Exercise Training as Therapeutic Approach in Cancer Cachexia: A Review of Potential Anti-inflammatory Effect on Muscle Wasting.

Cachexia is a multifactorial inflammatory syndrome with high prevalence in cancer patients. It is characterized by a metabolic chaos culminating in drastic reduction in body weight, mainly due to skeletal muscle and fat depletion. Currently, there is not a standard intervention for cachexia, but it is believed that a dynamic approach should be applied early in the course of the disease to maintain or slow the loss of physical function. The present review sought to explain the different clinical and experimental applications of different models of exercise and their contribution to a better prognosis of the disease. Here the advances in knowledge about the application of physical training in experimental models are elucidated, tests that contribute substantially to elucidate the cellular and biochemical mechanisms of exercise in different ways, as well as clinical trials that present not only the impacts of exercise in front cachexia but also the challenges of its application in clinical practice.

Combined Exercise Modulates Cortisol, Testosterone, and Immunoglobulin A Levels in Individuals Living With HIV/AIDS.

BACKGROUND: Combined exercise (CE) has been recommended for individuals living with HIV/AIDS (ILWHA) under antiretroviral therapy. However, depending on the intensity and duration, physical exercise may occasionally increase inflammatory parameters and reduce immunological responses that if not reversed, cause health injury specifically in this population. Information about immunological and hormonal responses after CE in ILWHA has not been completely elucidated. Therefore, the aim is to verify the acute effects of CE on cortisol, testosterone, immunoglobulin A, and pro-inflammatory and anti-inflammatory cytokines over 24 hours in ILWHA. METHODS: Noninfected individuals and ILWHA undergone 5 sessions of CE prior to the acute assessment session. Seventy-two hours after the last session, the subjects were submitted to one session of CE (aerobic exercise: 25 min at 60-70% reserve heart rate and resistance exercise: 3 sets of 15 maximum repetitions of 6 exercises). Saliva samples were collected before, immediately, 6 and 24 hours after CE. RESULTS: CE reduced cortisol (6 h: 2.54 [0.58] vs 0.65 [0.22] pg·mL-1; P = .02), increased testosterone (all moments) and immunoglobulin A levels (24 h: 255.3 [44.7] vs 349.2 [41.9] µm·mL-1; P = .01) without significant difference in cytokines levels in ILWHA. CONCLUSION: CE modulates cortisol, testosterone, and immunoglobulin A levels without the change in immunological parameters in ILWHA.

Toll-Like Receptor-4 Disruption Suppresses Adipose Tissue Remodeling and Increases Survival in Cancer Cachexia Syndrome.

Cancer-induced cachexia, characterized by systemic inflammation, body weight loss, adipose tissue (AT) remodeling and muscle wasting, is a malignant metabolic syndrome with undefined etiology. Here, we show that both genetic ablation and pharmacological inhibition of TLR4 were able to attenuate the main clinical markers of cachexia in mice bearing Lewis lung carcinoma (LLC). AT remodelling was not found in LLC tumor-bearing (TB) TLR4-/- mice due to reduced macrophage infiltration and adipocyte atrophy. TLR4-/- mice were also resistant to cold-induced browning of subcutaneous AT (scAT). Importantly, pharmacological inhibition of TLR4 (Atorvastatin) reproduced the main protective effect against AT remodeling found in TLR4-/- TB mice. Moreover, the treatment was effective in prolonging survival and attenuating tumor mass growth when compared to non-treated-TB animals. Furthermore, tumor-induced elevation of circulating pro-inflammatory cytokines was similarly abolished in both genetic ablation and pharmacological inhibition of TLR4. These data suggest that TLR4 is a critical mediator and a promising target for novel anti-cachexia therapies.

Peak Velocity as an Alternative Method for Training Prescription in Mice.

