Protective effect of lycopene against celecoxib induced fat deposition and glycogen reduction in liver cells.

Objective: Oxidative stress develops because of a shift in the prooxidant-antioxidant balance toward the former, because of disturbances in redox signaling and control. Celecoxib (Cb), a selective COX-2 inhibitor, is a drug that effectively decreases pain and inflammation. However, Cb causes oxidative injury to hepatic tissues via enhanced lipid peroxidation, thus resulting in excessive production of reactive oxygen species. Consequently, frequent or long-term Cb use may lead to hepatic, renal, and other noticeable adverse effects. Lycopene (lyco), a potent antioxidant naturally occurring in pigmented fruits and vegetables, actively eradicates singlet oxygen and other free radicals, thereby protecting cells against destruction of the plasma membrane by free radicals. Methods: We hypothesized that lyco might protect rat liver cells against Cb-induced oxidative stress, thus reducing fatty infiltration and glycogen depletion. Rats were randomized into three groups (with ten rats each) receiving control (group A, saline only), Cb (group B, 50 mg/kg, orally), or Cb + lyco (group C, 50 mg/kg, orally) for 30 days. Subsequently, liver tissues were examined, and the average liver weight and histological changes in fat and glycogen content were determined. Results: Lyco mitigated hepatocyte damage in Cb-treated rats, reducing fat accumulation and glycogen loss, probably through its antioxidant properties. Concomitant lyco and Cb intake prevented hepatotoxic adverse effects due to oxidative injury, as well as non-alcoholic fatty liver disease (NAFLD), a key component of metabolic syndrome. Moreover, the binding orientation of lyco in the binding site of COX-2 enzyme revealed that the docked complex had noteworthy binding strength. Conclusion: In conclusion, our study revealed lyco's protective effects against Cb-induced hepatic damage by reducing fat and glycogen depletion.

Effect of Low vs. High Carbohydrate Intake after Glycogen-Depleting Workout on Subsequent 1500 m Run Performance in High-Level Runners.

Carbohydrate (CHO) metabolism is crucial for short-duration, high-intensity exercise performance, but the effects of variations in glycogen availability have not been investigated in field trials of trained athletes. This study was designed to test how 1500 m time trial (TT) performance is affected by the manipulation of pre-race glycogen reserves. Competitive middle-distance runners (n = 11 (4 females)) completed a 1500 m individually paced indoor TT after abundant (high, >5 g/kg/d) or restricted (low, <1.5 g/kg/d) dietary CHO intake for 2 days after a glycogen-depleting session. Stride pattern, heart rate (HR), capillary blood lactate, and glucose and plasma malondialdehyde (MDA) response were determined. The TT was slower in low vs. high condition by 4.5 (4.5) s (~2%; p < 0.01), with a tendency toward shorter stride length. Blood lactate and glucose were lower before the TT in low vs. high condition (1.8 (0.5) vs. 2.2 (0.7) mmol/L and 5.4 (0.7) vs. 5.9 (0.8) mmol/L, p = 0.022 and 0.007, respectively), and peak lactate was higher in high vs. low condition (16.8 (3.1) vs. 14.5 (4.2) mmol/L, p = 0.039). Plasma MDA was the same before the TT, and 15 min after the TT, it increased similarly by 15% in low (p = 0.032) and high (p = 0.005) conditions. The restriction of pre-test CHO intake impaired 1500 m TT performance and reduced baseline and peak blood lactate concentrations but not blood glucose or MDA response.

Muscle glycogen unavailability and fat oxidation rate during exercise: Insights from McArdle disease.

