Skeletal muscle makes up 40-50% of body mass, and is thus considered to be a good adult stem cell source for autologous therapy. Although, several stem/progenitor cells have been fractionated from mouse skeletal muscle showing a high potential for therapeutic use, it is unclear whether this is the case in human. Differentiation and therapeutic potential of human skeletal muscle-derived cells (Sk-Cs) was examined. Samples (5-10 g) were obtained from the abdominal and leg muscles of 36 patients (age, 17-79 years) undergoing prostate cancer treatment or leg amputation surgery. All patients gave informed consent. Sk-Cs were isolated using conditioned collagenase solution, and were then sorted as CD34(-)/CD45(-)/CD29(+) (Sk-DN/29(+)) and CD34(+)/CD45(-) (Sk-34) cells, in a similar manner as for the previous mouse Sk-Cs. Both cell fractions were appropriately expanded using conditioned culture medium for about 2 weeks. Differentiation potentials were then examined during cell culture and in vivo transplantation into the severely damaged muscles of athymic nude mice and rats. Interestingly, these two cell fractions could be divided into highly myogenic (Sk-DN/29(+)) and multipotent stem cell (Sk-34) fractions, in contrast to mouse Sk-Cs, which showed comparable capacities in both cells. At 6 weeks after the separate transplantation of both cell fractions, the former showed an active contribution to muscle fiber regeneration, but the latter showed vigorous engraftment to the interstitium associated with differentiation into Schwann cells, perineurial/endoneurial cells, and vascular endothelial cells and pericytes, which corresponded to previous observations with mouse SK-Cs. Importantly, mixed cultures of both cells resulted the reduction of tissue reconstitution capacities in vivo, whereas co-transplantation after separate expansion showed favorable results. Therefore, human Sk-Cs are potentially applicable to therapeutic autografts and show multiple differentiation potential in vivo.

Serum albumin (SA), the most abundant protein in circulation, functions as a carrier protein, osmoregulator, and antioxidant. Generally, SA exerts its antioxidative effects by scavenging reactive oxygen species. Because marine mammals are superior divers, they are intermittently exposed to oxidative stress induced by rapid reperfusion of oxygen to ischemic tissues after the dive. Although several antioxidants in marine mammals have been described, SA activity remains largely uncharacterized. In this study, we investigated the antioxidative activity of SA in marine mammals by comparing features of the primary and steric structures, biochemical properties, and antioxidative activities of common bottlenose dolphin SA (DSA) and human SA (HSA). Our results revealed that DSA lacked free cysteine at position 34 that is important for the antioxidative activity of HSA; however, the antioxidative capacity and thiol activity of DSA were stronger than those of HSA. Circular dichroism spectra showed different patterns in DSA and HSA. Ultraviolet fluorescence intensities of DSA were higher than those of HSA, suggesting lower surface hydrophobicity of DSA. Additionally, DSA showed higher excess heat capacity than HSA. We then compared a homology model of DSA with a 3D model of HSA. Our results indicate that DSA was more unstable than HSA at least in the body-temperature range, probably due to the mode of molecules involved in the disulfide bonds and/or the lower surface hydrophobicity, and it may be related to the equivalent or stronger antioxidant potency of DSA. These data show that DSA is an effective antioxidant in the circulation of the dolphin.