Purpose: To compare the efficiency of an aerobic physical training program prescribed according to either velocity associated with maximum oxygen uptake (vVO2max) or peak running speed obtained during an incremental treadmill test (Vpeak_K) in mice. Methods: Twenty male Swiss mice, 60 days old, were randomly divided into two groups with 10 animals each: 1. group trained by vVO2max (GVO2), 2. group trained by Vpeak_K (GVP). After the adaptation training period, an incremental test was performed at the beginning of each week to adjust training load and to determine the amount of VO2 and VCO2 fluxes consumed, energy expenditure (EE) and run distance during the incremental test. Mice were submitted to 4 weeks of aerobic exercise training of moderate intensity (velocity referring to 70% of vVO2max and Vpeak_K) in a programmable treadmill. The sessions lasted from 30 to 40 min in the first week, to reach 60 min in the fourth week, in order to provide the mice with a moderate intensity exercise, totaling 20 training sessions. Results: Mice demonstrated increases in VO2max (ml·kg-1·min-1) (GVO2 = 49.1% and GVP = 56.2%), Vpeak_K (cm·s-1) (GVO2 = 50.9% and GVP = 22.3%), EE (ml·kg-0,75·min-1) (GVO2 = 39.9% and GVP = 51.5%), and run distance (cm) (GVO2 = 43.5% and GVP = 33.4%), after 4 weeks of aerobic training (time effect, P < 0.05); there were no differences between the groups. Conclusions: Vpeak_K, as well as vVO2max, can be adopted as an alternative test to determine the performance and correct prescription of systemized aerobic protocol training to mice.

Effects of physical training for people with HIV-associated lipodystrophy syndrome: a systematic review.

INTRODUCTION: Human immunodeficiency virus-associated lipodystrophy syndrome (HALS) is a major problem among people living with HIV/aids. The exercise training has been used for its treatment; however, the knowledge about benefits and safety still is emerging. The aim was systematically review the literature for physiological, metabolic, immunologic, and morphologic adaptations to aerobic, resistance, and concurrent training in people living with HALS. EVIDENCE ACQUISITION: A search of the Medline, Embase, Cinahl, Lilacs, Scielo, Web of Science, the Cochrane Controlled Trials Register Library and PEDro was performed. The study selection was performed by two blinded researchers follow screening of titles, abstracts, and full-text articles. Therefore, only randomised clinical trials, which investigated the effects of physical training in people with HALS, were included in the present review. The risk of bias was assessed using a Jadad's scale. EVIDENCE SYNTHESIS: From the electronic and manual searches, 332 studies were selected by title, 139 abstracts were read and 95 were excluded, leaving 44 studies, which were read in full. After full text examination only five studies were included in the qualitative analyses. The limitations were: heterogeneity in training prescription, nutritional recommendations, and diagnosis of lipodystrophy, small sample size, utilization of methods with questionable validity for assessments. CONCLUSIONS: There is no effect of physical training on CD4 cell count. In addition, aerobic and concurrent training improve VO2max, likewise resistance and concurrent training improve muscular strength.

Effects of 16 Weeks of Concurrent Training on Resting Heart Rate Variability and Cardiorespiratory Fitness in People Living With HIV/AIDS Using Antiretroviral Therapy: A Randomized Clinical Trial.

Pedro, RE, Guariglia, DA, Okuno, NM, Deminice, R, Peres, SB, and Moraes, SMF. Effects of 16 weeks of concurrent training on resting heart rate variability and cardiorespiratory fitness in people living with HIV/AIDS using antiretroviral therapy: a randomized clinical trial. J Strength Cond Res 30(12): 3494-3502, 2016-The study evaluated the effects of concurrent training on resting heart rate variability (HRVrest) and cardiorespiratory fitness in people living with HIV/AIDS undergoing antiretroviral therapy (ART). Fifty-eight participants were randomized into 2 groups (control and training group); however, only 33 were analyzed. The variables studied were HRVrest indices, submaximal values of oxygen uptake (V[Combining Dot Above]O2sub) and heart rate (HR5min), peak speed (Vpeak), and peak oxygen uptake (V[Combining Dot Above]O2peak). The training group performed concurrent training (15-20 minutes of aerobic exercise plus 40 minutes of resistance exercise), 3 times per week, for 16 weeks. Posttraining V[Combining Dot Above]O2peak and Vpeak increased, and HR5min decreased. Resting heart rate variability indices did not present statistical differences posttraining; however, the magnitude-based inferences demonstrated a "possibly positive effect" for high frequency (HF) and low frequency (LF) plus high frequency (LF + HF) and a "likely positive effect" for R-Rmean posttraining. In conclusion, concurrent training was effective at improving cardiorespiratory fitness and endurance performance. Moreover, it led to probably a positive effect on HF and a likely positive effect on R-Rmean in people living with HIV/AIDS undergoing ART.

