RESUMEN
The mechanisms by which the ageing process is associated to an unhealthy lifestyle and how they play an essential role in the aetiology of systemic arterial hypertension have not yet been completely elucidated. Our objective is to investigate the influence of NOS3 polymorphisms [-786T > C and (Glu298Asp)] on systolic blood pressure (SBP) and diastolic blood pressure (DBP) response, differentially methylated regions (DMRs), and physical fitness of adult and older women after a 14-week combined training intervention. The combined training was carried out for 14 weeks, performed 3 times a week, totalling 180 minutes weekly. The genotyping experiment used Illumina Infinium Global Screening Array version 2.0 (GSA V2.0) and Illumina's EPIC Infinium Methylation BeadChip. The participants were separated into SNP rs2070744 in TT (59.7 ± 6.2 years) and TC + CC (60.0 ± 5.2 years), and SNP rs17999 in GluGlu (58.8 ± 5.7 years) and GluAsp + AspAsp (61.6 ± 4.9 years). We observed an effect of time for variables BP, physical capacities, and cholesterol. DMRs related to SBP and DBP were identified for the rs2070744 and rs17999 groups pre- and decreased numbers of DMRs post-training. When we analysed the effect of exercise training in pre- and post-comparisons, the GluGlu SNP (rs17999) showed 10 DMRs, and after enrichment, we identified several biological biases. The combined training improved the SBP and DBP values of the participants regardless of the SNPs. In addition, exercise training affected DNA methylation differently between the groups of NOS3 polymorphisms.
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Presión Sanguínea , Metilación de ADN , Ejercicio Físico , Óxido Nítrico Sintasa de Tipo III , Polimorfismo de Nucleótido Simple , Humanos , Femenino , Persona de Mediana Edad , Óxido Nítrico Sintasa de Tipo III/genética , Presión Sanguínea/genética , Anciano , Hipertensión/genética , Epigénesis GenéticaRESUMEN
The anti-inflammatory role of physical exercise is mediated by interleukin 10 (IL-10), and their release is possibly upregulated in response to IL-6. Previous studies demonstrated that mice lacking IL-6 (IL-6 KO mice) exhibited diminished exercise tolerance, and reduced strength. Rev-erbα, a transcriptional suppressor involved in circadian rhythm, has been discovered to inhibit the expression of genes linked to bodily functions, encompassing inflammation and metabolism. It also plays a significant role in skeletal muscle and exercise performance capacity. Given the potential association between Rev-erbα and the immune system and the fact that both pathways are modulated following acute aerobic exercise, we examined the physical performance of IL-10 KO mice and analyzed the modulation of the atrophy and Rev-erbα pathways in the muscle of wild type (WT) and IL-10 KO mice following one session of acute exercise. For each phenotype, WT and IL-10 KO were divided into two subgroups (Control and Exercise). The acute exercise session started at 6 m/min, followed by 3 m/min increments every 3 min until animal exhaustion. Two hours after the end of the exercise protocol, the gastrocnemius muscle was removed and prepared for the reverse transcription-quantitative polymerase chain reaction (RT-q-PCR) and immunoblotting technique. In summary, compared to WT, the IL-10 KO animals showed lower body weight and grip strength in the baseline. The IL-10 control group presented a lower protein content of BMAL1. After the exercise protocol, the IL-10 KO group had higher mRNA levels of Trim63 (atrophy signaling pathway) and lower mRNA levels of Clock and Bmal1 (Rev-erbα signaling pathway). This is the first study showing the relationship between Rev-erbα and atrophy in IL-10 KO mice. Also, we accessed a public database that analyzed the gastrocnemius of MuRF KO mice submitted to two processes of muscle atrophy, a denervation surgery and dexamethasone (Dexa) injections. Independently of knockout, the denervation demonstrated lower Nr1d1 levels. In conclusion, IL-10 seems to be a determinant in the Rev-erbα pathway and atrophy after acute exercise, with no modulation in the baseline state.