Potassium channels are involved in membrane hyperpolarization and ion homeostasis regulation during human sperm capacitation. However, the types of potassium channels in human sperm remain controversial. The voltage-gated ion channel KCNQ1 is ubiquitously expressed and regulates key physiological processes in the human body. In the present study, we investigated whether KCNQ1 is expressed in human sperm and what role it might have in sperm function. The expression and localization of KCNQ1 in human sperm were evaluated using Western blotting and indirect immunofluorescence. During capacitation incubation, human sperm were treated with KCNQ1- specific inhibitor chromanol 293B. Sperm motility was analyzed using a computer-assisted sperm analyzer. The acrosome reaction was studied using fluorescein isothiocyanate-conjugated Pisum sativum agglutinin staining. Protein tyrosine phosphorylation levels and localization after capacitation were determined using Western blotting and immunofluorescence. Intracellular K+, Ca2+, Cl-, pH, and membrane potential were analyzed using fluorescent probes. The results demonstrate that KCNQ1 is expressed and localized in the head and tail regions of human sperm. KCNQ1 inhibition reduced sperm motility, acrosome reaction rates, and protein tyrosine phosphorylation but had no effect on hyperactivation. KCNQ1 inhibition also increased intracellular K+, membrane potential, and intracellular Cl-, while decreasing intracellular Ca2+ and pH. In conclusion, the KCNQ1 channel plays a crucial role during human sperm capacitation.

The healthy heart adapts continuously to a complex set of dynamically changing mechanical conditions. The mechanical environment is altered by, and contributes to, multiple cardiac diseases. Mechanical stimuli are detected and transduced by cellular mechano-sensors, including stretch-activated ion channels (SAC). The precise role of SAC in the heart is unclear, in part because there are few SAC-specific pharmacological modulators. That said, most SAC can be activated by inducers of membrane curvature. The lectin LecA is a virulence factor of Pseudomonas aeruginosa and essential for P. aeruginosa-induced membrane curvature, resulting in formation of endocytic structures and bacterial cell invasion. We investigate whether LecA modulates SAC activity. TREK-1 and Piezo1 have been selected, as they are widely expressed in the body, including cardiac tissue, and they are "canonical representatives" for the potassium selective and the cation non-selective SAC families, respectively. Live cell confocal microscopy and electron tomographic imaging were used to follow binding dynamics of LecA, and to track changes in cell morphology and membrane topology in human embryonic kidney (HEK) cells and in giant unilamellar vesicles (GUV). HEK cells were further transfected with human TREK-1 or Piezo1 constructs, and ion channel activity was recorded using the patch-clamp technique. Finally, freshly isolated cardiac cells were used for studies into cell type dependency of LecA binding. LecA (500 nM) binds within seconds to the surface of HEK cells, with highest concentration at cell-cell contact sites. Local membrane invaginations are detected in the presence of LecA, both in the plasma membrane of cells (by 17 min of LecA exposure) as well as in GUV. In HEK cells, LecA sensitizes TREK-1, but not Piezo1, to voltage and mechanical stimulation. In freshly isolated cardiac cells, LecA binds to non-myocytes, but not to ventricular or atrial cardiomyocytes. This cell type specific lack of binding is observed across cardiomyocytes from mouse, rabbit, pig, and human. Our results suggest that LecA may serve as a pharmacological tool to study SAC in a cell type-preferential manner. This could aid tissue-based research into the roles of SAC in cardiac non-myocytes.

Micro-RNAs (miRs) encapsulated inside urinary exosomes (uEs) have the potential as early biomarkers. Previously, we reported that a rise in uE miR-451 predicted albuminuria in diabetic rats; however, whether the rise was protective or detrimental, and occurred in response to injury or general hyperglycemia, was unknown. To address this, we studied both human and rat models of renal disease. In humans, uE miR-451 was approximately twofold higher in subjects with early-stage chronic kidney disease (CKD; serum creatinine < 2.0 mg/dl; n = 28), as compared to age-matched healthy controls (n = 23), and had a significant negative correlation with estimated glomerular filtration rate (eGFR) (r 2 = -0.10, p = 0.01). Subgroup analysis of CKD subjects showed that those without diabetes had slightly (∼30%) but significantly higher uE miR-451 as compared to those with diabetes, with no differences in albumin excretion, eGFR, serum sodium, and potassium. Using human proximal tubule (hPT) cells, we found that locked nucleic acid (LNA) inhibition of miR-451 resulted in a significant increase in the messenger RNA (mRNA) expression of kidney-injury-associated miR-451 targets, e.g., CAB39, TBX1, and YWHAZ, as compared to treatment with a control LNA. Moreover, hPT cells and their secreted exosomes showed an increase in miR-451 in response to mechanical injury but not high glucose (20 versus 5 mM). For further proof of concept, in diabetic rats, we showed that atorvastatin (AT), a treatment proven to attenuate renal injury without affecting systemic glucose levels, reduced uE miR-451 with the concomitant restoration of renal miR-451. These data elucidate the stimuli for renal miR-451 expression and exosomal release and support its role as a therapeutic target and early biomarker for renal injury in humans.

