity) or kept sedentary for 3 months and chronically instrumented (NTS and arterial cannulae). Mean arterial blood pressure (MAP) and heart rate (HR) were measured at rest and during an acute bout of exercise after NTS pretreatment with vehicle or OT antagonist (20 pmol of OT antagonist (200 nl of vehicle)-1). Oxytocin and OT receptor were quantified (35S-oligonucleotide probes, in situ hybridization) in other groups of rats. The SHR exhibited high MAP and HR (P < 0.05). Exercise training improved treadmill performance and reduced basal HR (on average -11%) in both groups, but did not change basal MAP. Blockade of NTS OT receptor increased exercise tachycardia only in trained groups, with a larger effect on trained WKY rats (+31 +/- 9 versus +12 +/- 3 beats min-1 in the trained SHR). Hypertension specifically reduced NTS OT receptor mRNA density (-46% versus sedentary WKY rats, P < 0.05); training did not change OT receptor density, but significantly increased OT mRNA expression (+2.5-fold in trained WKY rats and +15% in trained SHR). Concurrent hypertension- and training-induced plastic (peptide/receptor changes) and functional adjustments (HR changes) of oxytocinergic control support both the elevated basal HR in the SHR group and the slowing of the heart rate (rest and exercise) observed in trained WKY rats and SHR.

EFFECT OF ENDURANCE TRAINING ON HYPOTHALAMIC SEROTONIN CONCENTRATION AND PERFORMANCE

Serotonin is a neurotransmitter that modulates several functions, such as food intake, energy expenditure, motor activity, mood and sleep. Acute exhaustive endurance exercise increases the synthesis, concentration and metabolism of serotonin in the brain. This phenomenon could be responsible for central fatigue after prolonged and exhaustive exercise. However, the effect of chronic exhaustive training on serotonin is not known. The present study was conducted to examine the effect of exhaustive endurance training on performance and serotonin concentrations in the hypothalamus of trained rats. Rats were divided into three groups: sedentary rats (SED), moderately trained rats (MOD) and exhaustively trained rats (EXT), with an increase of 200% in the load carried during the final week of training. Hypothalamic serotonin concentrations were similar between the SED and MOD groups, but were higher in the EXT group (P < 0.05). Performance was lower in the EXT group compared with the MOD group (P < 0.05). Thus, the present study demonstrates that exhaustive training increases serotonin concentrations in the hypothalamus, together with decreased endurance performance after inadequate recovery time. However, the mechanism underlying these changes remains unknown.

Endurance training modulates lymphocyte function in rats with post-MI CHF

Purpose: Exercise training restores innate immune system cell function in post-myocardial infarction (post-MI) rats. However, studies of the involvement of lymphocyte (Ly) in the setting of the congestive heart failure (CHF) are few. To address this issue, we investigated the function of Ly obtained from cervical lymph nodes from post-MI CHF rats submitted to treadmill running training. Methods: Twenty-five male Wistar rats were randomly assigned to the following groups: rats submitted to ligation of the left coronary artery, which were sedentary (MI-S, N= 7, only limited activity) or trained (MI-T, N= 6, on a treadmill (0% grade at 13-20 m.m(-1)) for 60 min.d(-1), 5 d.wk(-1), for 8-10 wk); or sham-operated rats, which were sedentary (sham-S, N = 6) or trained (sham-T, N = 6). The incorporation of [2-C-14]-thymidine by Ly cultivated in the presence of concanavalin A (Con A) and lipopolysaccharide (LPS), cytokine production by Ly cultivated in the presence of phytohemagglutinin (PHA), and plasma concentration of glutamine were assessed in all groups, 48 h after the last exercise session. Results: Proliferative capacity was increased, following incubation with Con-A in the MI groups, when compared with the sham counterparts. When incubated in the presence of PHA, MI-S produced more IL-4 (96%) than sham-S (P < 0.001). The training protocol induced a 2.2-fold increase in the production of interleukin-2 (P < 0.001) of the cells obtained from the cervical lymph nodes of MI-T, compared with MI-S. Conclusion: The moderate endurance training protocol caused an increase in IL-2 production, and a trend toward the reversion of the Th-1/Th-2 imbalance associated with IL-4 production increased in the post-MI CHF animal model.