Carbohydrate availability affects fat metabolism during exercise; however, the effects of complete muscle glycogen unavailability on maximal fat oxidation (MFO) rate remain unknown. Our purpose was to examine the MFO rate in patients with McArdle disease, comprising an inherited condition caused by complete blockade of muscle glycogen metabolism, compared to healthy controls. Nine patients (three women, aged 36 ± 12 years) and 12 healthy controls (four women, aged 40 ± 13 years) were studied. Several molecular markers of lipid transport/metabolism were also determined in skeletal muscle (gastrocnemius) and white adipose tissue of McArdle (Pygm p.50R*/p.50R*) and wild-type male mice. Peak oxygen uptake ( V ̇ O 2 peak ${\dot V_{{{\rm{O}}_{\rm{2}}}{\rm{peak}}}}$ ), MFO rate, the exercise intensity eliciting MFO rate (FATmax) and the MFO rate-associated workload were determined by indirect calorimetry during an incremental cycle-ergometer test. Despite having a much lower V ̇ O 2 peak ${\dot V_{{{\rm{O}}_{\rm{2}}}{\rm{peak}}}}$ (24.7 ± 4 vs. 42.5 ± 11.4 mL kg-1  min-1 , respectively; P < 0.0001), patients showed considerably higher values for the MFO rate (0.53 ± 0.12 vs. 0.33 ± 0.10 g min-1 , P = 0.001), and for the FATmax (94.4 ± 7.2 vs. 41.3 ± 9.1 % of V ̇ O 2 peak ${\dot V_{{{\rm{O}}_{\rm{2}}}{\rm{peak}}}}$ , P < 0.0001) and MFO rate-associated workload (1.33 ± 0.35 vs. 0.81 ± 0.54 W kg-1 , P = 0.020) than controls. No between-group differences were found overall in molecular markers of lipid transport/metabolism in mice. In summary, patients with McArdle disease show an exceptionally high MFO rate, which they attained at near-maximal exercise capacity. Pending more mechanistic explanations, these findings support the influence of glycogen availability on MFO rate and suggest that these patients develop a unique fat oxidation capacity, possibly as an adaptation to compensate for the inherited blockade in glycogen metabolism, and point to MFO rate as a potential limiting factor of exercise tolerance in this disease. KEY POINTS: Physically active McArdle patients show an exceptional fat oxidation capacity. Maximal fat oxidation rate occurs near-maximal exercise capacity in these patients. McArdle patients' exercise tolerance might rely on maximal fat oxidation rate capacity. Hyperpnoea might cloud substrate oxidation measurements in some patients. An animal model revealed overall no higher molecular markers of lipid transport/metabolism.

Muscle metabolism and impaired sprint performance in an elite women's football game.

The present study examined skeletal muscle metabolism and changes in repeated sprint performance during match play for n = 20 competitive elite women outfield players. We obtained musculus vastus lateralis biopsies and blood samples before, after, and following intense periods in each half of a friendly match, along with 5 × 30-meter sprint tests and movement pattern analyses (10-Hz S5 Global Positioning System [GPS]). Muscle glycogen decreased by 39% and 42% after an intense period of the second half and after the match, respectively, compared to baseline (p < 0.05). Post-match, 80% type I fibers and 69% type II fibers were almost empty or completely empty of glycogen. Muscle lactate was higher (p < 0.05) after the intense period of the first half and post-match compared to baseline (14.3 ± 4.6 (±SEM) and 12.9 ± 5.7 vs. 6.4 ± 3.7 mmol/kg d.w.). Muscle phosphocreatine was reduced (p < 0.05) by 16% and 12%, respectively, after an intense period in the first and second half compared to baseline. Blood lactate and glucose increased during the match and peaked at 8.4 ± 2.0 and 7.9 ± 1.2 mmol/L, respectively. Mean 5 × 30 m sprint time declined by 3.2 ± 1.7 and 7.0 ± 2.1% after the first and second half, respectively, and 4.7 ± 1.6% (p < 0.05) after an intense period in the first half compared to baseline. In conclusion, match play in elite female football players resulted in marked glycogen depletion in both fiber types, which may explain fatigue at the end of a match. Repeated sprint ability was impaired after intense periods in the first half and after both halves, which may be associated with the observed muscle metabolite perturbations.

The Validity of Ultrasound Technology in Providing an Indirect Estimate of Muscle Glycogen Concentrations Is Equivocal.

Researchers and practitioners in sports nutrition would greatly benefit from a rapid, portable, and non-invasive technique to measure muscle glycogen, both in the laboratory and field. This explains the interest in MuscleSound®, the first commercial system to use high-frequency ultrasound technology and image analysis from patented cloud-based software to estimate muscle glycogen content from the echogenicity of the ultrasound image. This technique is based largely on muscle water content, which is presumed to act as a proxy for glycogen. Despite the promise of early validation studies, newer studies from independent groups reported discrepant results, with MuscleSound® scores failing to correlate with the glycogen content of biopsy-derived mixed muscle samples or to show the expected changes in muscle glycogen associated with various diet and exercise strategies. The explanation of issues related to the site of assessment do not account for these discrepancies, and there are substantial problems with the premise that the ratio of glycogen to water in the muscle is constant. Although further studies investigating this technique are warranted, current evidence that MuscleSound® technology can provide valid and actionable information around muscle glycogen stores is at best equivocal.

