Lactate-induced autophagy activation: unraveling the therapeutic impact of high-intensity interval training on insulin resistance in type 2 diabetic rats.

Impaired autophagy is a hallmark of diabetes. The current study proposed to investigate if high intensity interval training (HIIT) induced lactate accumulation could stimulate autophagy in type 2 diabetic male rats. 28 male Wistar rats were randomly assigned into four groups: Healthy Control (CO), Diabetes Control (T2D), Exercise (EX), and Diabetes + Exercise (T2D + EX). Diabetes was induced by feeding high-fat diet and administrating single dose of streptozotocin (35 mg/kg). After becoming diabetic, the animals in the exercise groups (EX and T2D + EX) performed an eight-week HIIT (4-10 interval, 80-100% Vmax, 5 days per week). Serum levels of lactate, glucose and insulin as well as the levels of lactate, pyruvate, lactate transporter monocarboxylate transporter 1 (MCT1), phosphorylated mitogen-activated protein kinases (p-MAP 1 and 2), phosphorylated extracellular signal-regulated protein kinases 1 and 2 (p-ERK 1 and 2), mammalian target of rapamycin (p-mTOR), ribosomal protein S6 kinase beta-1 (p-70S6k), p90 ribosomal S6 kinases (p-90RSK), autophagy related 7 (ATG7), Beclin-1, microtubule-associated protein 1A/1B, and 2A/2B -light chain 3 levels (LC3-I), (LC3- II), (LC3I/LC3II) in soleus muscle were measured. Homeostatic Model Assessment for Insulin Resistance (HOMA-IR) and serum glucose was lower in T2D + EX compared to T2D group (P < 0.0001). While serum and soleus muscle levels of lactate was not different between T2D and T2D + Ex, the levels of Pyruvate (P < 0.01), MCT1, p-ERK1/2, p-mTOR, p70S6k, P-90RSK, ATG7, LC3-II, and LC3-II/LC3I ratios were higher in T2D + EX compared to T2D group (P < 0.0001). We concluded that eight weeks of high-intensity interval training could activated ERK/P90SRK while inhibiting mTOR/P70S6K signaling pathway in lactate dependent manner. It means increased autophagy which resulted in improve insulin resistance (IR) and reduce blood glucose.

Lactate regulates autophagy through ROS-mediated activation of ERK1/2/m-TOR/p-70S6K pathway in skeletal muscle.

The role of autophagy and lysosomal degradation pathway in the regulation of skeletal muscle metabolism was previously studied. However, underlying molecular mechanisms are poorly understood. L-lactate which is utilized as an energetic substrate by skeletal muscle can also augment genes expression related to metabolism and up-regulate those being responsive to reactive oxygen species (ROS). Since ROS is the most important regulator of autophagy in skeletal muscle, we tested if there is a link between cellular lactate metabolism and autophagy in differentiated C2C12 myotubes and the gastrocnemius muscle of male wistar rats. C2C12 mouse skeletal muscle was exposed to 2, 6, 10, and 20 mM lactate and evaluated for lactate autophagic effects. Lactate dose-dependently increased autophagy and augmented ROS generation in differentiated C2C12 myotubes. The autophagic effect of lactate deterred in N-acetylcysteine presence (NAC, a ROS scavenger) indicated lactate regulates autophagy with ROS participation. Lactate-induced up-regulation of extracellular signal-regulated kinase 1/2 (ERK1/2) through ROS was required to regulate the autophagy by lactate. Further analysis about ERK1/2 up- and downstream indicated that lactate regulates autophagy through ROS-mediated the activation of ERK1/2/mTOR/p70S6K pathway in skeletal muscle. The in vitro effects of lactate on autophagy also occurred in the gastrocnemius muscle of male Wistar rats. In conclusion, we provided the lactate-associated regulation evidence of autophagy in skeletal muscle by activating ROS-mediated ERK1/2/mTOR/p70S6K pathway. Since the increase in cellular lactate concentration is a hallmark of energy deficiency, the results provide insight into a skeletal muscle mechanism to fulfill its enhanced energy requirement.

Resistance training-induced muscle hypertrophy is mediated by TGF-ß1-Smad signaling pathway in male Wistar rats.