Endurance training induces depot-specific changes in IL-10/TNF-alpha ratio in rat adipose tissue

White adipose tissue (WAT) is the source of pro- and anti-inflammatory cytokines and recently, it has been recognized as an important source of interleukin 10 (IL-10). Acute physical exercise is known to induce an anti-inflammatory cytokine profile, however, the effect of chronic physical exercise on the production of IL-10 by WAT has never been examined. We assessed IL-10 and TNF-alpha concentration in WAT of rats engaged in endurance training. Animals were randomly assigned to either a sedentary control group (S, n = 7) or an endurance trained group (T, n = 8). Trained rats ran on a treadmill 5 days/wk for 8 wk (55-65% VO(2max). Detection of IL-10 and TNF-alpha protein and mRNA expression, as well as the gene expression of PPAR-gamma, and immunocytochemistry to detect mononuclear phagocytes were carried out. A reduction in absolute retroperitoneal adipose tissue (RPAT) weight in T (44%; p < 0.01), when compared with S was observed. IL-10 concentration was increased (1.5-fold, p < 0.05), to a higher extent than that of TNF-alpha (66%. p < 0.05) in the mesenteric adipose tissue (MEAT) of the trained group, while no change related to training was observed in RPAT. In MEAT, IL-10/TNF-alpha ratio was increased in T, when compared with S (30%; p < 0.05). PPAR-gamma gene expression was increased in T (1.1-fold; p < 0.01), when compared with S in the same adipose depot. No monocyte infiltration was found. In conclusion, exercise training induced increased IL-10 expression in the mesenteric depot, resulting in a modified IL-10/TNF-alpha ratio. We also conclude that WAT presents a depot-specific response to endurance training regarding the studied aspects. (C) 2008 Elsevier Ltd. All rights reserved.

Effect of endurance training upon lipid metabolism in the liver of cachectic tumour-bearing rats

The syndrome of cancer cachexia is accompanied by several alterations in lipid metabolism, and the liver is markedly affected. Previous Studies showed that moderate exercise training may prevent liver fill accumulation through diminished delivery of lipids to the liver, increased hepatic oxidation and increased incorporation of triacylglycerol (TAG) into very low density lipoprotein (VLDL). Our aim was to examine the influence of moderate intensity training (8 weeks) upon TAG content, VLDL assembly and secretion, apolipoprotein B (apoB) and microsomal transfer protein (MTP) gene expression in the liver of cachectic tumour-bearing rats. Animals were randomly assigned to a sedentary control (SC), sedentary tumour-bearing (ST) or exercise-trained control (EC) or to all exercise trained tumour-bearing (ET) group. Trained rats ran on a treadmill (60% VO2max) for 60 min day(-1), 5 day week(-1), for 8 weeks. TAG content and the rate of VLDL secretion (followed for 3 h), its well its mRNA expression of apoB and MTP, and total cholesterol, VLDL-TAG, VLDL-cholesterol, high density lipoprotein cholesterol (HDL-cholesterol) and tumor weight were evaluated. VLDL-cholesterol showed a decrease in ST (p < 0.05) in relation to SC. Serum TAG, VLDL-TAG and tissue TAG content were all increased in ST (p < 0.01), when compared with SC. ST showed a lower rate of VLDL secretion (p < 0.05) and reduced expression of apoB (p < 0.001) and MTP (p < 0.001), when compared with SC. These parameters were restored to control values (p < 0.05) when the animals were submitted to the exercise training protocol. Tumour weight decreased 10-fold after training (p < 0.001). It is possible to affirm, therefore, that endurance training promoted the re-establishment of lipid metabolism in cachectic tumour-bearing animals, especially in relation to VLDL secretion and assembly. Copyright (C) 2008 John Wiley & Sons, Ltd.

Endurance training activates AMP-activated protein kinase, increases expression of uncoupling protein 2 and reduces insulin secretion from rat pancreatic islets

Endurance exercise is known to enhance peripheral insulin sensitivity and reduce insulin secretion. However, it is unknown whether the latter effect is due to the reduction in plasma substrate availability or alterations in beta-cell secretory machinery. Here, we tested the hypothesis that endurance exercise reduces insulin secretion by altering the intracellular energy-sensitive AMP-activated kinase (AMPK) signaling pathway. Male Wistar rats were submitted to endurance protocol training one, three, or five times per week, over 8 weeks. After that, pancreatic islets were isolated, and glucose-induced insulin secretion (GIIS), glucose transporter 2 (GLUT2) protein content, total and phosphorylated calmodulin kinase kinase (CaMKII), and AMPK levels as well as peroxisome proliferator-activated receptor-gamma coactivator-1-alpha (PGC-1 alpha) and uncoupling protein 2 (UCP2) content were measured. After 8 weeks, chronic endurance exercise reduced GIIS in a dose-response manner proportionally to weekly exercise frequency. Contrariwise, increases in GLUT2 protein content, CaMKII and AMPK phosphorylation levels were observed. These alterations were accompanied by an increase in UCP2 content, probably mediated by an enhancement in PGC-1 alpha protein expression. In conclusion, chronic endurance exercise induces adaptations in beta-cells leading to a reduction in GIIS, probably by activating the AMPK signaling pathway. Journal of Endocrinology (2011) 208, 257-264