Acute Effects of Supervised Making Weight on Health Markers, Hormones and Body Composition in Muay Thai Fighters.

Making weight is a practice often used in combat sports. This consists of a rapid weight loss (RWL) and a subsequent rapid weight gain (RWG) in the days preceding competition. However, this practice is often carried out based on anecdotal information provided by ex-athletes or non-professionals, which has led to several adverse events. This study aimed to assess the acute effects of a supervised nutritional period of RWL/RWG on health markers, hormone concentrations, and body composition. We performed a single-arm repeated-measures (baseline, after RWL and after RWG) clinical trial with twenty-one (8F:16M) Italian Muay Thai fighters. Body mass was significantly lower after the RWL (-4.1%) while there was a significantly higher glucose availability after RWL and RWG. Blood urea nitrogen, lipid profile, and creatinine were within the normal range after RWL/RWG. Testosterone decrease significantly after RWL and RWG in the men group. Male fighters had a significant reduction in thyroid-stimulating hormone concentration after the RWL and RWG intervention, but no change was found in women at pre-competition. Bioelectrical parameters were almost fully restored after RWG. An evidence-based and individualized nutrition methodology reduces the adverse events after an RWL and RWG practice, although the impact on the hormonal profile is inevitable.

Heterogeneity in subcellular muscle glycogen utilisation during exercise impacts endurance capacity in men.

KEY POINTS: When muscle biopsies first began to be used routinely in research on exercise physiology five decades ago, it soon become clear that the muscle content of glycogen is an important determinant of exercise performance. Glycogen particles are stored in distinct pools within the muscles, but the role of each pool during exercise and how this is affected by diet is unknown. Here, the effects of diet and exercise on these pools, as well as their relation to endurance during prolonged cycling were examined. We demonstrate here that an improved endurance capacity with high carbohydrate loading is associated with a temporal shift in the utilisation of the distinct stores of glycogen pools and is closely linked to the content of the glycogen pool closest to actin and myosin (intramyofibrillar glycogen). These findings highlight the functional importance of distinguishing between different subcellular microcompartments of glycogen in individual muscle fibres. ABSTRACT: In muscle cells, glycogen is stored in three distinct subcellular pools: between or within myofibrils (inter- and intramyofibrillar glycogen, respectively) or beneath the sarcolemma (subsarcolemmal glycogen) and these pools may well have different functions. Here, we investigated the effect of diet and exercise on the content of these distinct pools and their relation to endurance capacity in type 1 and 2 muscle fibres. Following consumption of three different diets (normal, mixed diet = MIX, high in carbohydrate = HIGH, or low in carbohydrate = LOW) for 72 h, 11 men cycled at 75% of V̇O2 max until exhaustion. The volumetric content of the glycogen pools in muscle biopsies obtained before, during, and after exercise were quantified by transmission electron micrographs. The mean (SD) time to exhaustion was 150 (30), 112 (22), and 69 (18) minutes in the HIGH, MIX and LOW trials, respectively (P < 0.001). As shown by multiple regression analyses, the intramyofibrillar glycogen content in type 1 fibres, particularly after 60 min of exercise, correlated most strongly with time to exhaustion. In the HIGH trial, intramyofibrillar glycogen was spared during the initial 60 min of exercise, which was associated with levels and utilisation of subsarcolemmal glycogen above normal. In all trials, utilisation of subsarcolemmal and intramyofibrillar glycogen was more pronounced than that of intermyofibrillar glycogen in relative terms. In conclusion, the muscle pool of intramyofibrillar glycogen appears to be the most important for endurance capacity in humans. In addition, a local abundance of subsarcolemmal glycogen reduces the utilisation of intramyofibrillar glycogen during exercise.

In vivo investigation on the chronic hepatotoxicity induced by sertraline.

Although sertraline is widely prescribed as relatively safe antidepressant drug, hepatic toxicity was reported in some patients with sertraline treatment. The present study was conducted to investigate the morphometric, hepatotoxicity, and change in gene expression of drug metabolizing enzymes. Male healthy adult rabbits (Oryctolagus cuniculus) ranging from 1050 to 1100 g were exposed to oral daily doses of sertraline (0, 1, 2, 4, 8 mg/kg) for 9 weeks. The animals were subjected to morphometric, hepatohistological, histochemical and quantitative real-time polymerase chain reaction analyses. Sertraline chronic exposure induced morphometric changes and provoked histological and histochemical alterations including: hepatocytes hydropic degeneration, necrosis, nuclear alteration, sinusoidal dilation, bile duct hyperplasia, inflammatory cells infiltration, portal vessel congestion, Kupffer cells hyperplasia, portal fibrosis and glycogen depletion. In addition, the gene expression of drug and arachidonic acid metabolizing enzymes were reduced significantly (p value <0.05). The most affected genes were cyp4a12, ephx2, cyp2d9 and cyp1a2, demonstrating 5 folds or more down-regulation. These findings suggest that chronic sertraline treatment induced toxic histological alterations in the hepatic tissues and reduced the gene expression of drug metabolizing enzymes. Patients on chronic sertraline treatment may be on risk of hepatotoxicity with reduced capacity to metabolize drugs and fatty acids.