The TGF-ß1-Smad pathway is a well-known negative regulator of muscle growth; however, its potential role in resistance training-induced muscle hypertrophy is not clear. The present study proposed to determine whether and how this pathway may be involved in resistance training-induced muscle hypertrophy. Skeletal muscle samples were collected from the control, trained (RT), control + SB431542 (CITGF ), and trained + SB431542 (RTITGF ) animals following 3, 5, and 8 weeks of resistance training. Inhibition of the TGF-ß1-Smad pathway by SB431542 augmented muscle satellite cells activation, upregulated Akt/mTOR/S6K1 pathway, and attenuated FOXO1 and FOXO3a expression in the CITGF group (all p < .01), thereby causing significant muscle hypertrophy in animals from the CITGF . Resistance training significantly decreased muscle TGF-ß1 expression and Smad3 (P-Smad3S423/425 ) phosphorylation at COOH-terminal residues, augmented Smad2 (P-Smad2-LS245/250/255 ) and Smad3 (P-Smad3-LSer208 ) phosphorylation levels at linker sites (all p < .01), and led to a muscle hypertrophy which was unaffected by SB431542, suggesting that the TGF-ß1-Smad signaling pathway is involved in resistance training-induced muscle hypertrophy. The effects of inhibiting the TGF-ß1-Smad signaling pathway were not additive to the resistance training effects on FOXO1 and FOXO3a expression, muscle satellite cells activation, and the Akt/mTOR/S6K1 pathway. Resistance training effect of satellite cell differentiation was independent of the TGF-ß1-Smad signaling pathway. These results suggested that the effect of the TGF-ß1-Smad signaling pathway on resistance training-induced muscle hypertrophy can be attributed mainly to its diminished inhibitory effects on satellite cell activation and protein synthesis. Suppressed P-Smad3S423/425 and enhanced P-Smad2-LS245/250/255 and P-Smad3-LSer208 are the molecular mechanisms that link the TGF-ß1-Smad signaling pathway to resistance training-induced muscle hypertrophy.

Antiretroviral therapy adherence based on information, motivation, and behavioral skills model and its association with depression among HIV-positive patients: Health promotion strategy towards the 909090 target.

BACKGROUND: HIV-infected patients with poor antiretroviral therapy (ART) adherence are prone to depression, and depression can exacerbate the disease condition. This study was conducted to determine ART Adherence based on Information, Motivation, and Behavioral Skills (IMB) Model and its association with depression among HIV-positive patients. MATERIALS AND METHODS: This descriptive-correlational study was carried out on people over the age of 18 years with HIV/AIDS, who referred to the Behavioral Diseases Counseling Center in Kerman City, Iran, in 2017. In this regard, 119 patients were selected using the table of random numbers. To collect the data, we used the Beck's depressioninventory-II and the IMB researcher made questionnaire to evaluate the ART adherence. RESULTS: The results of the study reveal that a significant association was observed between the total adherence and all constructs of the IMB model (P < 0.001). Risk perception and self-efficacy had the highest mean scores regarding the ART adherence. The prevalence of depression was 71.5% among patients. Information, personal motivation, and total adherence had a significant association with depression. CONCLUSIONS: IMB model was an appropriate and practical strategy with regard to the ART adherence among people living with HIV who are prone to depression and drug consumption is crucial for them to achieve the 90-90-90 target. This article created a questionnaire to assist policy-makers and health professionals designing interventions to improve adherence and health outcomes of ART.

Adherence to Medication and Physical Activity among People Living with HIV/AIDS.

BACKGROUND: The aim of this study was to investigate the adherence to medication and Physical Activity (PA) among People Living with HIV (PLHIV). MATERIALS AND METHODS: In the present cross-sectional study, 122 PLHIV were selected. The research tools included the Baecke questionnaire and the AIDS Clinical Trials Group questionnaire. Data were analyzed by independent t test and multiple logistic regression. RESULTS: The results of 7- and 30-day recalls showed that 76.21 and 82.23% of patients had proper medication adherence. The mean score of PA in patients was less than the recommended average score in the questionnaire. Furthermore, there was no significant difference observed between the medication adherence and PA. CONCLUSIONS: Although the adherence to medication was appropriate, nurses and health care providers should increase the level of PA for PLHIV by dealing with the related barriers to live an active life.

