Exercise training improves radiotherapy efficiency in a murine model of prostate cancer.

Engaging in exercise while undergoing radiotherapy (RT) has been reported to be safe and achievable. The impact of exercise training (ET) on RT efficiency is however largely unknown. Our study aims to investigate the interactions between ET and RT on prostate cancer growth. Athymic mice received a subcutaneous injection of PPC-1 cells and were randomly assigned to either cancer control, cancer ET, cancer RT, or cancer RT combined with ET (CaRT-ET). Mice were sacrificed 24 days post-injection. All three intervention groups had reduced tumor size, the most important decrease being observed in CaRT-ET mice. Apoptotic marker cleaved caspase-3 was not modified by ET, but enhanced with RT. Importantly, this increase was the highest when the two strategies were combined. Furthermore, NK1.1 staining and gene expression of natural killer (NK) cell receptors Klrk1 and Il2rß were not affected by ET alone but were increased with RT, this effect being potentiated when combined with ET. Overall, our study shows that (a) ET enhances RT efficiency by potentiating NK cell infiltration, and (b) while ET alone and ET combined with RT both reduce tumor growth, the mechanisms mediating these effects are different.

Skeletal muscle ceramides do not contribute to physical-inactivity-induced insulin resistance.

Physical inactivity increases the risk to develop type 2 diabetes, a disease characterized by a state of insulin resistance. By promoting inflammatory state, ceramides are especially recognized to alter insulin sensitivity in skeletal muscle. The present study was designed to analyze, in mice, whether muscle ceramides contribute to physical-inactivity-induced insulin resistance. For this purpose, we used the wheel lock model to induce a sudden reduction of physical activity, in combination with myriocin treatment, an inhibitor of de novo ceramide synthesis. Mice were assigned to 3 experimental groups: voluntary wheel access group (Active), a wheel lock group (Inactive), and wheel lock group treated with myriocin (Inactive-Myr). We observed that 10 days of physical inactivity induces hyperinsulinemia and increases basal insulin resistance (HOMA-IR). The muscle ceramide content was not modified by physical inactivity and myriocin. Thus, muscle ceramides do not play a role in physical-inactivity-induced insulin resistance. In skeletal muscle, insulin-stimulated protein kinase B phosphorylation and inflammatory pathway were not affected by physical inactivity, whereas a reduction of glucose transporter type 4 content was observed. Based on these results, physical-inactivity-induced insulin resistance seems related to a reduction in glucose transporter type 4 content rather than defects in insulin signaling. We observed in inactive mice that myriocin treatment improves glucose tolerance, insulin-stimulated protein kinase B, adenosine-monophosphate-activated protein kinase activation, and glucose transporter type 4 content in skeletal muscle. Such effects occur regardless of changes in muscle ceramide content. These findings open promising research perspectives to identify new mechanisms of action for myriocin on insulin sensitivity and glucose metabolism.

Cancer-induced cardiac cachexia: Pathogenesis and impact of physical activity (Review).

Cachexia is a wasting syndrome observed in many patients suffering from several chronic diseases including cancer. In addition to the progressive loss of skeletal muscle mass, cancer cachexia results in cardiac function impairment. During the severe stage of the disease, patients as well as animals bearing cancer cells display cardiac atrophy. Cardiac energy metabolism is also impeded with disruption of mitochondrial homeostasis and reduced oxidative capacity, although the available data remain equivocal. The release of inflammatory cytokines by tumor is a key mechanism in the initiation of heart failure. Oxidative stress, which results from the combination of chemotherapy, inadequate antioxidant consumption and chronic inflammation, will further foster heart failure. Protein catabolism is due to the concomitant activation of proteolytic systems and inhibition of protein synthesis, both processes being triggered by the deactivation of the Akt/mammalian target of rapamycin pathway. The reduction in oxidative capacity involves AMP-activated protein kinase and peroxisome proliferator-activated receptor gamma coactivator 1α dysregulation. The nuclear factor-κB transcription factor plays a prominent role in the coordination of these alterations. Physical exercise appears as an interesting non-pharmaceutical way to counteract cancer cachexia-induced-heart failure. Indeed, aerobic training has anti-inflammatory effects, increases anti-oxidant defenses, prevents atrophy and promotes oxidative metabolism. The present review points out the importance of better understanding the concurrent structural and metabolic changes within the myocardium during cancer and the protective effects of exercise against cardiac cachexia.

Exercise training combined with antioxidant supplementation prevents the antiproliferative activity of their single treatment in prostate cancer through inhibition of redox adaptation.