Glucagon-like peptide-1 (GLP-1), an incretin hormone plays an important role in regulating glucose homeostasis. The therapeutic use of native GLP-1 is inadequate due to its short in vivo half-life. We recently developed a novel GLP-1 mimetics supaglutide, and demonstrated that this formulation retained native GLP-1 biological activities and possessed long-lasting GLP-1 actions. In this study, we further examined its abilities in regulating blood glucose in diabetic mice. We found that supaglutide stimulated insulin secretion in both mouse and human islets in a dose-dependent fashion. Oral glucose tolerance test conducted in normal ICR mice showed that supaglutide significantly decreased postprandial glucose excursions in a dose-dependent fashion. In type 2 diabetic db/db mice, a single-dose injection of supaglutide significantly decreased blood glucose levels, and this efficacy was lasted for at least 72 h in a dose-dependent fashion. During a 4-weeks intervention course supaglutide (twice injections per week) dose-dependently and significantly decreased fasting and random blood glucose levels in hyperglycemic db/db mice. Supaglutide, at a dose of 1.2 mg/kg, significantly reduced serum fructosamine levels. This was associated with significant enlargement of beta-cell mass, increased pancreatic insulin content, and increased plasma insulin level. Notably, during the intervention course supaglutide significantly reduced body-weight gain in these obese diabetic mice, associated with reduced fat mass (but not the lean mass), improved lipid profile, i.e., declined serum triglyceride, and free fatty acid levels compared to the placebo control. These finding reveals that supaglutide exerts beneficial effects in regulating blood glucose and lipid homeostasis in diabetic db/db mice.

Drug-induced liver injury (DILI) is a matter of concern in the course of drug development and patient safety, often leading to discontinuation of drug-development programs or early withdrawal of drugs from market. Hepatocellular toxicity or impairment of bile acid (BA) metabolism, known as cholestasis, are the two clinical forms of DILI. Whole-body physiology-based modelling allows a mechanistic investigation of the physiological processes leading to cholestasis in man. Objectives of the present study were: (1) the development of a physiology-based model of the human BA metabolism, (2) population-based model validation and characterisation, and (3) the prediction and quantification of altered BA levels in special genotype subgroups and after drug administration. The developed physiology-based bile acid (PBBA) model describes the systemic BA circulation in humans and includes mechanistically relevant active and passive processes such as the hepatic synthesis, gallbladder emptying, transition through the gastrointestinal tract, reabsorption into the liver, distribution within the whole body, and excretion via urine and faeces. The kinetics of active processes were determined for the exemplary BA glycochenodeoxycholic acid (GCDCA) based on blood plasma concentration-time profiles. The robustness of our PBBA model was verified with population simulations of healthy individuals. In addition to plasma levels, the possibility to estimate BA concentrations in relevant tissues like the intracellular space of the liver enhance the mechanistic understanding of cholestasis. We analysed BA levels in various tissues of Benign Recurrent Intrahepatic Cholestasis type 2 (BRIC2) patients and our simulations suggest a higher susceptibility of BRIC2 patients toward cholestatic DILI due to BA accumulation in the liver. The effect of drugs on systemic BA levels were simulated for cyclosporine A (CsA). Our results confirmed the higher risk of DILI after CsA administration in healthy and BRIC2 patients. The presented PBBA model enhances our mechanistic understanding underlying cholestasis and drug-induced alterations of BA levels in blood and organs. The developed PBBA model might be applied in the future to anticipate potential risk of cholestasis in patients.