Physiological determinants of wrestling success in elite Iranian senior and junior Greco-Roman wrestlers.

BACKGROUND: Fitness profile and the physiological determinants of wrestling success in Greco-Roman wrestlers were investigated. METHODS: The wrestlers from the Iranian National Greco-Roman Team (14 junior wrestlers and 12 senior wrestlers) participated in this study. The junior and senior wrestlers were divided into two groups of successful and less successful athletes based on their performance during the previous wrestling season. The wrestlers were evaluated for anthropometric measurements, flexibility, muscular endurance, explosive power, peak and mean power of upper and lower limbs, cardiovascular endurance, running speed, agility, and muscular strength. RESULTS: In senior wrestler, significant differences in favor of the successful wrestlers were found for relative grip strength (P<0.01), pull-ups (P<0.01), peak and mean anaerobic power of upper limbs (P<0.05), and oxygen consumption (O2) corresponding to ventilatory threshold (VT). The results of discriminant analysis revealed that the relative grip strength, pull-ups, and mean anaerobic power were the most important variables separating the groups. In junior wrestlers, the successful wrestlers had significantly more relative grip strength (P<0.01), pull-ups (P<0.01), peak and mean anaerobic power of upper limbs (P<0.05), and peak anaerobic power of lower limbs (P<0.05). However, the results of discriminant analysis showed that the model could not successfully determine group membership. CONCLUSIONS: In summary, muscular strength, muscular endurance, and anaerobic capacity are the most important variables in Greco-Roman wrestling and athletes must pay particular attention to improving these variables to be a successful wrestler.

Exercise-induced lactate accumulation regulates intramuscular triglyceride metabolism via transforming growth factor-ß1 mediated pathways.

The mechanism regulating the utilization of intramuscular triacylglycerol (IMTG) during high-intensity interval training (HIIT) and post-exercise recovery period remains elusive. In this study, the acute and long-term effects of HIIT on transforming growth factor beta 1 (TGF-ß1) abundance in rat skeletal muscle and role of lactate and TGF-ß1 in IMTG lipolysis during post-exercise recovery period were examined. TGF-ß1 and Adipose triacylglycerol lipase (ATGL) abundance as well as total lipase activity in the gastrocnemius muscle significantly increased to a maximum value 10 h after acute bout of HIIT. Inhibition of TGF-ß1 signaling by intramuscular injection of SB431542 30 min prior to the acute exercise attenuated ATGL abundance and total lipase activity in the gastrocnemius muscle in response to acute exercise. Intramuscular acute injection of lactate increased TGF-ß1 and ATGL abundance in the gastrocnemius muscle and there were a significant increase in Muscle TGF-ß1 and ATGL abundance after 5 weeks of HIIT/lactate treatment. These results indicate that exercise-induced lactate accumulation regulates intramuscular triglyceride metabolism via transforming growth factor-ß1 mediated pathways during post-exercise recovery from strenuous exercise.

Determination of Anaerobic Threshold by Monitoring the O2 Pulse Changes in Endurance Cyclists.

The purpose of this study was to determine the validity of anaerobic threshold (AnT)-equivalent to the second turn point for lactate (LTP2)-estimation using the O2 pulse changes in highly trained endurance cyclists who do not show heart rate deflection point (HRDP) during incremental testing. Sixteen endurance cyclists (age, 24.8 ± 4.7 years) and fifteen active men (age, 24.8 ± 3.7 years) performed an incremental cycling test to exhaustion. Pulmonary oxygen uptake (V[Combining Dot Above]O2) and other hemodynamic variables, heart rate, and blood lactate concentration were measured continuously throughout the test. O2 pulse anaerobic threshold (O2 pulse-AnT) was defined as the second turn point in O2 pulse-workload curve. LTP2 was considered as gold standard assessment of AnT and was applied to confirm the validity of O2 pulse-AnT. Intraclass correlation coefficients and the Bland-Altman method were used to determine the relationship and agreement between the O2 corresponding to LTP2 and O2 pulse-AnT, respectively. The active men and 68.7% of the endurance cyclists showed HRDP, whereas all subjects showed O2 pulse-AnT during incremental testing. In both groups, the values for V[Combining Dot Above]O2 corresponding to LTP2 were not significantly different from the V[Combining Dot Above]O2 at O2 pulse-AnT. The V[Combining Dot Above]O2 at LTP2 and O2 pulse-AnT were highly correlated (endurance cyclists: R = 0.68; standard error of estimate [SEE] = 3.74 ml·kg·min and active men: R = 0.58; SEE = 2.91 ml·kg·min) and Bland-Altman plot revealed the limit of agreement of O2 at LTP2 and O2 pulse-AnT differences between 5.1 and 8.6 ml·kg·min (95% CI). In summary, results of this study showed that the second turn point in the O2 pulse-workload curve occurs around LTP2. Therefore, using O2 pulse-AnT is recommended for the noninvasive determination of AnT in highly trained endurance cyclists who do not show HRDP during incremental exercise.