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Factores de Transcripción ARNTL , Interleucina-10 , Animales , Ratones , Factores de Transcripción ARNTL/genética , Factores de Transcripción ARNTL/metabolismo , Atrofia , Interleucina-10/genética , Interleucina-6/genética , Ratones Noqueados , Proteínas Musculares/genética , Músculo Esquelético/metabolismo , ARN Mensajero/metabolismo , Proteínas de Motivos Tripartitos , Ubiquitina-Proteína LigasasRESUMEN
Aging can modify the morphology and function of the liver, such as generating a decrease in the mitochondria content, autophagy, and cell senescence. Although exercise training has several beneficial effects on hepatic metabolism, its actions on autophagy processes, mitochondrial function, and cellular senescence need to be more widely explored. The present study verified the effects of aging and exercise on hepatic circadian markers, autophagy, and mitochondria activity in 24-month-old mice with a combined exercise training protocol. In addition, we used public datasets from human livers in several conditions and BMAL1 knockout mice. C57BL/6 mice were distributed into Control (CT, young, 6-month-old mice), sedentary old (Old Sed, sedentary, 24-month-old mice), and exercised old (Old Ex, 24-month-old mice submitted to a combined exercise training protocol). The exercise training protocol consisted of three days of endurance exercise - treadmill running, and two days of resistance exercise - climbing a ladder, for three weeks. At the end of the protocol, the liver was removed and prepared for histological analysis, reverse transcription-quantitative polymerase chain reaction (RT-qPCR), immunoblotting technique, and oxygen consumption. Heatmaps were built using a human dataset and Bmal1 knockout samples. In summary, the Old Sed had reduced strength, coordination, and balance, as well as a decrease in Bmal1 expression and the presence of degenerated liver cells. Still, this group upregulated the transcription factors related to mitochondrial biogenesis. The Old Ex group had increased strength, coordination, and balance, improved glucose sensitivity, as well as restored Bmal1 expression and the mitochondrial transcription factors. The human datasets indicated that mitochondrial markers and autophagy strongly correlate with specific liver diseases but not aging. We can speculate that mitochondrial and autophagy molecular markers alterations may depend on long-term training.
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Factores de Transcripción ARNTL , Hígado , Condicionamiento Físico Animal , Animales , Ratones , Factores de Transcripción ARNTL/genética , Factores de Transcripción ARNTL/metabolismo , Hígado/metabolismo , Ratones Endogámicos C57BL , Ratones Noqueados , Mitocondrias/metabolismoRESUMEN
Dysfunction of the adipose tissue metabolism is considered as a significant hallmark of aging. It has been proposed that α-ß hydrolase domain containing 5 (ABHD5) plays a critical role in the control of lipolysis. However, the role of ABHD5 in the control of lipolysis during aging or exercise is unknown. Here we combined the experimental mouse model with transcriptomic analyzes by using murine and human databases to explore the role of ABHD5 in the adipose tissue during aging and in response to exercise. Transcriptomic data revealed a downregulation of Abhd5 messenger RNA levels in the subcutaneous white adipose tissue (scWAT) over time in individuals from 20 to 69 years old. Aged mice displayed dramatic reduction of ABHD5 protein content and lipolytic-related proteins in the scWAT. Interestingly, 4 weeks of high-intensity interval training increased ABHD5 protein level and restored the lipolytic pathway in the scWAT of aged mice. Altogether, our findings demonstrated that aging affects ABHD5 content in the adipose tissue of mice and humans. Conversely, exercise increases ABHD5 activity, recovering the lipolytic activity in aged mice.
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1-Acilglicerol-3-Fosfato O-Aciltransferasa , Tejido Adiposo , Envejecimiento , Ejercicio Físico , Lipólisis , Adulto , Anciano , Animales , Humanos , Ratones , Persona de Mediana Edad , Adulto Joven , 1-Acilglicerol-3-Fosfato O-Aciltransferasa/genética , 1-Acilglicerol-3-Fosfato O-Aciltransferasa/metabolismo , Tejido Adiposo/enzimología , Envejecimiento/metabolismo , Hidrolasas/genética , Hidrolasas/metabolismoRESUMEN
Many conditions, such as inflammation and physical exercise, can induce endoplasmic reticulum (ER) stress. Toll-like Receptor 4 (TLR4) can trigger inflammation and ER stress events. However, there are still no data in the literature regarding the role of TLR4 in ER stress during exercise in skeletal muscle. Therefore, the current investigation aimed to verify the responses of ER stress markers in wild-type (WT) and Tlr4 global knockout (KO) mice after acute and chronic physical exercise protocols. Eight-week-old male WT and KO mice were submitted to acute (moderate or high intensity) and chronic (4-week protocol) treadmill exercises. Under basal conditions, KO mice showed lower performance in the rotarod test. Acute high-intensity exercise increased eIF2α protein in the WT group. After the acute high-intensity exercise, there was an increase in Casp3 and Ddit3 mRNA for the KO mice. Acute moderate exercise increased the cleaved Caspase-3/Caspase-3 in the KO group. In response to chronic exercise, the KO group showed no improvement in any performance evaluation. The 4-week chronic protocol did not generate changes in ATF6, CHOP, p-IRE1α, p-eIF2α/eIF2α, and cleaved Caspase-3/Caspase-3 ratio but reduced BiP protein compared with the KO-Sedentary group. These results demonstrate the global deletion of Tlr4 seems to have the same effects on UPR markers of WT animals after acute and chronic exercise protocols but decreased performance. The cleaved Caspase-3/Caspase-3 ratio may be activated by another pathway other than ER stress in Tlr4 KO animals.