Psychological stress is deeply involved in the pathophysiology of not only mental illness but also functional gastrointestinal disorders. In the present study, we examined the relationship between psychological stress and abnormality of stool properties, focusing on the alteration of plasma glucocorticoid and guanylin (GN)/uroguanylin (UGN) expression in the colon. A murine model of chronic social defeat stress (CSDS) was established by exposing a C57BL/6N intruder mouse to a CD-1 aggressor mouse for 3-5 min. Thereafter the mice were kept in the same cage but separated by a divider for the remainder of the day. This procedure was repeated for 10 consecutive days, and then a social interaction test was performed to evaluate social avoidance. Fresh fecal and blood samples were collected for stool property analysis and measurement of the plasma glucocorticoid level by ELISA. The expression of GN, UGN, and guanylate cyclase 2C in the colonic tissues was examined by real-time RT-PCR and immunohistochemistry. Moreover, Lovo cells were stimulated with dexamethasone, and the expression of GN/UGN mRNA was examined. In the CSDS group, the time spent in the social interaction zone was significantly shorter when the CD-1 aggressor mouse was present than when it was absent. The social interaction ratio was also significantly lower in the CSDS group relative to the controls. The mean Bristol scale score was significantly lower in the CSDS group, but the fecal sodium concentration did not differ between CSDS mice and controls. The level of plasma corticosterone was significantly higher in the CSDS group than in the controls immediately after the 10th day of CSDS. The expression of both GN and UGN was significantly decreased in the CSDS mice. GN was expressed in all colonic epithelial cells, and UGN was expressed in ovoid or pyramidal epithelial cells in the colonic mucosa. The expression of both GN and UGN was significantly decreased in the CSDS mice relative to controls. The expression of both GN and UGN was significantly suppressed in Lovo cells upon stimulation with dexamethasone. Psychological stress-induced glucocorticoid may suppress colonic GN/UGN expression, resulting in a change in stool properties leading to constipation.

Several studies have demonstrated an acute and chronic increase of brain-derived neurotrophic factor (BDNF) in relation to different types of physical exercise. Currently, many individuals seek physical training strategies that present different types of stimulation and volume/intensity. Thus, the extreme conditioning methodology has gained great notoriety in the scientific and non-scientific environment. Knowing that BDNF values increase in an effort-dependent manner, it is necessary to study the effects of this strategy on BDNF levels. This study aimed to evaluate the acute response of BDNF in trained men submitted to an extreme conditioning program (ECP) session. Ten volunteers underwent an acute ECP session using the "as many reps as possible" (WOD-AMRAP) method, including three types of exercise (clean, wall ball and double or single-unders) for 9 min. BDNF was measured in the plasma, being collected baseline and immediately after the session. Total load of the clean exercise was five times greater than wall ball exercise (p < 0.05; 2096.1 ± 387.4 kg vs 415.8 ± 81.03 kg), which influenced little in the total load (p < 0.05, 2511.9 ± 358.52 kg) used. For the total volume, practitioners averaged 1.7 times more repetitions in the wall ball exercise compared to clean (46.2 ± 9 vs 29.5 ± 3.8 repetitions). The volunteers averaged 75.7 ± 12.6 double-unders repetitions, bringing the total volume of training to 151.4 ± 23.7 repetitions. Regarding the BDNF values, there was a significant difference (p = 0.05) between the pre- vs post-moments (11209.85 ± 1270.4 vs 12132.96 ± 1441.93 pg/ml). Effect size for this change as moderate (ES = 0.79). We found a positive correlation between total volume of clean exercise and delta BDNF values (p = 0.049). In conclusion, a single extreme conditioning session, through the practice of the WOD-AMRAP method, is capable of increasing the acute concentrations of plasma BDNF. In practical terms, we may suggest that future studies evaluate the effect of ECP as a strategy in the treatment of disorders associated with central degenerative changes.