Exercise-induced changes in tumour LDH-B and MCT1 expression are modulated by oestrogen-related receptor alpha in breast cancer-bearing BALB/c mice.

KEY POINTS: Monocarboxylate transporters (MCTs) and lactate dehydrogenase A (LDH-A) play important roles in sustaining the glycolytic phenotype seen in cancer. Endurance training improves aerobic capacity; however, whether endurance training alters the metabolic phenotype of a solid tumour, from the perspective of lactate metabolism, is yet to be proven. This study showed that endurance training decreases expression of the MCT1 basigin (CD147) and LDH-A , and also increases LDH-B expression in solid tumours and attenuates tumour lactate metabolism. Similar results for MCT1 and LDH-B were found with inhibition of the oestrogen-related receptor alpha (ERRα). The training effects were not additive to the ERRα effects on MCT1 and LDH-B expression in the tumour, which indicated that exercise-induced alterations in MCT1 and LDH-B expression were modulated by ERRα. These results suggest that endurance training could be a useful tool in cancer therapy, especially in basal-like and luminal-like breast carcinomas. ABSTRACT: Several factors, including overexpression of lactate dehydrogenase (LDH) and monocarboxylate transporters (MCTs), promote an aerobic lactate production that allows some cancer cells to sustain higher proliferation rates in hostile environments outside the cell. To elucidate the effect of endurance training on the metabolic phenotype of solid tumours, we focused on the tumour expression of LDH-A, LDH-B, MCT1, MCT4, oestrogen-related receptor alpha (ERRα) and LDH isozymes in control (C), trained (T), control+XCT790 (CX) and trained+XCT790 (TX) mice. First, we found that the metabolically altered tumours from the trained animals exhibited lower values for lactate concentration than the control group. The decreased lactate concentration was associated with a shift in the tumour LDH isozyme profile towards LDH-1. These exercise-induced changes were also associated with decreases in the expression of the tumour MCT1, ERRα and CD147 in the trained animals. Secondly, the inhibition of ERRα by treatment of MC4-L2 human breast cancer cells with XCT790 (inverse agonist ligand of ERRα) before injection into the animals not only increased LDH-B expression in the tumour, but also decreased MCT1 expression in the CX group in comparison to the C group. The effects of ERRα inhibition were not additive to the training effects on the expressions of MCT1 and LDH-B in the solid tumours. In conclusion, our results suggest that exercise-induced suppression of ERRα expression modulates alterations in solid tumour expression of LDH-B and MCT1 and contributes towards the prevention of tumour development.

Prediction of aerobic and anaerobic capacities of elite cyclists from changes in lactate during isocapnic buffering phase.

