Thiago Gomes Heck

HSP70 expression: does it a novel fatigue signalling factor from immune system to the brain?

Integrative physiology studies have shown that immune system and central nervous system interplay very closely towards behavioural modulation. Since the 70‐kDa heat shock proteins (HSP70s), whose heavy expression during exercise is well documented in the skeletal muscle and other tissues, is also extremely well conserved in nature during all evolutionary periods of species, it is conceivable that HSP70s might participate of physiologic responses such as fatigue induced by some types of physical exercise. In this way, increased circulating levels of extracellular HSP70 (eHSP70) could be envisaged as an immunomodulatory mechanism induced by exercise, besides other chemical messengers (e.g. cytokines) released during an exercise effort, that are able to binding a number of receptors in neural cells. Studies from this laboratory led us to believe that increased levels of eHSP70 in the plasma during exercise and the huge release of eHSP70 from lymphocytes during high‐load exercise bouts may participate in the fatigue sensation, also acting as a danger signal from the immune system. Copyright

The Chaperone Balance Hypothesis: The Importance of the Extracellular to Intracellular HSP70 Ratio to Inflammation-Driven Type 2 Diabetes, the Effect of Exercise, and the Implications for Clinical Management

Recent evidence shows divergence between the concentrations of extracellular 70 kDa heat shock protein [eHSP70] and its intracellular concentrations [iHSP70] in people with type 2 diabetes (T2DM). A vital aspect regarding HSP70 physiology is its versatility to induce antagonistic actions, depending on the location of the protein. For example, iHSP70 exerts a powerful anti-inflammatory effect, while eHSP70 activates proinflammatory pathways. Increased eHSP70 is associated with inflammatory and oxidative stress conditions, whereas decreased iHSP70 levels are related to insulin resistance in skeletal muscle. Serum eHSP70 concentrations are positively correlated with markers of inflammation, such as C-reactive protein, monocyte count, and TNF-α, while strategies to enhance iHSP70 (e.g., heat treatment, chemical HSP70 inducers or coinducers, and physical exercise) are capable of reducing the inflammatory profile and the insulin resistance state. Here, we present recent findings suggesting that imbalances in the HSP70 status, described by the [eHSP70]/[iHSP70] ratio, may be determinant to trigger a chronic proinflammatory state that leads to insulin resistance and T2DM development. This led us to hypothesize that changes in this ratio value could be used as a biomarker for the management of the inflammatory response in insulin resistance and diabetes.

Alanyl-glutamine and glutamine plus alanine supplements improve skeletal redox status in trained rats: Involvement of heat shock protein pathways

AIMS We hypothesized that oral l-glutamine supplementations could attenuate muscle damage and oxidative stress, mediated by glutathione (GSH) in high-intensity aerobic exercise by increasing the 70-kDa heat shock proteins (HSP70) and heat shock factor 1 (HSF1). MAIN METHODS Adult male Wistar rats were 8-week trained (60-min/day, 5 days/week) on a treadmill. During the last 21 days, the animals were supplemented with either l-alanyl-l-glutamine dipeptide (1.5 g/kg, DIP) or a solution containing the amino acids l-glutamine (1g/kg) and l-alanine (0.67 g/kg) in their free form (GLN+ALA) or water (controls). KEY FINDINGS Plasma from both DIP- and GLN+ALA-treated animals showed higher l-glutamine concentrations and reduced ammonium, malondialdehyde, myoglobin and creatine kinase activity. In the soleus and gastrocnemius muscle of both supplemented groups, l-glutamine and GSH contents were increased and GSH disulfide (GSSG) to GSH ratio was attenuated (p<0.001). In the soleus muscle, cytosolic and nuclear HSP70 and HSF1 were increased by DIP supplementation. GLN+ALA group exhibited higher HSP70 (only in the nucleus) and HSF1 (cytosol and nucleus). In the gastrocnemius muscle, both supplementations were able to increase cytosolic HSP70 and cytosolic and nuclear HSF1. SIGNIFICANCE In trained rats, oral supplementation with DIP or GLN+ALA solution increased the expression of muscle HSP70, favored muscle l-glutamine/GSH status and improved redox defenses, which attenuate markers of muscle damage, thus improving the beneficial effects of high-intensity exercise training.