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Apoptosis , Músculo Esquelético , Receptor Toll-Like 4 , Animales , Masculino , Ratones , Caspasa 3/metabolismo , Estrés del Retículo Endoplásmico , Endorribonucleasas/metabolismo , Inflamación/metabolismo , Ratones Endogámicos C57BL , Ratones Noqueados , Músculo Esquelético/metabolismo , Músculo Esquelético/patología , Receptor Toll-Like 4/genética , Receptor Toll-Like 4/metabolismo , Condicionamiento Físico AnimalRESUMEN
The transcriptional repressor REV-ERB-α, encoded by Nuclear Receptor Subfamily 1 Group D Member 1 (Nr1d1), has been considered to play an essential role in the skeletal muscle oxidative capacity adaptation and muscle mass control. Also, this molecule regulates autophagy via the repression of autophagy-related genes both in skeletal muscle and brain regions. Classically, training programs based on endurance or strength characteristics enhance skeletal muscle mass content and/or oxidative capacity, leading to autophagy activation in several tissues. Thus, it seems that REV-ERB-α regulates similar responses induced by exercise. However, how this molecule responds to different exercise models/intensities in different tissues is still unclear. Therefore, the main aim was to characterize the responses of REV-ERB-α and autophagy-related genes to different exercise protocols (endurance/interval run/strength) in distinct tissues (gastrocnemius, soleus and hippocampus). Since REV-ERB-α presents a circadian rhythm, the analyses were performed in a time-course manner. The endurance and strength groups attenuated REV-ERB-α transcriptional response during the time course in gastrocnemius and soleus. Conversely, the interval group enhanced the Nr1d1 expression in the hippocampus. All protocols downregulated the REV-ERB-α protein levels in gastrocnemius following the exercise session with concomitant nuclear exclusion. The major autophagy-related genes presented downregulation after the exercise session in all analyzed tissues. Altogether, these results highlight that REV-ERB-α is extremely sensitive to physical exercise stimuli, including different models and intensities in skeletal muscle and the hippocampus.
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Ritmo Circadiano , Ejercicio Físico , Ritmo Circadiano/genética , Autofagia/genética , Músculo Esquelético , HipocampoRESUMEN
Interleukin 6 (IL-6) acts as a pro and anti-inflammatory cytokine, has an intense correlation with exercise intensity, and activates various pathways such as autophagy and mitochondrial unfolded protein response. Also, IL-6 is interconnected to circadian clock-related inflammation and can be suppressed by the nuclear receptor subfamily 1, group D, member 1 (Nr1d1, protein product REV-ERBα). Since IL-6 is linked to physical exercise-modulated metabolic pathways such as autophagy and mitochondrial metabolism, we investigated the relationship of IL-6 with REV-ERBα in the adaptations of these molecular pathways in response to acute intense physical exercise in skeletal muscle. The present study was divided into three experiments. In the first one, wild-type (WT) and IL-6 knockout (IL-6 KO) mice were divided into three groups: Basal time (Basal; sacrificed before the acute exercise), 1 hour (1hr post-Ex; sacrificed 1 hour after the acute exercise), and 3 hours (3hr post-Ex; sacrificed 3 hours after the acute exercise). In the second experiment, C2C12 cells received IL-6 physiological concentrations or REV-ERBα agonist, SR9009. In the last experiment, WT mice received SR9009 injections. After the protocols, the gastrocnemius muscle or the cells were collected for reverse transcription-quantitative polymerase chain reaction (RTq-PCR) and immunoblotting techniques. In summary, the downregulation of REV-ERBα, autophagic flux, and most mitochondrial genes was verified in the IL-6 KO mice independent of exercise. The WT and IL-6 KO treated with SR9009 showed an upregulation of autophagic genes. C2C12 cells receiving IL-6 did not modulate the Nr1d1 mRNA levels but upregulated the expression of some mitochondrial genes. However, when treated with SR9009, IL-6 and mitochondrial gene expression were upregulated in C2C12 cells. The autophagic flux in C2C12 suggest the participation of REV-ERBα protein in the IL-6-induced autophagy. In conclusion, the present study verified that the adaptations required through physical exercise (increases in mitochondrial content and improvement of autophagy machinery) might be intermediated by an interaction between IL-6 and REVERBα.