This study predicted aerobic and anaerobic capacities using relative changes of arterial blood lactate during the isocapnic buffering phase (relative [La]ISBP). Fourteen male professional cyclists (sprint-trained [n = 6] and endurance [n = 8]) performed 2 exercise sessions to exhaustion on a cycle ergometer; 1 incremental standard test to determine the isocapnic buffering phase, buffering capacities, and relative [La]ISBP and 1 supramaximal exercise test to determine maximal accumulated oxygen deficit (MAOD). The time between Lactate threshold (LT) and respiratory compensatory threshold (RCT) was considered to be the isocapnic buffering phase. Total buffering capacity was calculated as Δ[La]·ΔpH. Bicarbonate buffering was calculated as Δ[HCO3]·ΔpH, and the difference between -Δ[La]·ΔpH and Δ[HCO3]·ΔpH was considered as nonbicarbonate buffering. The lactate concentration for LT (p ≤ 0.05) and RCT (p ≤ 0.05), and relative [La]ISBP (p < 0.01) were significantly lower for endurance cyclists than for sprint-trained cyclists. A significant difference was found for bicarbonate buffering capacity between groups (p < 0.01). A significant correlation was found between relative [La]ISBP with (Equation is included in full-text article.)(r = -0.71, p ≤ 0.05) and MAOD (r = 0.73, p < 0.01). Relative [La]ISBP was useful for predicting aerobic power (R = 51%) and anaerobic capacity (R = 53%). These results demonstrated that relative [La]ISBP is an important variable in intermediary metabolism and in addition to (Equation is included in full-text article.)and LT is recommended for better evaluation of performance of athletes who show nearly equal contributions from the aerobic and anaerobic energy systems during exercise.

Effect of endurance training on retinol-binding protein 4 gene expression and its protein level in adipose tissue and the liver in diabetic rats induced by a high-fat diet and streptozotocin.

AIMS/INTRODUCTION: The present study was designed to investigate from which tissues the decrease in retinol-binding protein 4 (RBP4) expression could contribute to the improvement of serum RBP4 and insulin resistance (IR) after endurance training. MATERIALS AND METHODS: Male 7-week-old Wistar rats were randomly assigned into four groups including control (C), trained (T), diabetic control (DC) and trained diabetic (TD). At 8 weeks-of-age, diabetes was induced by a high-fat diet and intraperitoneal injection of low-dose streptozotocin (STZ; 35 mg/kg). Rats in the T and TD groups carried out a 7-week exercise program on a motorized treadmill (15-20 m/min for 20 min/day for 5 weeks), whereas the C and DC remained sedentary in their cages. Tissues gene expression and protein levels of RBP4 were assessed by using real-time polymerase chain reaction and western blot, respectively, while serum RBP4 was measured using an enzyme-linked immunosorbent assay kit. RESULTS: Exercise significantly improved IR and reduced serum concentration of RBP4 in the TD group. This reduction of serum RBP4 was accompanied by decreased RBP4 protein expression in visceral fat tissue. In contrast, exercise had no significant effect on RBP4 expression in liver and subcutaneous fat tissue in the TD group. Exercise also significantly decreased RBP4 gene expression in visceral fat tissue and muscle, whereas the effect of exercise on liver RBP4 messenger ribonucleic acid expression was not significant. CONCLUSIONS: The present study showed that the mechanism for RBP4 reducing the effect of endurance training could involve decreased RBP4 messenger ribonucleic acid expression and its protein level in adipose tissue in STZ-induced diabetic rats.

The effect of high-fat diet and streptozotocin-induced diabetes and endurance training on plasma levels of calcitonin gene-related peptide and lactate in rats.

OBJECTIVE: The aim of this study was to investigate the effect of type 2 diabetes induced by high-fat diet and streptozotocin, and the effect of endurance training on basal circulating levels of calcitonin gene-related peptide (CGRP) and lactate. METHODS: Male Wistar rats were randomly divided into 4 groups: 1) control (n=8); 2) trained (n=8); 3) diabetic (n=8) and 4) trained diabetic (n=8). At the age of 7 weeks, diabetes was induced by feeding the animals a high-fat diet and injecting them with a low dose of streptozotocin (35 mg/kg). The animals at 10 weeks of age underwent an endurance training protocol on a treadmill for 7 weeks. Plasma lactate concentrations were measured by a lactate assay kit, and an enzyme immunoassay kit was used to measure CGRP. RESULTS: The diabetic rats showed significant increases in plasma CGRP (3.0±1 ng/mL vs. 0.5±0.3 ng/mL, p<0.001) and plasma lactate levels (3.6±0.5 mmol/L vs. 1.3±0.5 mmol/L, p<0.001). Further, significant decrease in basal plasma lactate (2.6±0.5 mmol/L vs. 3.6±0.5 mmol/L, p<0.025) but not plasma CGRP levels (2.5±1.2 ng/mL vs. 3.0±1.3 ng/mL) were found in the diabetic subjects after the endurance training. CONCLUSIONS: The results showed that endurance training could modify the basal circulating levels of lactate but not CGRP, which were elevated in this model of type 2 diabetic rats, indicating the lack of correspondence between the endurance training-induced changes of lactate and CGRP in this model of diabetes.