Pioglitazone treatment increases survival and prevents body weight loss in tumor-bearing animals: possible anti-cachectic effect.

Cachexia is a multifactorial syndrome characterized by profound involuntary weight loss, fat depletion, skeletal muscle wasting, and asthenia; all symptoms are not entirely attributable to inadequate nutritional intake. Adipose tissue and skeletal muscle loss during cancer cachexia development has been described systematically. The former was proposed to precede and be more rapid than the latter, which presents a means for the early detection of cachexia in cancer patients. Recently, pioglitazone (PGZ) was proposed to exhibit anti-cancer properties, including a reduction in insulin resistance and adipose tissue loss; nevertheless, few studies have evaluated its effect on survival. For greater insight into a potential anti-cachectic effect due to PGZ, 8-week-old male Wistar rats were subcutaneously inoculated with 1 mL (2×107) of Walker 256 tumor cells. The animals were randomly assigned to two experimental groups: TC (tumor + saline-control) and TP5 (tumor + PGZ/5 mg). Body weight, food ingestion and tumor growth were measured at baseline and after removal of tumor on days 7, 14 and 26. Samples from different visceral adipose tissue (AT) depots were collected on days 7 and 14 and stored at -80o C (5 to 7 animals per day/group). The PGZ treatment showed an increase in the survival average of 27.3% (P< 0.01) when compared to TC. It was also associated with enhanced body mass preservation (40.7 and 56.3%, p< 0.01) on day 14 and 26 compared with the TC group. The treatment also reduced the final tumor mass (53.4%, p<0.05) and anorexia compared with the TC group during late-stage cachexia. The retroperitoneal AT (RPAT) mass was preserved on day 7 compared with the TC group during the same experimental period. Such effect also demonstrates inverse relationship with tumor growth, on day 14. Gene expression of PPAR-γ, adiponectin, LPL and C/EBP-α from cachectic rats was upregulated after PGZ. Glucose uptake from adipocyte cells (RPAT) was entirely re-established due to PGZ treatment. Taken together, the results demonstrate beneficial effects of PGZ treatment at both the early and final stages of cachexia.

Mechanisms of obesity and related pathologies: transcriptional control of adipose tissue development.

Obesity and its associated disorders, including diabetes and cardiovascular disease, have now reached epidemic proportions in the Western world, resulting in dramatic increases in healthcare costs. Understanding the processes and metabolic perturbations that contribute to the expansion of adipose depots accompanying obesity is central to the development of appropriate therapeutic strategies. This minireview focuses on a discussion of the recent identification of molecular mechanisms controlling the development and function of adipose tissues, as well as how these mechanisms contribute to the regulation of energy balance in mammals.

C/EBPalpha and the corepressors CtBP1 and CtBP2 regulate repression of select visceral white adipose genes during induction of the brown phenotype in white adipocytes by peroxisome proliferator-activated receptor gamma agonists.