Force transmission between rat ankle plantar-flexors has been found for physiological muscle lengths and relative positions, but only with all muscles maximally activated. The aims of this study were to assess intermuscular mechanical interactions between ankle plantar-flexors during (i) fully passive conditions, (ii) excitation of soleus (SO), (iii) excitation of lateral gastrocnemius (LG), and (iv) during co-activation of SO, and LG (SO&LG). We assessed effects of proximal lengthening of LG and plantaris (PL) muscles (i.e., simulating knee extension) on forces exerted at the distal SO tendon (FSO) and on the force difference between the proximal and distal LG+PL tendons (ΔFLG+PL) of the rat. LG+PL lengthening increased FSO to a larger extent (p = 0.017) during LG excitation (0.0026 N/mm) than during fully passive conditions (0.0009 N/mm). Changes in FSO in response to LG+PL lengthening were lower (p = 0.002) during SO only excitation (0.0056 N/mm) than during SO&LG excitation (0.0101 N/mm). LG+PL lengthening changed ΔFLG+PL to a larger extent (p = 0.007) during SO excitation (0.0211 N/mm) than during fully passive conditions (0.0157 N/mm). In contrast, changes in ΔFLG+PL in response to LG+PL lengthening during LG excitation (0.0331 N/mm) were similar (p = 0.161) to that during SO&LG excitation (0.0370 N/mm). In all conditions, changes of FSO were lower than those of ΔFLG+PL. This indicates that muscle forces were transmitted not only between LG+PL and SO, but also between LG+PL and other surrounding structures. In addition, epimuscular myofascial force transmission between rat ankle plantar-flexors was enhanced by muscle activation. However, the magnitude of this interaction was limited.

High-intensity muscle actions have the potential to temporarily improve muscle contractile properties (i.e., postactivation potentiation, PAP) thereby inducing acute performance enhancements. There is evidence that balance training can improve performance during strength exercises. Taking these findings together, the purpose of this study was to examine the acute effects of a combined balance and strength (B+S) exercise vs. a strength only (S) exercise on twitch contractile properties, maximum voluntary strength, and jump performance in young athletes. Female elite young soccer players (N = 12) aged 14-15 years conducted three experimental conditions in randomized order: S included 3 sets of 8-10 dynamic leg extensions at 80% of the 1-repetition maximum, B+S consisted of 3 sets of 40 s double-leg stances on a balance board prior to leg extensions (same as S), and a resting control period. Before and 7 min after exercise, participants were tested for their electrically-evoked isometric twitches (i.e., twitch peak torque, twitch rate of torque development) and maximal voluntary contraction (MVC) torque of the plantar flexor muscles. Additionally, countermovement (CMJ) and drop jump (DJ) performances (i.e., CMJ/DJ height, DJ ground contact time) were assessed. Significant effects of condition on twitch contractile properties (p < 0.05, d = 1.1) and jump performance outputs (p < 0.05, 1.1 ≤ d ≤ 1.2) were found. Post-hoc tests revealed that S compared to control produced larger PAP for twitch peak torques by trend (p = 0.07, d = 1.8, 33 vs. 21%) and significantly larger PAP for twitch rate of torque development (p < 0.05, d = 2.4, 55 vs. 43%). Following B+S compared to control, significant improvements in CMJ height (p < 0.01, d = 1.9, 3%) and DJ contact time were found (p < 0.01, d = 2.0, 10%). This study revealed protocol-specific acute performance improvements. While S resulted in significant increases in twitch contractile properties, B+S produced significant enhancements in jump performance. It is concluded that PAP effects in the plantar flexors may not directly translate to improved jump performance in female elite young soccer players. Therefore, the observed gains in jump performance following B+S are most likely related to neuromuscular changes (e.g., intramuscular coordination) rather than improved contractile properties.