Heat shock proteins and heat therapy for type 2 diabetes: pros and cons.

Purpose of reviewHeat therapy, such as sauna and hot tub, has become an increasingly regular therapeutical practice around the world since several studies have shown benefits of heat therapy in metabolic and cardiovascular diseases. The use of heat therapy in people with type 2 diabetes mellitus revealed a striking reduction of 1% unit in the glycated hemoglobin, suggesting this therapy for the treatment of diabetes. Herein, we shall discuss the use of heat therapy and the mechanisms involved, and suggest a provisional guide for the use of heat therapy in obesity and diabetes. Recent findingsHuman studies indicate that heat therapy reduces fasting glycemia, glycated hemoglobin, body weight, and adiposity. Animal studies have indicated that nitric oxide and the increase in heat shock protein 70 expression is involved in the improvements induced by heat therapy on insulin sensitivity, adiposity, inflammation, and vasomotricity. SummaryHeat therapy is a promising and inexpensive tool for the treatment of obesity and diabetes. We proposed that transient increments in nitric oxide and heat shock protein 70 levels may explain the benefits of heat therapy. We suggest that heat therapy (sauna: 80–100°C; hot tub: at 40°C) for 15 min, three times a week, for 3 months, is a safe method to test its efficiency.

L-glutamine Supplementations Enhance Liver Glutamine-Glutathione Axis and Heat Shock Factor-1 Expression in Endurance-Exercise Trained Rats

Liver L-glutamine is an important vehicle for the transport of ammonia and intermediary metabolism of amino acids between tissues, particularly under catabolic situations, such as high-intensity exercise. Hence, the aim of this study was to investigate the effects of oral supplementations with L-glutamine in its free or dipeptide forms (with L-alanine) on liver glutamine-glutathione (GSH) axis, and 70 kDa heat shock proteins (HSP70)/heat shock transcription factor 1 (HSF1) expressions. Adult male Wistar rats were 8-week trained (60 min/day, 5 days/week) on a treadmill. During the last 21 days, the animals were daily supplemented with 1 g of L-glutamine/kg body weight per day in either l-alanyl-L-glutamine dipeptide (DIP) form or a solution containing L-glutamine and l-alanine in their free forms (GLN+ALA) or water (controls). Exercise training increased cytosolic and nuclear HSF1 and HSP70 expression, as compared with sedentary animals. However, both DIP and GLN+ALA supplements enhanced HSF1 expression (in both cytosolic and nuclear fractions) in relation to exercised controls. Interestingly, HSF1 rises were not followed by enhanced HSP70 expression. DIP and GLN+ALA supplements increased plasma glutamine concentrations (by 62% and 59%, respectively) and glutamine to glutamate plasma ratio in relation to trained controls. This was in parallel with a decrease in plasma ammonium levels. Supplementations increased liver GSH (by 90%), attenuating the glutathione disulfide (GSSG) to GSH ratio, suggesting a redox state protection. In conclusion, oral administration with DIP and GLN+ALA supplements in endurance-trained rats improve liver glutamine-GSH axis and modulate HSF1 pathway.

Subclinical Processes in the Development of Type Two Diabetes

The imbalance in metabolic homeostasis in type 2 diabetes (T2DM) is accompanied by cellular stress, altered expression and circulating concentration of heat shock proteins (HSP) and cytokines (pro and anti-inflammatory). Also T2DM subjects had altered redox state (oxidative stress) and erythrocytes parameters. This set of molecular, biochemical and immuno haematological alterations are usually subclinical events, but characterizes chemical and biological processes associated with the development of insulin resistance and the pathophysiology of T2DM. These process and markers of T2DM complications and development will be briefly outlined throughout this mini-review article. The establishment of new strategies for glycemic control required more attention and more studies about inflammatory related biomarkers in T2DM.

Role of Heat Shock Proteins in Skeletal Muscle

The ability of the human organism to respond with rapid and appropriate modification during physiological challenges is an essential feature for its own survival. These modifications are inseparable from a satisfactory adjustment of the physiological processes of the whole body, where physiological systems tend to maintain relatively constant composition of the internal environment (milieu interieur), despite the constant challenges that the body is submitted daily to, which is known as homeostatic control [1, 2].