Beetroot juice ingestion during prolonged moderate-intensity exercise attenuates progressive rise in O2 uptake.

Nitrate-rich beetroot juice (BR) supplementation has been shown to increase biomarkers of nitric oxide availability with implications for the physiological responses to exercise. We hypothesized that BR supplementation before and during prolonged moderate-intensity exercise would maintain an elevated plasma nitrite concentration ([[Formula: see text]]), attenuate the expected progressive increase in V̇o2 over time, and improve performance in a subsequent time trial (TT). In a double-blind, randomized, crossover design, 12 men completed 2 h of moderate-intensity cycle exercise followed by a 100-kJ TT in three conditions: 1) BR before and 1 h into exercise (BR + BR); 2) BR before and placebo (PL) 1 h into exercise (BR + PL); and 3) PL before and 1 h into exercise (PL + PL). During the 2-h moderate-intensity exercise bout, plasma [[Formula: see text]] declined by ~17% in BR + PL but increased by ~8% in BR + BR such that, at 2 h, plasma [[Formula: see text]] was greater in BR + BR than both BR + PL and PL + PL ( P < 0.05). V̇o2 was not different among conditions over the first 90 min of exercise but was lower at 120 min in BR + BR (1.73 ± 0.24 l/min) compared with BR + PL (1.80 ± 0.21 l/min; P = 0.08) and PL + PL (1.83 ± 0.27 l/min; P < 0.01). The decline in muscle glycogen concentration over the 2-h exercise bout was attenuated in BR + BR (~28% decline) compared with BR + PL (~44% decline) and PL + PL (~44% decline; n = 9, P < 0.05). TT performance was not different among conditions ( P > 0.05). BR supplementation before and during prolonged moderate-intensity exercise attenuated the progressive rise in V̇o2 over time and appeared to reduce muscle glycogen depletion but did not enhance subsequent TT performance. NEW & NOTEWORTHY We show for the first time that ingestion of nitrate during exercise preserves elevated plasma [nitrite] and negates the progressive rise in O2 uptake during prolonged moderate-intensity exercise.

Effect of sodium-glucose cotransporter 2 (SGLT2) inhibition on weight loss is partly mediated by liver-brain-adipose neurocircuitry.

Sodium-glucose cotransporter 2 (SGLT2) inhibitors have both anti-diabetic and anti-obesity effects. However, the precise mechanism of the anti-obesity effect remains unclear. We previously demonstrated that the glycogen depletion signal triggers lipolysis in adipose tissue via liver-brain-adipose neurocircuitry. In this study, therefore, we investigated whether the anti-obesity mechanism of SGLT2 inhibitor is mediated by this mechanism. Diet-induced obese mice were subjected to hepatic vagotomy (HVx) or sham operation and loaded with high fat diet containing 0.015% tofogliflozin (TOFO), a highly selective SGLT2 inhibitor, for 3 weeks. TOFO-treated mice showed a decrease in fat mass and the effect of TOFO was attenuated in HVx group. Although both HVx and sham mice showed a similar level of reduction in hepatic glycogen by TOFO treatment, HVx mice exhibited an attenuated response in protein phosphorylation by protein kinase A (PKA) in white adipose tissue compared with the sham group. As PKA pathway is known to act as an effector of the liver-brain-adipose axis and activate triglyceride lipases in adipocytes, these results indicated that SGLT2 inhibition triggered glycogen depletion signal and actuated liver-brain-adipose axis, resulting in PKA activation in adipocytes. Taken together, it was concluded that the effect of SGLT2 inhibition on weight loss is in part mediated via the liver-brain-adipose neurocircuitry.

Zinc oxide nanoparticles hepatotoxicity: Histological and histochemical study.