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Interleucina-6 , Miembro 1 del Grupo D de la Subfamilia 1 de Receptores Nucleares , Animales , Ratones , Autofagia/genética , Biomarcadores , Productos del Gen rev , Interleucina-6/genética , Interleucina-6/metabolismo , Músculo Esquelético/metabolismo , Miembro 1 del Grupo D de la Subfamilia 1 de Receptores Nucleares/genética , Miembro 1 del Grupo D de la Subfamilia 1 de Receptores Nucleares/metabolismoAsunto(s)
Hígado , Sirolimus , Autofagia , Lipogénesis , Hígado/metabolismo , Sirolimus/metabolismo , Sirolimus/farmacologíaRESUMEN
Regular endurance exercise is a non-pharmacological strategy to protect the liver against diseases. Conversely, exercise may be harmful when excessive, the so-called overtraining. As expected, mice who underwent an overtraining protocol presented higher levels of proinflammatory cytokines in the serum and liver. Based on the relationship among overtraining, inflammation and mammalian target of rapamycin complex 1 (mTORC1) upregulation, the present study verified if animals submitted to an overtraining protocol, but with inhibition of the mTOR pathway via rapamycin injections could mitigate the liver and serum inflammation. Once autophagy can be linked to the improvement of hepatic dysfunction, we also investigated if the inhibition of mTORC1 by rapamycin can improve hepatic autophagy. The animals were randomized into four groups: control (CT; sedentary mice), overtraining by downhill running (OT; mice submitted to the downhill running-based overtraining protocol), overtraining by downhill running with chronic administration of rapamycin (OT/Rapa; mice submitted to the downhill running-based overtraining protocol with intraperitoneal injections of rapamycin) and aerobic (AER; submitted to aerobic training protocol). The serum and liver of the animals were used for biochemical analysis, reverse transcription-quantitative polymerase chain reaction (RT-qPCR) and immunoblotting. The main results are (a) OT and OT/Rapa protocols decreased the performance; (b) the protein levels of interleukin 6 (IL-6) were higher for the OT group; the OT/Rapa group reduced the autophagic genes, increased the microtubule-associated protein light chain 3 II/I (LC3II/LC3I) protein ratio and decreased the sequestosome 1 (SQSTM1) protein. In conclusion, rapamycin appears efficiently to increase the autophagy proteins and decrease IL-6 protein in the liver of overtraining mice.
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Interleucina-6 , Sirolimus , Animales , Autofagia , Inflamación/metabolismo , Mamíferos/metabolismo , Diana Mecanicista del Complejo 1 de la Rapamicina/metabolismo , Ratones , Proteínas Asociadas a Microtúbulos/metabolismo , Sirolimus/farmacologíaRESUMEN
The intensity, duration, type of contraction, and muscle damage influence interleukin-6 (IL-6) response to acute exercise. However, in response to an exhaustive exercise session, the upregulation of IL-6 in the serum and heart is associated with an inflammatory condition and can inhibit autophagy. This study aimed to investigate the role of IL-6 in autophagy pathway responses and mitochondrial function in the heart of mice submitted to acute exhaustive physical exercise. The mice were allocated into three groups, five animals per group, for the wild type (WT) and the IL-6 knockout (IL-6 KO): Basal (sedentary; Basal), 1 h (after 1 h of the acute exercise; 1 h), and 3 h (after 3 h of the acute exercise; 3 h). After the specific time for each group, the blood was collected, each mouse heart was removed, and the left ventricle (LV) was isolated. In summary, under basal conditions, without the influence of the acute exercise, the IL-6 KO group showed lower number of nuclei in the cardiac tissue, but higher collagen deposition; lower messenger RNA (mRNA) levels of Prkaa1 and Mtco1, but higher mRNA levels of Ulk1; and higher protein levels of the ratio p-AMPK/AMPK in the heart when compared to WT at the same time point. After the acute exercise (1 and 3 h), the IL-6 KO group had lower mRNA levels of Tfam, Mtnd1, Mtco1, and Nampt in the heart when compared to WT after exercise; higher serum levels of creatine kinase (CK), CK-MB, and lactate dehydrogenase for the IL-6 group when compared to the WT group after the exercise. Specifically, the heat-shock protein 60 protein levels in the heart increased 3 h after exhaustive exercise in the WT group, but not in the IL-6 KO group. The study emphasizes that IL-6 may offer cardioprotective effects, including mitochondrial adaptations in response to acute exhaustive exercise.