Physiological rhythms in mammals are essential for maintaining health, whereas disruptions may cause or exacerbate disease pathogenesis. As such, our objective was to characterize how cigarette smoke exposure affects physiological rhythms of otherwise healthy mice using telemetry and cosinor analysis.

Background and Purpose: Elevated sympathetic nervous system (SNS) activity is a characteristic of obesity and type 2 diabetes (T2D) that contributes to target organ damage and cardiovascular risk. In this study we examined whether baseline metabolic status influences the degree of sympathoinhibition attained following equivalent dietary weight loss. Methods: Un-medicated obese individuals categorized as normal glucose tolerant (NGT, n = 15), impaired glucose tolerant (IGT, n = 24), and newly-diagnosed T2D (n = 15) consumed a hypocaloric diet (29% fat, 23% protein, 45% carbohydrate) for 4-months. The three groups were matched for baseline age (56 ± 1 years), body mass index (BMI, 32.9 ± 0.7 kg/m2), and gender. Clinical measurements included whole-body norepinephrine kinetics, muscle sympathetic nerve activity (MSNA, by microneurography), spontaneous cardiac baroreflex sensitivity (BRS), and oral glucose tolerance test. Results: Weight loss averaged -7.5 ± 0.8, -8.1 ± 0.5, and -8.0 ± 0.9% of body weight in NGT, IGT, and T2D groups, respectively. T2D subjects had significantly greater reductions in fasting glucose, 2-h glucose and glucose area under the curve (AUC0-120) compared to NGT and IGT (group effect, P <0.001). Insulinogenic index decreased in IGT and NGT groups and increased in T2D (group × time, P = 0.04). The magnitude of reduction in MSNA (-7 ± 3, -8 ± 4, -15 ± 4 burst/100 hb, respectively) and whole-body norepinephrine spillover rate (-28 ± 8, -18 ± 6, and -25 ± 7%, respectively), time effect both P <0.001, did not differ between groups. After adjustment for age and change in body weight, Δ insulin AUC0-120 was independently associated with reduction in arterial norepinephrine concentration, whilst Δ LDL-cholesterol and improvement in BRS were independently associated with decrease in MSNA. Conclusions: Equivalent weight loss through hypocaloric diet is accompanied by similar sympathoinhibition in matched obese subjects with different baseline glucose tolerance. Attenuation of hyperinsulinemia and hyperlipidemia, rather than glycemic indices, is associated with reduction in SNS activity following weight loss intervention.

Up until now, the specific mechanisms involved in doxorubicin (DOX)-induced cardiotoxicity have not been fully elucidated. Since thiamine deficiency is associated with myocardial dysfunction and it may lead to cardiomyopathy, we aimed to investigate whether thiamine (Vitamin B1) treatment provides cardioprotection and modulates DOX mediated subchronic cardiotoxicity as well as to determine possible mechanisms of its effects. The study involved 48 Wistar albino rats divided into four groups: healthy non-treated rats and healthy rats treated with thiamine and DOX rats without treatment and DOX rats treated with thiamine. DOX was applied as a single i.p.injection (15mg/kg), while thiamine treatment lasted 7days (25mg/kg/dayi.p.). Before and after the treatment hemodynamic changes were monitored in vivo by echocardiography. When the protocol was completed, animals were sacrificed and rat hearts were isolated in order to evaluate parameters of cardiac oxidative stress [superoxide anion radical-O2 -, hydrogen peroxide-H2O2, nitric oxide-NO-, index of lipid peroxidation-thiobarbituric acid (TBA) reactive substances (TBARS), superoxide dismutase - SOD, catalase (CAT), and reduced glutathione-GSH] and apoptosis (Bax, Bcl-2, caspases). DOX treatment significantly reduced the ejection fraction, while thiamine treatment led to its minor increase in the DOX-treated group. In that sense, heart oxidative stress markers were significantly increased in DOX-treated rats, while therapeutic dose of thiamine decreased the levels of free radicals. Our study demonstrated the promising ameliorative effects of thiamine against DOX-induced cardiotoxicity through modulation of oxidative stress, suppression of apoptosis, and possibility to improve myocardial performance and morphometric structure of rats` hearts.