Exercise Training under Exposure to Low Levels of Fine Particulate Matter: Effects on Heart Oxidative Stress and Extra-to-Intracellular HSP70 Ratio

Fine particulate matter (PM2.5) promotes heart oxidative stress (OS) and evokes anti-inflammatory responses observed by increased intracellular 70 kDa heat shock proteins (iHSP70). Furthermore, PM2.5 increases the levels of these proteins in extracellular fluids (eHSP70), which have proinflammatory roles. We investigated whether moderate and high intensity training under exposure to low levels of PM2.5 modifies heart OS and the eHSP70 to iHSP70 ratio (H-index), a biomarker of inflammatory status. Male mice (n = 32), 30 days old, were divided into six groups for 12 weeks: control (CON), moderate (MIT) and high intensity training (HIT), exposure to 5 μg of PM2.5 daily (PM2.5), and moderate and high intensity training exposed to PM2.5 (MIT + PM2.5 and HIT + PM2.5 groups). The CON and PM2.5 groups remained sedentary. The MIT + PM2.5 group showed higher heart lipid peroxidation levels than the MIT and PM2.5 groups. HIT and HIT + PM2.5 showed higher heart lipid peroxidation levels and lower eHSP70 and H-index levels compared to sedentary animals. No alterations were found in heart antioxidant enzyme activity or iHSP70 levels. Moderate exercise training under exposure to low levels of PM2.5 induces heart OS but does not modify eHSP70 to iHSP70 ratio (H-index). High intensity exercise training promotes anti-inflammatory profile despite exposure to low levels of PM2.5.

Efeitos do tratamento com glutamina via enteral em modelo animal de sepse

The aim of study was to evaluate the effects of enteral glutamine treatment on clinical parameters in an animal model of sepsis. Were used 24 mice (B6129SF2/J) in two experiments: First 11 mice were divided into three groups to evaluate the animal model better to simulate the sepsis. Animals received saline (control) or faecal solution 10 or 20% (i.p), and were evaluated glycaemia and rectal temperature for 24h. Second 13 mice were divided into: Control, Sepsis, Glutamine and Sepsis+Glutamine. Glutamine was administered by gavage (1 g/kg) each 4h for 47h. Glycaemia, rectal temperature, leukocyte count and body weight was evaluated. Results: The administration of 20% faecal solution induced hypodynamic phase of sepsis with hypothermia, hypoglycaemia and low leukocyte count. The treatment with glutamine avoids the decrease in leukocyte. Conclusion: Since the immune response is essential in sepsis, the use of glutamine can be useful as adjuvant therapy in sepsis.

Resistance training and L-arginine supplementation are determinant in genomic stability, cardiac contractility and muscle mass development in rats

L-arginine supplementation has been related to increased maximum strength and improvement of hemodynamic parameters in several diseases. The aim of our study was to evaluate the effect of L-arginine supplementation and resistance training on muscle mass, hemodynamic function and DNA damage in healthy rats subjected to a low-arginine concentration diet. Twenty three Wistar rats (290-320g) were divided into 4 groups: Sedentary (SED-Arg, n = 6), Sedentary+Arg (SED+Arg, n = 6), Resistance Training (RT-Arg, n = 5), Resistance Training+Arg (RT+Arg, n = 6). Trained animals performed resistance training protocol in a squat apparatus adapted for rats (4 sets of 10–12 repetitions, 90s of interval, 4x/week, 65–75% of One Maximum Repetition, for 8 weeks). Comet assay was performed to measure DNA damage in leukocytes. The resistance training induced higher muscle mass in trained groups. The L-arginine supplementation increased both gastrocnemius and left ventricle to body mass ratio and increased left ventricle contractility without changing hemodynamic variables. The SED+Arg group showed higher concentration of extracellular heat shock protein 72 (eHSP72) and total testosterone, as well as lower uric acid concentration in blood versus SED-Arg group. The administration of isolated L-arginine supplementation and its association with resistance training promoted less damage in leukocytes DNA. In conclusion, the L-arginine supplementation showed synergistic effect with resistance training regarding leukocyte genomic stability in a low-L-arginine diet scenario.