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Interleucina-6 , Condicionamiento Físico Animal , Proteínas Quinasas Activadas por AMP , Animales , Interleucina-6/genética , Interleucina-6/metabolismo , Ratones , Ratones Noqueados , Condicionamiento Físico Animal/fisiología , ARN Mensajero/metabolismoRESUMEN
The endoplasmic reticulum (ER) is an organelle responsible for the post-translational folding and modification of proteins. Under stress conditions, such as physical exercise, there is accumulation of misfolded proteins. The increased load of proteins in the ER results in ER stress, which activates the unfolded protein response (UPR). UPR is comprised of three parallel pathways, responsible for ensuring the quality of secreted proteins. Scientific studies show that resistance or endurance acute physical exercise can induce ER stress and activate the UPR pathways. On the other hand, regular moderate-intensity exercise can attenuate the responses of genes and proteins related to ER stress. However, these positive adaptations do not occur when exercise intensity and volume increase without adequate rest periods, which is observed in overtraining. The current review discusses the frontier-of-knowledge findings on the effects of different acute and chronic physical exercise protocols on skeletal muscle ER stress and its metabolic consequences.
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Estrés del Retículo Endoplásmico , Transducción de Señal , Estrés del Retículo Endoplásmico/fisiología , Ejercicio Físico , Músculo Esquelético , Transducción de Señal/fisiología , Respuesta de Proteína DesplegadaRESUMEN
Autophagic dysregulation contributes to liver diseases. Although some investigations have examined the effects of endurance and resistance exercise on autophagy activation, potential myokines responsible for skeletal muscle-liver crosstalk are still unknown. Based on experimental studies and bioinformatics, we hypothesized that interleukin 6 (IL-6) and irisin might be key players in the contraction-induced release of molecules that regulate liver autophagic responses.
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Autofagia , Ejercicio Físico , Fibronectinas , Interleucina-6 , Hígado , Fibronectinas/fisiología , Humanos , Interleucina-6/fisiología , Músculo EsqueléticoRESUMEN
Strategies capable of attenuating TLR4 can attenuate metabolic processes such as inflammation, endoplasmic reticulum (ER) stress, and apoptosis in the body. Physical exercise has been a cornerstone in suppressing inflammation and dysmetabolic outcomes caused by TRL4 activation. Thus, the present study aimed to evaluate the effects of a chronic physical exercise protocol on the TLR4 expression and its repercussion in the inflammation, ER stress, and apoptosis pathways in mice hearts. Echocardiogram, RT-qPCR, immunoblotting, and histological techniques were used to evaluate the left ventricle of wild-type (WT) and Tlr4 knockout (TLR4 KO) mice submitted to a 4-week physical exercise protocol. Moreover, we performed a bioinformatics analysis to expand the relationship of Tlr4 mRNA in the heart with inflammation, ER stress, and apoptosis-related genes of several isogenic strains of BXD mice. The TLR4 KO mice had higher energy expenditure and heart rate in the control state but lower activation of apoptosis and ER stress pathways. The bioinformatics analysis reinforced these data. In the exercised state, the WT mice improved performance and cardiac function. However, these responses were blunted in the KO group. In conclusion, TLR4 has an essential role in the inhibition of apoptosis and ER stress pathways, as well as in the training-induced beneficial adaptations.