Numerous national associations and multiple reviews have documented the safety and efficacy of strength training for children and adolescents. The literature highlights the significant training-induced increases in strength associated with youth strength training. However, the effectiveness of youth strength training programs to improve power measures is not as clear. This discrepancy may be related to training and testing specificity. Most prior youth strength training programs emphasized lower intensity resistance with relatively slow movements. Since power activities typically involve higher intensity, explosive-like contractions with higher angular velocities (e.g., plyometrics), there is a conflict between the training medium and testing measures. This meta-analysis compared strength (e.g., training with resistance or body mass) and power training programs (e.g., plyometric training) on proxies of muscle strength, power, and speed. A systematic literature search using a Boolean Search Strategy was conducted in the electronic databases PubMed, SPORT Discus, Web of Science, and Google Scholar and revealed 652 hits. After perusal of title, abstract, and full text, 107 studies were eligible for inclusion in this systematic review and meta-analysis. The meta-analysis showed small to moderate magnitude changes for training specificity with jump measures. In other words, power training was more effective than strength training for improving youth jump height. For sprint measures, strength training was more effective than power training with youth. Furthermore, strength training exhibited consistently large magnitude changes to lower body strength measures, which contrasted with the generally trivial, small and moderate magnitude training improvements of power training upon lower body strength, sprint and jump measures, respectively. Maturity related inadequacies in eccentric strength and balance might influence the lack of training specificity with the unilateral landings and propulsions associated with sprinting. Based on this meta-analysis, strength training should be incorporated prior to power training in order to establish an adequate foundation of strength for power training activities.

Hot-water immersion following exercise in a temperate environment can elicit heat acclimation in endurance-trained individuals. However, a delay between exercise cessation and immersion is likely a common occurrence in practice. Precisely how such a delay potentially alters hot-water immersion mediated acute physiological responses (e.g., total heat-load) remains unexplored. Such data would aid in optimizing prescription of post-exercise hot-water immersion in cool environments, relative to heat acclimation goals. Twelve male recreational runners (mean ± SD; age: 38 ± 13 years, height: 180 ± 7 cm, body mass: 81 ± 13.7 kg, body fat: 13.9 ± 3.5%) completed three separate 40-min treadmill runs (18°C), followed by either a 10 min (10M), 1 h (1H), or 8 h (8H) delay, prior to a 30-min hot-water immersion (39°C), with a randomized crossover design. Core and skin temperatures, heart rate, sweat, and perceptual responses were measured across the trials. Mean core temperature during immersion was significantly lower in 1H (37.39 ± 0.30°C) compared to 10M (37.83 ± 0.24°C; p = 0.0032) and 8H (37.74 ± 0.19°C; p = 0.0140). Mean skin temperature was significantly higher in 8H (32.70 ± 0.41°C) compared to 10M (31.93 ± 0.60°C; p = 0.0042) at the end of the hot-water immersion. Mean and maximal heart rates were also higher during immersion in 10M compared to 1H and 8H (p < 0.05), despite no significant differences in the sweat or perceptual responses. The shortest delay between exercise and immersion (10M) provoked the greatest heat-load during immersion. However, performing the hot-water immersion in the afternoon (8H), which coincided with peak circadian body temperature, provided a larger heat-load stimulus than the 1 h delay (1H).