Efficacy and safety of concurrent training in systemic sclerosis

Pinto, ALS, Oliveira, NC, Gualano, B, Christmann, RB, Painelli, VS, Artioli, GG, Prado, DML, and Lima, FR. Efficacy and safety of concurrent training in systemic sclerosis. J Strength Cond Res 25(5): 1423-1428, 2011-The optimal training model for patients with systemic sclerosis (SSc) is unknown. In this study, we aimed to investigate the effects of a 12-week combined resistance and aerobic training program (concurrent training) in SSc patients. Eleven patients with no evidence of pulmonary involvement were recruited for the exercise program. Lower and upper limb dynamic strengths (assessed by 1 repetition maximum [1RM] of a leg press and bench press, respectively), isometric strength (assessed by back pull and handgrip tests), balance and mobility (assessed by the timed up-and-go test), muscle function (assessed by the timed-stands test), Rodnan score, digital ulcers, Rayland`s phenomenon, and blood markers of muscle inflammation (creatine kinase and aldolase) were assessed at baseline and after the 12-week program. Exercise training significantly enhanced the 1RM leg press (41%) and 1RM bench press (13%) values and back pull (24%) and handgrip strength (11%). Muscle function was also improved (15%), but balance and mobility were not significantly changed. The time-to-exhaustion was increased (46.5%, p = 0.0004), the heart rate at rest condition was significantly reduced, and the workload and time of exercise at ventilatory thresholds and peak of exercise were increased. However, maximal and submaximal (V)over dotO(2) were unaltered (p > 0.05). The Rodnan score was unchanged, and muscle enzymes remained within normal levels. No change was observed in digital ulcers and Raynaud`s phenomenon. This is the first study to demonstrate that a 12-week concurrent training program is safe and substantially improves muscle strength, function, and aerobic capacity in SSc patients.

Effects of high-intensity aerobic interval training vs. moderate exercise on hemodynamic, metabolic and neuro-humoral abnormalities of young normotensive women at high familial risk for hypertension

Exercise training has an important role in the prevention and treatment of hypertension, but its effects on the early metabolic and hemodynamic abnormalities observed in normotensive offspring of hypertensive parents (FH+) have not been studied. We compared high-intensity interval (aerobic interval training, AIT) and moderate-intensity continuous exercise training (CMT) with regard to hemodynamic, metabolic and hormonal variables in FH+ subjects. Forty-four healthy FH+ women (25.0+/-4.4 years) randomized to control (ConFH+) or to a three times per week equal-volume AIT (80-90% of VO(2MAX)) or CMT (50-60% of VO(2MAX)) regimen, and 15 healthy women with normotensive parents (ConFH-; 25.3+/-3.1 years) had their hemodynamic, metabolic and hormonal variables analyzed at baseline and after 16 weeks of follow-up. Ambulatorial blood pressure (ABP), glucose and cholesterol levels were similar among all groups, but the FH+ groups showed higher insulin, insulin sensitivity, carotid-femoral pulse wave velocity (PWV), norepinephrine and endothelin-1 (ET-1) levels and lower nitrite/ nitrate (NOx) levels than ConFH- subjects. AIT and CMT were equally effective in improving ABP (P<0.05), insulin and insulin sensitivity (P<0.001); however, AIT was superior in improving cardiorespiratory fitness (15 vs. 8%; P<0.05), PWV (P<0.01), and BP, norepinephrine, ET-1 and NOx response to exercise (P<0.05). Exercise intensity was an important factor in improving cardiorespiratory fitness and reversing hemodynamic, metabolic and hormonal alterations involved in the pathophysiology of hypertension. These findings may have important implications for the exercise training programs used for the prevention of inherited hypertensive disorder. Hypertension Research (2010) 33, 836-843; doi:10.1038/hr.2010.72; published online 7 May 2010