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Apoptosis/genética , Estrés del Retículo Endoplásmico/genética , Metabolismo Energético/genética , Ventrículos Cardíacos , Condicionamiento Físico Animal , Receptor Toll-Like 4/genética , Función Ventricular , Animales , Proteínas Reguladoras de la Apoptosis/genética , Proteínas Reguladoras de la Apoptosis/metabolismo , Ecocardiografía , Eliminación de Gen , Glucógeno/metabolismo , Frecuencia Cardíaca , Inflamación/genética , Inflamación/patología , Ratones , Ratones Noqueados , ARN Mensajero/metabolismoRESUMEN
Although physical exercise-induced autophagy activation has been considered a therapeutic target to enhance tissue health and extend lifespan, the effects of different exercise models on autophagy in specific metabolic tissues are not completely understood. This descriptive investigation compared the acute effects of endurance (END), exhaustive (ET), strength (ST), and concurrent (CC) physical exercise protocols on markers of autophagy, genes, and proteins in the gastrocnemius muscle, heart, and liver of mice. The animals were euthanized immediately (0 h) and six hours (6 h) after the acute exercise for the measurement of glycogen levels, mRNA expression of Prkaa1, Ppargc1a, Mtor, Ulk1, Becn1, Atg5, Map1lc3b, Sqstm1, and protein levels of Beclin 1 and ATG5. The markers of autophagy were measured by quantifying the protein levels of LC3II and Sqstm1/p62 in response to three consecutive days of intraperitoneal injections of colchicine. In summary, for gastrocnemius muscle samples, the main alterations in mRNA expressions were observed after 6 h and for the ST group, and the markers of autophagy for the CC group were increased (i.e., LC3II and Sqstm1/p62). In the heart, the Beclin 1 and ATG5 levels were downregulated for the ET group. Regarding the markers of autophagy, the Sqstm1/p62 in the heart tissue was upregulated for the END and ST groups, highlighting the beneficial effects of these exercise models. The liver protein levels of ATG5 were downregulated for the ET group. After the colchicine treatment, the liver protein levels of Sqstm1/p62 were decreased for the END and ET groups compared to the CT, ST, and CC groups. These results could be related to diabetes and obesity development or liver dysfunction improvement, demanding further investigations.
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Autofagia , Regulación de la Expresión Génica , Proteínas Musculares/biosíntesis , Músculo Esquelético/metabolismo , Condicionamiento Físico Animal , Animales , Biomarcadores/metabolismo , Masculino , RatonesRESUMEN
Interleukin-6 (IL-6) is associated with pathological cardiac hypertrophy and can be dramatically increased in serum after an acute strenuous exercise session. However, IL-6 is also associated with the increased production and release of anti-inflammatory cytokines and the inhibition of tumor necrosis factor-alpha (TNF-α) after chronic moderate exercise. To elucidate the relevance of IL-6 in inflammatory and hypertrophic signaling in the heart in response to an acute strenuous exercise session, we combined transcriptome analysis using the BXD mice database and exercised IL-6 knockout mice (IL-6KO). Bioinformatic analysis demonstrated that low or high-levels of Il6 mRNA in the heart did not change the inflammation- and hypertrophy-related genes in BXD mice strains. On the other hand, bioinformatic analysis revealed a strong positive correlation between Il6 gene expression in skeletal muscle with inflammation-related genes in cardiac tissue in several BXD mouse strains, suggesting that skeletal muscle-derived IL-6 could alter the heart's intracellular signals, particularly the inflammatory signaling. As expected, an acute strenuous exercise session increased IL-6 levels in wild-type, but not in IL-6KO mice. Despite not showing morphofunctional differences in the heart at rest, the IL-6KO group presented a reduction in physical performance and attenuated IL-6, TNF-α, and IL-1beta kinetics in serum, as well as lower p38MAPK phosphorylation, Ampkalpha expression, and higher Acta1 and Tnf gene expressions in the left ventricle in the basal condition. In response to strenuous exercise, IL-6 ablation was linked to a reduction in the pro-inflammatory response and higher activation of classical physiological cardiac hypertrophy proteins.