White adipose tissue (WAT) stores energy in the form of triglycerides, whereas brown tissue (BAT) expends energy, primarily by oxidizing lipids. WAT also secretes many cytokines and acute-phase proteins that contribute to insulin resistance in obese subjects. In this study, we have investigated the mechanisms by which activation of peroxisome proliferator-activated receptor gamma (PPARgamma) with synthetic agonists induces a brown phenotype in white adipocytes in vivo and in vitro. We demonstrate that this phenotypic conversion is characterized by repression of a set of white fat genes ("visceral white"), including the resistin, angiotensinogen, and chemerin genes, in addition to induction of brown-specific genes, such as Ucp-1. Importantly, the level of expression of the "visceral white" genes is high in mesenteric and gonadal WAT depots but low in the subcutaneous WAT depot and in BAT. Mutation of critical amino acids within helix 7 of the ligand-binding domain of PPARgamma prevents inhibition of visceral white gene expression by the synthetic agonists and therefore shows a direct role for PPARgamma in the repression process. Inhibition of the white adipocyte genes also depends on the expression of C/EBPalpha and the corepressors, carboxy-terminal binding proteins 1 and 2 (CtBP1/2). The data further show that repression of resistin and angiotensinogen expression involves recruitment of CtBP1/2, directed by C/EBPalpha, to the minimal promoter of the corresponding genes in response to the PPARgamma ligand. Developing strategies to enhance the brown phenotype in white adipocytes while reducing secretion of stress-related cytokines from visceral WAT is a means to combat obesity-associated disorders.

Pinealectomy reduces hepatic and muscular glycogen content and attenuates aerobic power adaptability in trained rats.

The current study emphasizes the crucial role of the pineal gland on the effects of chronic training in different tissues focusing on carbohydrate metabolism. We investigated the maximal oxygen uptake (aerobic power), muscle and liver glycogen content, and also the enzymes involved in the carbohydrate metabolism of rat adipose tissue. Pinealectomized and sham-operated adult male Wistar rats were distributed into four groups: pinealectomized (PINX) untrained, pinealectomized trained, control untrained and control trained. The maximal oxygen uptake capability was assayed before and after the training protocol by indirect open circuit calorimetry. The rats were killed after 8 wk of training. Blood samples were collected for glucose and insulin determinations. The glycogen content was assayed in the liver and muscle. Maximal activities of epididymal adipose tissue enzymes (hexokinase, pyruvate kinase, lactate dehydrogenase, citrate synthase and malic enzyme) as well as adipocyte size were determined. The exercise training in control animals promoted an increase in the aerobic power and in liver glycogen content but caused a reduction in the malic enzyme activity in adipose tissue. However, PINX trained animals, in contrast to trained controls, showed a decrease in the aerobic power and in liver and muscle glycogen content, as well as an increase in the activity of the adipocyte enzymes involved in carbohydrate metabolism. In conclusion, these data show that the pineal gland integrity is necessary for the homeostatic control of energy metabolism among adipose, muscle and hepatic tissues. The pinealectomized animals showed alterations in adaptive responses of the maximal oxygen uptake to training. Therefore, the pineal gland must be considered an influential participant in the complex adaptation to exercise and is involved in the improvement of endurance capacity.

Neonatal streptozotocin-induced diabetes mellitus: a model of insulin resistance associated with loss of adipose mass.

The use of experimental models of diabetes mellitus (DM) has been useful in understanding the complex pathogenesis of DM. Streptozotocin (STZ) injected in rats during the neonatal period has usually led to the major features described in diabetic patients (hyperglycemia, polyphagia, polydipsia, polyuria, and abnormal glucose tolerance) in a short period. Diabetes mellitus is a product of low insulin sensibility and pancreatic beta-cell dysfunction. Its process is characterized by a symptomless prediabetic phase before the development of the disease. In this study, we investigated the long-term effects of diabetes induction regarding the cellular metabolic aspects of this model and its similarities with diabetes found in humans. Male Wistar rats (5-day old) were intraperitoneally injected with STZ (150 mg/kg) and followed up for 12 weeks. On the 12th week, animals were decapitated and peri-epididymal fat pads were excised for adipocyte isolation. The following studies were performed: insulin-stimulated 2-deoxy-d-[(3)H]glucose uptake; incorporation of d-[U-(14)C]-glucose into lipids and conversion into (14)CO(2); and insulin binding. The weight gain rate of the STZ-treated group became significantly lower by the eighth week. These rats developed polyphagia, polydipsia, polyuria, and glycosuria, and impaired glucose tolerance. Biological tests with isolated adipocytes revealed a reduction in the insulin receptor number and an impairment in their ability to oxidize glucose as well as to incorporate it into lipids. Interestingly, parallel to reduced body weight, the adipocyte size of STZ rats was significantly small. We concluded that apart of a decrease in pancreatic insulin content, this experimental model of DM promotes a remarkable and sustained picture of insulin resistance in adulthood that is strongly related to a loss in adipose mass.