AGE DOES NOT AFFECT EXERCISE INTENSITY PROGRESSION AMONG WOMEN

Ciolac, EG, Brech, GC, and Greve, JMD. Age does not affect exercise intensity progression among women. J Strength Cond Res 24(11): 3023-3031, 2010-It has been recommended that the intensity of exercise training (ET) should progress slowly with lower increments in older than in young people. However, scientific evidence supporting this recommendation is lacking. Our aim was to examine possible influences of age on exercise intensity progression in healthy women. Seventeen young (29.1 +/- 5.7 years) and 16 older women (64.5 +/- 4.5 years) underwent 13 weeks of ET consisting of cycle ergometry (CE, 65-75% of reserve heart rate), whole-body resistance exercise (RE, 60% of 1 repetition maximum [1RM]), and stretching. Muscle strength was assessed before and after ET by the 1RM. Cycle ergometry and RE workloads were recorded for each exercise session, and increases of 5-10% were made whenever adaptation occurred. Absolute muscle strength after ET improved (p < 0.001) in both groups, and there were no significant differences between groups. Relative exercise intensity progression was not significantly different between groups for RE (Pearson`s correlation = 0.98 +/- 0.01), but it was greater in older women for CE (p = 0.047). The ET was safe because no injuries or major muscle pain was observed in either group. These results suggest that healthy older women are capable of exercising and increasing exercise intensity in the same way as young women.

Effect of the duration of daily aerobic physical training on cardiac autonomic adaptations

The present study has investigated in conscious rats the influence of the duration of physical training sessions on cardiac autonomic adaptations by using different approaches; 1) double blockade with methylatropine and propranolol; 2) the baroreflex sensitivity evaluated by alternating bolus injections of phenylephrine and sodium nitroprusside; and 3) the autonomic modulation of HRV in the frequency domain by means of spectral analysis. The animals were divided into four groups: one sedentary group and three training groups submitted to physical exercise (swimming) for 15, 30, and 60 min a day during 10 weeks. All training groups showed similar reduction in intrinsic heart rate (IHR) after double blockade with methylatropine and propranolol. However, only 30-min and 60-min physical training presented an increase in the vagal autonomic component for determination of basal heart rate (HR) in relation to group sedentary. Spectral analysis of HR showed that the 30-min and 60-min physical training presented the reduction in low-frequency oscillations (LF = 0.20-0.75 Hz) and the increase in high-frequency oscillations (HF = 0.75-2.5 Hz) in normalized units. These both groups only showed an increased baroreflex sensitivity to tachycardiac responses in relation to group sedentary, however when compared, the physical training of 30-min exhibited a greater gain. In conclusion, cardiac autonomic adaptations, characterised by the increased predominance of the vagal autonomic component, were not proportional to the duration of daily physical training sessions. In fact, 30-minute training sessions provided similar cardiac autonomic adaptations, or even more enhanced ones, as in the case of baroreflex sensitivity compared to 60-minute training sessions. (C) 2010 Elsevier B.V. All rights reserved.

Comparison of the effects of aerobic and resistance training on cardiac autonomic adaptations in ovariectomized rats

We have compared the effects of two types of physical training on the cardiac autonomic control in ovariectomized and sham-operated rats according to different approaches: double autonomic blockade (DAB) with methylatropine and propranolol; baroreflex sensibility (BRS) and spectral analysis of heart rate variability (HRV). Wistar female rats (+/- 250 g) were divided into two groups: sham-operated and ovariectomized. Each group was subdivided into three subgroups: sedentary rats, rats submitted to aerobic trained and rats submitted to resistance training. Ovariectomy did not change arterial pressure, basal heart rate (HR), DAB and BRS responses, but interfered with HRV by reducing the low-frequency oscillations (LF = 0.20-0.75 Hz) in relation to sedentary sham-operated rats. The DAB showed that both types of training promoted an increase in the predominance of vagal tonus in sham-operated rats, but HR variations due to methylatropine were decreased in the resistance trained rats compared to sedentary rats. Evaluation of BRS showed that resistance training for sham-operated and ovariectomized rats reduced the tachycardic responses in relation to aerobic training. Evaluation of HRV in trained rats showed that aerobic training reduced LF oscillations in sham-operated rats, whereas resistance training had a contrary effect. In the ovariectomized rats, aerobic training increased high frequency oscillations (HF = 0.75-2.5 Hz), whereas resistance training produced no effect. In sham-operated rats, both types of training increased the vagal autonomic tonus, but resistance training reduced HF oscillations and BRS as well. In turn, both types of training had similar results in ovariectomized rats, except for HRV, as aerobic training promoted an increase in HF oscillations. (C) 2011 Elsevier B.V. All rights reserved.