Zinc oxide nanoparticles (ZnO NPs) are widely used in industry and cosmetic products with promising investment in medical diagnosis and treatment. However, these particles may reveal a high potential risk for human health with no information about hepatotoxicity that might be associated with their exposure. The present work was carried out to investigate the histological and histochemical alterations induced in the hepatic tissues by naked 35nm ZnO NPs. Male Wistar albino rats were exposed to ZnO NPs at a daily dose of 2mg/kg for 21days. Liver biopsies from all rats under study were subjected to histopathological examinations. In comparison with the control rats, the following histological and histochemical alterations were demonstrated in the hepatic tissues of rats exposed to ZnO NPs: sinusoidal dilatation, Kupffer cells hyperplasia, lobular and portal triads inflammatory cells infiltration, necrosis, hydropic degeneration, hepatocytes apoptosis, anisokaryosis, karyolysis, nuclear membrane irregularity, glycogen content depletion and hemosidrosis. The findings of the present work might indicate that ZnO NPs have potential oxidative stress in the hepatic tissues that may affect the function of the liver. More work is needed to elucidate the toxicity and pathogenesis of zinc oxide nanoparticles on the vital organs.

Repeated high-intensity interval exercise shortens the positive effect on executive function during post-exercise recovery in healthy young males.

A single bout of aerobic exercise improves executive function (EF), but only for a short period. Compared with a single bout of aerobic exercise, we recently found that high-intensity interval exercise (HIIE) could maintain a longer improvement in EF. However, the mechanism underlying the effect of different exercise modes on the modifications of EF remains unclear. The purpose of the current investigation was to test our hypothesis that the amount of exercise-induced lactate production and its accumulation affects human brain function during and after exercise, thereby affecting post-exercise EF. Ten healthy male subjects performed cycle ergometer exercise. The HIIE protocol consisted of four 4-min bouts at 90% peak VO2 with a 3-min active recovery period at 60% peak VO2. The amount of lactate produced during exercise was manipulated by repeating the HIIE twice with a resting period of 60min between the 1st HIIE and 2nd HIIE. To evaluate EF, a color-word Stroop task was performed, and reverse-Stroop interference scores were obtained. EF immediately after the 1st HIIE was significantly improved compared to that before exercise, and the improved EF was sustained during 40min of the post-exercise recovery. However, for the 2nd HIIE, the improved EF was sustained for only 10min of the post-exercise recovery period, despite the performance of the same exercise. In addition, during and following HIIE, the glucose and lactate accumulation induced by the 2nd HIIE was significantly lower than that induced by the 1st HIIE. Furthermore, there was an inverse relationship between lactate and EF by plotting the changes in lactate levels against changes in EF from pre-exercise during the late phase of post-exercise recovery. These findings suggested the possibility that repeated bouts of HIIE, which decreases lactate accumulation, may dampen the positive effect of exercise on EF during the post-exercise recovery.

Carbohydrate restricted recovery from long term endurance exercise does not affect gene responses involved in mitochondrial biogenesis in highly trained athletes.

The aim was to determine if the metabolic adaptations, particularly PGC-1α and downstream metabolic genes were affected by restricting CHO following an endurance exercise bout in trained endurance athletes. A second aim was to compare baseline expression level of these genes to untrained. Elite endurance athletes (VO2max 66 ± 2 mL·kg(-1)·min(-1), n = 15) completed 4 h cycling at ~56% VO2max. During the first 4 h recovery subjects were provided with either CHO or only H2O and thereafter both groups received CHO. Muscle biopsies were collected before, after, and 4 and 24 h after exercise. Also, resting biopsies were collected from untrained subjects (n = 8). Exercise decreased glycogen by 67.7 ± 4.0% (from 699 ± 26.1 to 239 ± 29.5 mmol·kg(-1)·dw(-1)) with no difference between groups. Whereas 4 h of recovery with CHO partly replenished glycogen, the H2O group remained at post exercise level; nevertheless, the gene expression was not different between groups. Glycogen and most gene expression levels returned to baseline by 24 h in both CHO and H2O. Baseline mRNA expression of NRF-1, COX-IV, GLUT4 and PPAR-α gene targets were higher in trained compared to untrained. Additionally, the proportion of type I muscle fibers positively correlated with baseline mRNA for PGC-1α, TFAM, NRF-1, COX-IV, PPAR-α, and GLUT4 for both trained and untrained. CHO restriction during recovery from glycogen depleting exercise does not improve the mRNA response of markers of mitochondrial biogenesis. Further, baseline gene expression of key metabolic pathways is higher in trained than untrained.