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Biomarcadores/metabolismo , Corazón/fisiopatología , Inflamación/patología , Interleucina-6/deficiencia , Condicionamiento Físico Animal , Adenilato Quinasa/metabolismo , Animales , Biomarcadores/sangre , Cardiomegalia/sangre , Cardiomegalia/genética , Electrocardiografía , Perfilación de la Expresión Génica , Regulación de la Expresión Génica , Corazón/diagnóstico por imagen , Interleucina-6/genética , Interleucina-6/metabolismo , Ratones Endogámicos C57BL , Ratones Noqueados , Músculo Esquelético/metabolismo , Fosforilación , Proteínas Proto-Oncogénicas c-akt/metabolismo , ARN Mensajero/genética , ARN Mensajero/metabolismo , Descanso , Transducción de Señal , Serina-Treonina Quinasas TOR/metabolismoRESUMEN
Physical exercise-induced skeletal muscle damage may be characterized by increased oxidative stress, inflammation, and apoptosis which may be beneficial when exercise is regular, but it is rather harmful when exercise is exhaustive and performed acutely by unaccustomed individuals. Molecular hydrogen (H2) has emerged as a potent antioxidant, anti-inflammatory, and anti-apoptotic agent, but its action on the deleterious effects of acute exhaustive exercise in muscle damage remain unknown. Therefore, we tested the hypothesis that H2 decreases acute exhaustive exercise-induced skeletal muscle damage of sedentary rats. Rats ran to exhaustion on a sealed treadmill inhaling an H2-containing mixture or the control gas. We measured oxidative stress (SOD, GSH, and TBARS), inflammatory (TNF-α, IL-1ß, IL-6, IL-10, and NF-κB phosphorylation), and apoptotic (expression of caspase-3, Bcl-2, and HSP70) markers. Exercise caused no changes in SOD activity but increased TBARS levels. H2 caused increases in exercise-induced SOD activity and blunted exercise-induced increased TBARS levels. We observed exercise-induced TNF-α and IL-6 surges as well as NF-κB phosphorylation, which were blunted by H2. Exercise increased cleaved caspase-3 expression, and H2 reduced this response. In conclusion, H2 effectively downregulates muscle damage, reducing oxidative stress, inflammation, and apoptosis after acute exhaustive exercise performed by an unaccustomed organism.
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Estrés Oxidativo , Animales , Antiinflamatorios , Antioxidantes , Inflamación , RatasRESUMEN
BACKGROUND: Beta-alanine has become a dietary supplement widely used by athletes due to its ergogenic effect. However, there is still no consensus on the performance benefit of beta-alanine on exercise lasting longer than ten minutes. The present study aimed to evaluate the effect of beta-alanine supplementation on running performance and the expression of TauT and PAT1. METHODS: This double-blind, randomized study enrolled 16 long-distance runners (37±8 years) who were randomly allocated to two groups: placebo (PLA) and beta-alanine (BA) (4.8 g/day 1) for four weeks. Maximal oxygen consumption, anthropometry, body composition, and food intake were determined. Before and after the intervention, the athletes undertook a 5000 m running time trial. Venous blood (TauT and PAT1 expressions) and ear lobe capillary blood (lactate) collected before and after exercise. Between tests, we monitored the training variables. RESULTS: The results were analyzed by t-tests and an ANOVA of repeated measures, with Sidak's post hoc (P<0.05). PLA exhibited lower body fat than BA (8.7±2.2 vs. 11.5±2.8%, P=0.04). After supplementation, there was an increase in PAT1 expression in BA when compared to PLA (1.17±0.47 vs. 0.77±0.18, P=0.04). No significant differences were shown for the 5000 m running time in PLA (PRE: 1128±72; POST: 1123±72s) and BA (PRE: 1107±95; POST: 1093±86s). CONCLUSIONS: Although beta-alanine supplementation increased PAT1 expression, there was no statistically significant improvement in 5000 m running performance. However, individual responses should be considered as the BA showed a higher delta than the PLA.
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Sistemas de Transporte de Aminoácidos/metabolismo , Rendimiento Atlético , Sustancias para Mejorar el Rendimiento , Carrera , Simportadores/metabolismo , beta-Alanina/administración & dosificación , Adulto , Suplementos Dietéticos , Método Doble Ciego , Humanos , Ácido Láctico , Glicoproteínas de Membrana/metabolismo , Proteínas de Transporte de Membrana/metabolismo , Persona de Mediana Edad , Sustancias para Mejorar el Rendimiento/administración & dosificación , Resistencia Física , Fenómenos Fisiológicos en la Nutrición DeportivaRESUMEN
The protective effects of chronic moderate exercise-mediated autophagy include the prevention and treatment of several diseases and the extension of lifespan. In addition, physical exercise may impair cellular structures, requiring the action of the autophagy mechanism for clearance and renovation of damaged cellular components. For the first time, we investigated the adaptations on basal autophagy flux in vivo in mice's liver, heart, and skeletal muscle tissues submitted to four different chronic exercise models: endurance, resistance, concurrent, and overtraining. Measuring the autophagy flux in vivo is crucial to access the functionality of the autophagy pathway since changes in this pathway can occur in more than five steps. Moreover, the responses of metabolic, performance, and functional parameters, as well as genes and proteins related to the autophagy pathway, were addressed. In summary, the regular exercise models exhibited normal/enhanced adaptations with reduced autophagy-related proteins in all tissues. On the other hand, the overtrained group presented higher expression of Sqstm1 and Bnip3 with negative morphological and physical performance adaptations for the liver and heart, respectively. The groups showed different adaptions in autophagy flux in skeletal muscle, suggesting the activation or inhibition of basal autophagy may not always be related to improvement or impairment of performance.