Chronic exercise decreases cytokine production in healthy rat skeletal muscle

Skeletal muscle is the source of pro- and anti-inflammatory cytokines, and recently, it has been recognized as an important source of interleukin-6 (IL-6). Acute physical exercise is known to induce a pro-inflammatory cytokine profile in the plasma. However, the effect of chronic physical exercise in the production of pro- and anti-inflammatory cytokines by the skeletal muscle has never been examined. We assessed IL-6, TNF-alpha, IL-1 beta and IL-10 levels in the skeletal muscle of rats submitted to endurance training. Animals were randomly assigned to either a Sedentary group (S, n = 7) or an endurance exercise trained group (T, n = 8). Trained rats ran on a treadmill for 5 days week(-1) for 8 weeks (60% VO(2max)). Detection of IL-6, TNF-alpha, IL-1 beta and IL-10 protein expression was carried out by ELISA. We found decreased expression of IL-1 beta, IL-6, TNF-alpha and IL-10 (28%, 27%. 32% and 37%, respectively, p < 0.05) in the extensor digital longus (EDL) from T, when compared with S. In the soleus, IL-1 beta, TNF-alpha and IL-10 protein levels were similarly decreased (34%, 42% and 50%, respectively, p < 0.05) in T in relation to S, while IL-6 expression was not affected by the training protocol. In conclusion, exercise training induced decreased cytokine protein expression in the skeletal muscle. These data show that in healthy rats, 8-week moderate-intensity aerobic training down regulates skeletal muscle production of cytokines involved in the onset, maintenance and regulation of inflammation, and that the response is heterogeneous according to fibre composition. Copyright (C) 2009 John Wiley & Sons, Ltd.

Effect of gender on training-induced vascular remodeling in SHR

There is accumulating evidence that physical inactivity, associated with the modern sedentary lifestyle, is a major determinant of hypertension. It represents the most important modifiable risk factor for cardiovascular diseases, which are the leading cause of morbidity and mortality for both men and women. In addition to involving sympathetic overactivity that alters hemodynamic parameters, hypertension is accompanied by several abnormalities in the skeletal muscle circulation including vessel rarefaction and increased arteriole wall-to-lumen ratio, which contribute to increased total peripheral resistance. Low-intensity aerobic training is a promising tool for the prevention, treatment and control of high blood pressure, but its efficacy may differ between men and women and between male and female animals. This review focuses on peripheral training-induced adaptations that contribute to a blood pressure-lowering effect, with special attention to differential responses in male and female spontaneously hypertensive rats (SHR). Heart, diaphragm and skeletal muscle arterioles (but not kidney arterioles) undergo eutrophic outward remodeling in trained male SHR, which contributed to a reduction of peripheral resistance and to a pressure fall. In contrast, trained female SHR showed no change in arteriole wall-to-lumen ratio and no pressure fall. On the other hand, training-induced adaptive changes in capillaries and venules (increased density) were similar in male and female SHR, supporting a similar hyperemic response to exercise.

Time course of training-induced microcirculatory changes and of vegf expression in skeletal muscles of spontaneously hypertensive female rats

Exercise-induced vessel changes modulate arterial pressure (AP) in male spontaneously hypertensive rats (SHR). Vascular endothelial growth factor (VEGF) is important for angiogenesis of skeletal muscle. The present study evaluated the time course of VEGF and angiogenesis after short- and long-term exercise training of female SHR and Wistar Kyoto (WKY) rats, 8-9 weeks (200-250 g). Rats were allocated to daily training or remained sedentary for 3 days (N = 23) or 13 weeks (N = 23). After training, the carotid artery was catheterized for AP measurements. Locomotor (tibialis anterior and gracilis) and non-locomotor skeletal muscles (temporalis) were harvested and prepared for histologic and protein expression analyses. Training increased treadmill performance by all groups (SHR = 28%, WKY = 64%, 3 days) and (SHR = 141%, WKY = 122%, 13 weeks). SHR had higher values of AP than WKY (174 ± 4 vs 111 ± 2 mmHg) that were not altered by training. Three days of running increased VEGF expression (SHR = 28%, WKY = 36%) simultaneously with an increase in capillary-to-fiber ratio in gracilis muscle (SHR = 19%, WKY = 15%). In contrast, 13 weeks of training increased gracilis capillary-to-fiber ratio (SHR = 18%, WKY = 19%), without simultaneous changes in VEGF expression. Training did not change VEGF expression and capillarity of temporalis muscle. We conclude that training stimulates time- and tissue-dependent VEGF protein expression, independent of pressure levels. VEGF triggers angiogenesis in locomotor skeletal muscle shortly after the exercise starts, but is not involved in the maintenance of capillarity after long-term exercise in female rats.