In preclinical models, exercise training (ET) or pomegranate juice (PJ) prevents prostate cancer progression. Here, we hypothesized that physical exercise combined with antioxidants could induce synergistic effects through oxidative stress modulation. Forty male Copenhagen rats with prostate tumors were divided into four groups: control, PJ, ET, and PJ+ET. Rats from the PJ group consumed 750 µl of PJ daily, rats from the ET group ran on a treadmill 5 days per week, and PJ+ET rats received the combined treatment. Each week, tumor growth was evaluated. After 4 weeks of treatment, the rats were euthanized and blood, muscles, and tumors were collected. Tumor Ki67, extracellular signal-regulated kinase (ERK) activation, Bcl-2 expression, and enzymatic and nonenzymatic antioxidant defenses, as well as oxidative stress markers (oxidized base, lipid peroxidation, protein carbonylation), were measured. PJ or ET significantly decreased prostate tumor proliferation (Ki67 staining, p<0.05) through the modulation of ERK phosphorylation, whereas the combination of treatments did not limit cancer progression. PJ significantly reduced Bcl-2 expression in tumors (p<0.05) and the combination of PJ and ET prevented this effect. PJ or ET increased enzymatic antioxidant defenses in muscle, PJ increased nonenzymatic antioxidant defenses in plasma and whole blood. In addition, PJ reduced TBARS and 8-oxodGuo levels in tumors as well as ET (p<0.05), whereas protein carbonyl levels were not affected by these two strategies. Paradoxically, association of PJ+ET did not increase antioxidant defenses and no reduction in oxidative stress markers was induced. Loading cancer cells with antioxidants blunts the positive effects of ET and interferes with important reactive oxygen species-mediated physiological processes such as antioxidant adaptations.

Combined insulin treatment and intense exercise training improved basal cardiac function and Ca(2+)-cycling proteins expression in type 1 diabetic rats.

This study investigated the effects of 8 weeks of intense exercise training combined with insulin treatment on the Ca(2+)-cycling protein complex expression and their functional consequences on cardiac function in type 1 diabetic rat hearts. Diabetic Wistar rats were randomly assigned into the following groups: received no treatment, insulin-treated diabetic, trained diabetic, and trained insulin-treated diabetic. A control group was also included. Insulin treatment and (or) treadmill intense exercise training were conducted over 8 weeks. Basal cardiac function was evaluated by Langendorff technique. Cardiac expression of the main Ca(2+)-cycling proteins (RyR2, FKBP 12.6, SERCA2, PLB, NCX1) was assessed by Western blot. Diabetes altered basal cardiac function (±dP/dt) and decrease the expression of the main Ca(2+)-cycling proteins expression: RyR2, SERCA2, and NCX1 (p < 0.05). Whereas combined treatment was not able to normalize -dP/dt, it succeeded to normalize +dP/dt of diabetic rats (p < 0.05). Moreover, both insulin and intense exercise training, applied solely, increased the expression of the Ca(2+)-cycling proteins: RyR2, SERCA2, PLB. and NCX1 (p < 0.05). But this effect was higher when the 2 treatments were combined. These data are the first to show that combined insulin treatment and intense exercise training during diabetes synergistically act on the expression of the main Ca(2+)-cycling proteins, providing insights into mechanisms by which the dual treatment during diabetes improves cardiac function.

The effects of exercise training on myocardial adrenergic and muscarinic receptors.

We investigated the effects of exercise training on heart rate variability (HRV) and myocardial adrenergic and muscarinic receptors in rats. Exercise training induced a decrease in body mass while ventricular size remained unchanged, a development we considered as a relative cardiac hypertrophy. In addition, there was a reduction in the density of myocardial beta(1)-adrenergic receptors. These structural changes were associated with functional adaptations, as illustrated by the increased response of the sinus node to sympathetic blockade.

Relationships between sports-specific characteristics of athlete's heart and maximal oxygen uptake.

BACKGROUND: Improvement to maximal oxygen uptake is mainly due to myocardial adaptations brought about by physical training. As a consequence, the athlete's heart echocardiographic modifications associated with these adaptations are already well-known. We studied the relationships between maximal oxygen uptake (ml/min) and resting echocardiographic patterns in three athlete groups. METHODS: Tumbling (n=16), canoeing (n=12), cycling (n=12) and untrained (n=19) participants performed clinical examination and an echocardiogram. Trained groups performed a maximal graded exercise test on a cycle ergometer with gas exchange analysis. RESULTS: Sport-specific cardiac hypertrophy was observed. No significant echocardiographic difference was noted between untrained and tumbling participants. Canoeists showed higher end-diastolic thickness of the interventricular septum (P<0.001) and left ventricle mass (P<0.05) than untrained and higher posterior wall thickness (P<0.001) and than untrained and tumbling participants. In comparison between untrained, tumbling and cycling participants, left ventricular end-diastolic diameter (P<0.001) and left ventricular mass (P<0.001) was higher in cyclists. In trained subjects studied as a global group, the main linear correlation with maximal oxygen uptake concerned left ventricular end-diastolic diameter (r=0.92; P<0.001), left ventricular mass (r=0.60; P<0.001) and to a lesser extent aortic (r=0.39; P<0.01) and left atrium (r=0.36; P<0.05) diameters and E (r=0.38; P<0.05) and A (r=-0.33; P<0.05) Doppler peak velocities. Each trained group showed specific correlations between echocardiographic parameters and absolute maximal oxygen uptake. No further correlation was noted with left ventricular end-diastolic diameter or left ventricle mass when each group was studied individually. CONCLUSIONS: In athletes, maximal oxygen uptake is partly linked to some resting echocardiographic parameters. Specific relationships between maximal oxygen uptake and some echocardiographic parameters in relation to the sport practised are also observed.