Asunto(s)
Autofagia/fisiología , Condicionamiento Físico Animal/fisiología , Adaptación Fisiológica/genética , Adaptación Fisiológica/fisiología , Animales , Autofagia/genética , Proteínas Relacionadas con la Autofagia/genética , Proteínas Relacionadas con la Autofagia/metabolismo , Hígado/citología , Masculino , Ratones , Ratones Endogámicos C57BL , Modelos Biológicos , Músculo Esquelético/citología , Músculo Esquelético/metabolismo , Miocardio/citología , Miocardio/metabolismo , Especificidad de Órganos , Resistencia Física/genética , Resistencia Física/fisiología , ARN Mensajero/genética , ARN Mensajero/metabolismoRESUMEN
During overnight sleep, the longest postabsorptive and inactive phase of the day causes protein catabolism and loss. However, the daytime ingestion of dairy proteins has been shown to stimulate muscle protein synthesis and growth. This study compared the effects of pre-sleep supplementation of a protein blend (PB) composed of micellar casein (MCa) and whey protein (1:1) versus isolate MCa on the plasma levels of branched-chain amino acids (BCAAs) and the activation of the mechanistic target of rapamycin (mTOR) signaling, a critical intracellular pathway involved in the regulation of muscle protein synthesis. After 10 h of fasting during the active phase, rats were fed with a single dose of PB or MCa (5.6 g protein/kg of body mass) by gavage, and samples of blood and gastrocnemius muscle were collected at 30, 90, and 450 min. PB and MCa supplementations induced an increase (~3-fold, P < 0.001) of plasma BCAAs at 30 and 90 min. Most importantly, the stimulatory phosphorylation levels of mTOR and its downstream target p70 ribosomal protein S6 kinase (p70S6K) were similarly higher (~2.5-fold, P < 0.001) 30 and 90 min after MCa and PB. Plasma levels of leucine, isoleucine, valine, and overall BCAAs were correlated with the activation of mTOR (P < 0.001) and p70S6K (P < 0.001). MCa and PB supplementations before the inactive phase of rats resulted in an anabolic milieu in the skeletal muscle by inducing a transient increase in plasma BCAAs and a similar activation of the mTOR/p70S6K axis.
Asunto(s)
Músculo Esquelético , Animales , Caseínas , Suplementos Dietéticos , Leucina , Fosforilación , Ratas , Sirolimus , Serina-Treonina Quinasas TORRESUMEN
BACKGROUND: Based on the crosstalk of inflammation with apoptosis, autophagy, and endoplasmic reticulum (ER) stress, the main objective of this study was to explore the role of interleukin-6 (IL-6) on genes and proteins related to these phenomena in the livers of mice submitted to acute exhaustive exercise. METHODS: Reverse transcription-quantitative polymerase chain reaction and immunoblotting technique were used to evaluate the livers of wild-type (WT) and IL-6 knockout (KO) mice at baseline (BL) and 3 h after the acute exhaustive physical exercise (EE). RESULTS: Compared to the WT at baseline, the IL-6 KO had lower exhaustion velocity, mRNA levels of Mtor, Ulk1, Map1lc3b, and Mapk14, and protein contents of ATG5 and p-p70S6K/p70S6K. For the WT group, the EE decreased glycemia, mRNA levels of Casp3, Mtor, Ulk1, Foxo1a, Mapk14, and Ppargc1a, and protein contents of ATG5 and p-p70S6K/p70S6K, but increased mRNA levels of Sqstm1. For the IL-6 KO group, the EE decreased glycemia, mRNA levels of Casp3 and Foxo1a, and protein contents of pAkt/Akt and Mature/Pro IL-1beta, but increased mRNA levels of Sqstm1, and protein contents of p-AMPK/AMPK. CONCLUSION: The inhibition of the hepatic autophagy markers induced by the acute EE was attenuated in IL-6 KO mice, highlighting a new function of this cytokine.