Aim: Hyperthyroidism is associated with a decreased peripheral vascular resistance, which could be caused by the vasodilator genomic or non-genomic effects of thyroid hormones (TH). Non-genomic, or acute, effects develop within several minutes and involve a wide tissue-specific spectrum of molecular pathways poorly studied in vasculature. We aimed to investigate the mechanisms of acute effects of TH on rat skeletal muscle arteries. Methods: Sural arteries from male Wistar rats were used for isometric force recording (wire myography) and phosphorylated protein content measurement (Western blotting). Results: Both triiodothyronine (T3) and thyroxine (T4) reduced contractile response of sural arteries to α1-adrenoceptor agonist methoxamine. The effect of T4 was more prominent than T3 and not affected by iopanoic acid, an inhibitor of deiodinase 2. Endothelium denudation abolished the effect of T3, but not T4. Integrin αvβ3 inhibitor tetrac abolished the effect of T4 in endothelium-denuded arteries. T4 weakened methoxamine-induced elevation of phospho-MLC2 (Ser19) content in arterial samples. The effect of T4 in endothelium-denuded arteries was abolished by inhibiting ERK1/2 activation with U0126 as well as by ILK inhibitor Cpd22 but persisted in the presence of Src- or Rho-kinase inhibitors (PP2 and Y27632, respectively). Conclusion: Acute non-genomic relaxation of sural arteries induced by T3 is endothelium-dependent and that induced by T4 is endothelium-independent. The effect of T4 on α1-adrenergic contraction is stronger compared to T3 and involves the suppression of extracellular matrix signaling via integrin αvβ3, ERK1/2 and ILK with subsequent decrease of MLC2 (Ser19) phosphorylation.

The aim of this study was to evaluate whether possible preglomerular arterial-to-venous oxygen shunting is affected by the interaction between renal preglomerular carbon dioxide and oxygen transport. We hypothesized that a reverse (venous-to-arterial) shunting of carbon dioxide will increase partial pressure of carbon dioxide and decrease pH in the arteries and thereby lead to increased oxygen offloading and consequent oxygen shunting. To test this hypothesis, we employed a segment-wise three-dimensional computational model of coupled renal oxygen and carbon dioxide transport, wherein coupling is achieved by shifting the oxygen-hemoglobin dissociation curve in dependence of local changes in partial pressure of carbon dioxide and pH. The model suggests that primarily due to the high buffering capacity of blood, there is only marginally increased acidity in the preglomerular vasculature compared to systemic arterial blood caused by carbon dioxide shunting. Furthermore, effects of carbon dioxide transport do not promote but rather impair preglomerular oxygen shunting, as the increase in acidity is higher in the veins compared to that in the arteries. We conclude that while substantial arterial-to-venous oxygen shunting might take place in the postglomerular vasculature, the net amount of oxygen shunted at the preglomerular vasculature appears to be marginal.

Body composition (BC) does not always vary as a function of exercise induced energy expenditure (exercise EE - resting EE). Energy balance variables were measured to understand energy compensation (EC) in response to an exercise intervention performed at low (LOW) or moderate (MOD) intensity.

Scope: The hypothalamus is a key brain region involved in the control of feeding and energy expenditure. Hypothalamic inflammation and oxidative stress are landmarks of both obesity and aging processes, although the molecular mechanisms are still unknown. Therefore, with the aim to understand the neurobiological mechanisms of energy homeostasis during aging, we evaluate the effects of long feeding high-fat diet (HFD) in rats, at different age, on modulation of hypothalamic molecular pathway, oxidative stress, and inflammation. Procedures: Male Wistar rats were divided into two groups: control group, receiving standard diet (CD), and treated group, receiving HFD. Both groups were treated with the appropriate diet for 1, 3, 6, 12, or 18 weeks. We investigated energy balance and body composition, as well as lipid profile, homeostatic model assessment index, and inflammatory state in serum. Furthermore, we also analyzed, at hypothalamic level, inflammation and oxidative stress, and adenosine monophosphate-dependent kinase (AMPK) and pAMPK expression levels. Results: Our data showed that aging and HFD induce increased energy intake and energy efficiency and decreased energy expenditure associated, at hypothalamic level, with inflammation and oxidative stress and activation of AMPK. Conclusion: Our results indicate that the age at which HFD feeding starts and the diet duration are critical in obesity development. The prolonged activation of hypothalamic AMPK may be related to the alterations in energy homeostasis.