Extreme running competition decreases blood antioxidant defense capacity.

OBJECTIVE: We tested whether an extreme running competition ("Marathon of Sands") might alter the blood's enzymatic and non-enzymatic antioxidant status in 6 well-trained athletes. METHODS: The Marathon of Sands is a competition consisting of six long duration races in the desert in which the athletes carry their own food. Blood samples were collected from an antecubital vein while the athletes were at rest before the competition and then again 72 hours after. Erythrocyte antioxidant enzyme activity (glutathione peroxidase, superoxide dismutase), erythrocyte glutathione level, plasma non-enzymatic status (vitamin C, alpha-tocopherol, retinol, beta-carotene and carotenoids) and plasma lipid peroxidation marker (TBARS) were measured. RESULTS: The Marathon of Sands induced a significant alteration of the blood antioxidant defense capacity. Indeed, 72 hours after the race, significant decreases were recorded in erythrocyte superoxide dismutase activity and in plasma concentrations of retinol, beta-carotene and other carotenoids. These changes were associated with a concomitant increase in erythrocyte glutathione and in plasma TBARS levels. CONCLUSION: This study indicated that such extreme competition induced an imbalance between oxidant and antioxidant protection.

Effect of training on beta1 beta2 beta3 adrenergic and M2 muscarinic receptors in rat heart.

OBJECTIVE: Physical training is known to alter several cardiovascular parameters. These adaptations are for a great part linked to an alteration of the myocardial responses to its autonomic nervous regulation. To further explain the parasympathetic and catecholamine effects, we hypothesized that endurance training could modify rat myocardial beta1, beta2, beta3 adrenoreceptors (AR) and M2 muscarinic cholinergic receptor (AchR) densities. METHODS: Two groups of adults female Wistar rats were studied: controls (C) (N = 7) and trained (T) (N = 9). An 8-wk treadmill training protocol was performed, 5 d x wk and of 1 h x d. At the end of the training session, left ventricle and atria muscle were isolated and weighed. Then, quantification of beta1, beta2, beta3 AR and M2 AchR was performed using Western blot analysis. RESULTS: M2 AchR densities were not modified in left ventricle or in atria by training (respectively, 100 +/- 22%, C vs 101 +/- 14%, T and 100 +/- 23%, C vs 119 +/- 30%, T). Concerning the left ventricle beta AR isoforms, beta1AR density was decreased in T (80 +/- 10% T vs 100 +/- 14% C, P = 0.01), beta2AR was unaltered (102 +/- 12%, T vs 100 +/- 17%, C), and beta3 AR density was increased in T (139 +/- 38% T vs 100 +/- 15% C; P < 0.05). CONCLUSIONS: Our results show for the first time that in female rats an 8-wk treadmill training protocol alters specifically the left ventricle beta AR isoforms densities but not the M2 AchR one. These results could explain some of the beneficial cardiovascular adaptations of the physically trained heart.

Estrogen receptor alpha mRNA in human skeletal muscles.

INTRODUCTION/PURPOSE: To explain the effect of estrogen on skeletal muscle, the presence of estrogen receptor alpha mRNA (ERalpha mRNA) was investigated in human skeletal muscle. METHODS: The highly sensitive technique of nested reverse transcriptase-polymerase chain reaction (nested RT-PCR) was applied on a variety of tissue samples of both sexes: women (deltoid, pectoral, and uterus muscles) (N= 3) and men (deltoid muscle) (N= 3). The total ribonucleic acid was isolated from each tissue sample, reverse transcribed in a thermocycler, and nested PCR was then performed with specific primers. The by-products were analyzed by agarose gel electrophoresis. Internal standard 28S was simultaneously amplified. The ERalpha mRNA level was quantitated by using the ERalpha mRNA/28S mRNA ratio. RESULTS: The expected 204-bp product corresponding to ERalpha was amplified in all tested tissue samples, i.e., deltoid, pectoral, and uterine muscles from women and deltoid muscle from men. The ERalpha mRNA/28S mRNA ratios indicating the receptor expression levels in deltoid muscle from men and women were 0.945 +/- 0.393 (mean +/- SD) (N= 3) and 0.973 +/- 0.136 (mean +/- SD) (N= 2), respectively. CONCLUSIONS: In conclusion, the nested RT-PCR technique identified the presence of transcript encoding ERalpha mRNA in human skeletal muscles. Semi-quantification did not reveal gender difference.