Reduced lipolysis and increased lipogenesis in adipose tissue from pinealectomized rats adapted to training.

The current study investigated the effects of chronic training and pinealectomy on the lipogenic and lipolytic activity of adipose tissue. Pinealectomized and sham-operated adult male Wistar rats were distributed in to four subgroups: pinealectomized untrained, pinealectomized trained, control untrained and control trained. At the end of the training period (8 wk) the rats were killed. Blood samples were collected for glucose, insulin and leptin determinations. Peri-epididymal adipocytes were isolated for measurement of in vitro rates of lipolysis and incorporation of substrates (D-[U-14C]-glucose, L-[U-14C]-lactate, [2-14C]-acetate and [1-14C]-palmitate) into lipids, and samples of epididymal adipose tissue were homogenized for evaluation of glucose-6-phosphate dehydrogenase maximal activity. Pinealectomy resulted in a significantly increased lipolytic capacity in response to isoproterenol and a decrease in circulating leptin levels without affecting the rates of incorporation of different substrates into lipids. However, only in the intact control group did training promote a higher basal and isoproterenol-stimulated lipolysis, increase the incorporation of palmitate (esterification), decrease the incorporation of acetate (lipogenesis) into lipids and diminish circulating leptin levels. These effects of exercise training were not seen in pinealectomized rats. However, pinealectomized trained animals showed a marked reduction in lipolysis and an increased rate of acetate incorporation. In conclusion, we demonstrated for the first time that the pineal gland plays an important role in the regulation of lipid metabolism in such a way that its absence caused a severe alteration in the balance between lipogenesis and lipolysis, which becomes evident with the adaptation to exercise training.

Pinealectomy impairs adipose tissue adaptability to exercise in rats.

This study investigated the effects of pinealectomy and exercise training on rat adipose tissue metabolism. Pinealectomized (PINX) and sham-operated (CONTROL) adult male Wistar rats were subdivided into four subgroups, including PINX untrained, PINX trained, CONTROL untrained and CONTROL trained. At the end of the training period (8 wk), the rats were killed and peri-epididymal adipocytes were isolated for in vitro insulin-stimulated glucose uptake, conversion of D-[U-14C]-glucose, l-[U-14C]-lactate, [2-14C]-acetate and [1-14C]-palmitate into 14CO2, and insulin binding. Pinealectomy resulted in a significantly decreased insulin-stimulated glucose uptake in adipocytes without affecting insulin-binding capacity. However, in intact control animals only, training promoted a higher baseline glucose uptake in adipocytes. Training influenced the adipocyte ability to oxidize the different substrates: the rates of glucose and palmitate oxidation increased while the rates of lactate and acetate diminished. Nevertheless, these effects of exercise training were not seen in pinealectomized rats. Additionally, an increase in palmitate oxidation was observed in sedentary pinealectomized animals. In conclusion, these data show that the pineal gland alters the patterns of substrate utilization by the adipocyte, in such a way that its absence disrupts the ability to adapt to the metabolic demands evoked by exercise training in rats.

Endurance exercise training increases insulin responsiveness in isolated adipocytes through IRS/PI3-kinase/Akt pathway.