Endurance training increases brain lactate uptake during hypoglycemia by up regulation of brain lactate transporters.

The capacity of the brain to metabolize non-glucose substrates under hypoglycemic state maintains its energy requirements. We hypothesized that exercise-induced increase in capacity for brain utilization of lactate by up regulation of the monocarboxylate transporters (MCTs) may contribute metabolic substrates during hypoglycemia in diabetic rats induced by streptozotocin. The induced diabetes increased MCT1 and MCT2 expression in the cortex and the hippocampus in the sedentary diabetic animals. There were exercise-induced increases in MCT1 in the cortex and the hippocampus and MCT2 expression in the cortex in trained diabetic animals; whereas, no changes were found in the healthy trained animals. Both diabetic and healthy trained animals showed higher values for brain lactate uptake during insulin-induced hypoglycemia when animals were intraperitoneally injected by L(+)-lactic acid. However, the response of counterregulatory hormones during hypoglycemia were blunted in the diabetic trained animals which indicates to carefully monitoring of glycemic targets both during and following prolonged exercise.

Exercise-induced changes of MCT1 in cardiac and skeletal muscles of diabetic rats induced by high-fat diet and STZ

We hypothesized that a part of therapeutic effects of endurance training on insulin resistance is mediated by increase in cardiac and skeletal muscle mitochondrial lactate transporter, monocarboxylate transporter 1 (MCT1). Therefore, we examined the effect of 7 weeks endurance training on the mRNA and protein expression of MCT1 and MCT4 and their chaperon, CD147, on both sarcolemmal and mitochondrial membrane, separately, in healthy and type 2 diabetic rats. Diabetes was induced by injection of low dose of streptozotocin and feeding with high-fat diet. Insulin resistance was confirmed by homeostasis model assessment-estimated insulin resistance index and accuracy of two membranes separation was confirmed by negative control markers (glucose transporter 1 and cytochrome c oxidase. Real-time PCR and western blotting were used for mRNA and protein expression, respectively. Diabetes dramatically reduced MCT1 and MCT4 mRNA and their expression on sarcolemmal membrane whereas the reduction in MCT1 expression was less in mitochondrial membrane. Training increased the MCT1 mRNA and protein expression in both membranes and decreased insulin resistance as an adaptive consequence. In both tissues increase in CD147 mRNA was only parallel to MCT1 expression. The response of MCT1 on sarcolemmal and mitochondrial membranes was different between cardiac and skeletal muscles which indicate that intracellular lactate kinetic is tissue specific that allows a tissue to coordinate whole organism metabolism (AU)

Exercise-induced changes of MCT1 in cardiac and skeletal muscles of diabetic rats induced by high-fat diet and STZ.

We hypothesized that a part of therapeutic effects of endurance training on insulin resistance is mediated by increase in cardiac and skeletal muscle mitochondrial lactate transporter, monocarboxylate transporter 1 (MCT1). Therefore, we examined the effect of 7 weeks endurance training on the mRNA and protein expression of MCT1 and MCT4 and their chaperon, CD147, on both sarcolemmal and mitochondrial membrane, separately, in healthy and type 2 diabetic rats. Diabetes was induced by injection of low dose of streptozotocin and feeding with high-fat diet. Insulin resistance was confirmed by homeostasis model assessment-estimated insulin resistance index and accuracy of two membranes separation was confirmed by negative control markers (glucose transporter 1 and cytochrome c oxidase. Real-time PCR and western blotting were used for mRNA and protein expression, respectively. Diabetes dramatically reduced MCT1 and MCT4 mRNA and their expression on sarcolemmal membrane whereas the reduction in MCT1 expression was less in mitochondrial membrane. Training increased the MCT1 mRNA and protein expression in both membranes and decreased insulin resistance as an adaptive consequence. In both tissues increase in CD147 mRNA was only parallel to MCT1 expression. The response of MCT1 on sarcolemmal and mitochondrial membranes was different between cardiac and skeletal muscles which indicate that intracellular lactate kinetic is tissue specific that allows a tissue to coordinate whole organism metabolism.