Endurance exercise training promotes important metabolic adaptations, and the adipose tissue is particularly affected. The aim of this study was to investigate how endurance exercise training modulates some aspects of insulin action in isolated adipocytes and in intact adipose tissue. Male Wistar rats were submitted to daily treadmill running (1 h/day) for 7 wk. Sedentary age-matched rats were used as controls. Final body weight, body weight gain, and epididymal fat pad weight did not show any statistical differences between groups. Adipocytes from trained rats were smaller than those from sedentary rats (205 +/- 16.8 vs. 286 +/- 26.4 pl; P < 0.05). Trained rats showed decreased plasma glucose (4.9 +/- 0.13 vs. 5.3 +/- 0.07 mM; P < 0.05) and insulin levels (0.24 +/- 0.012 vs. 0.41 +/- 0.049 mM; P < 0.05) and increased insulin-stimulated glucose uptake (23.1 +/- 3.1 vs. 12.1 +/- 2.9 pmol/cm(2); P < 0.05) compared with sedentary rats. The number of insulin receptors and the insulin-induced tyrosine phosphorylation of insulin receptor-beta subunit did not change between groups. Insulin-induced tyrosine phosphorylation insulin receptor substrates (IRS)-1 and -2 increased significantly (1.57- and 2.38-fold, respectively) in trained rats. Insulin-induced IRS-1/phosphatidylinositol 3 (PI3)-kinase (but not IRS-2/PI3-kinase) association and serine Akt phosphorylation also increased (2.06- and 3.15-fold, respectively) after training. The protein content of insulin receptor-beta subunit, IRS-1 and -2, did not differ between groups. Taken together, these data support the hypothesis that the increased adipocyte responsiveness to insulin observed after endurance exercise training is modulated by IRS/PI3-kinase/Akt pathway.

Endurance training improves responsiveness to insulin and modulates insulin signal transduction through the phosphatidylinositol 3-kinase/Akt-1 pathway.

BACKGROUND: Endurance training increases insulin-stimulated muscle glucose transport and leads to improved metabolic control in diabetic patients. OBJECTIVE: To analyze the effects of endurance training on the early steps of insulin action in muscle of rats. DESIGN: Male rats submitted to daily swimming for 6 weeks were compared with sedentary controls. At the end of the training period, anesthetized animals received an intravenous (i.v.) injection of insulin and had a fragment of their gastrocnemius muscle excised for the experiments. METHODS: Associations between insulin receptor, insulin receptor substrates (IRS)-1 and -2 and phosphatidylinositol 3-kinase (PI3-kinase) were analyzed by immunoprecipitation and immunoblotting. Akt-1 serine phosphorylation and specific protein quantification were detected by immunoblotting of total extracts, and IRS-1/IRS-2-associated PI3-kinase activity were determined by thin-layer chromatography. RESULTS: Insulin-induced phosphorylation of IRS-1 and IRS-2 increased respectively by 1.8-fold (P<0.05) and 1.5-fold (P<0.05), whereas their association with PI3-kinase increased by 2.3-fold (P<0.05) and 1.9-fold (P<0.05) in trained rats as compared with sedentary controls, respectively. The activity of PI3-kinase associated with IRS-1 and IRS-2 increased by 1.8-fold (P<0.05) and 1.7-fold (P<0.05) respectively, in trained rats as compared with their untrained counterparts. Serine phosphorylation of Akt-1/PKB increased 1.7-fold (P<0.05) in trained rats in response to insulin. These findings were accompanied by increased responsiveness to insulin as demonstrated by a reduced area under the curve for insulin during an i.v. glucose tolerance test, by increased glucose disappearance rate during an insulin tolerance test, and by increased expression of glucose transporter-4. CONCLUSIONS: The increased responsiveness to insulin induced by chronic exercise in rat skeletal muscle may result, at least in part, from the modulation of the insulin signaling pathway at different molecular levels.