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Exercise elicits physiological adaptations, including hyperpnea. However, the mechanisms underlying exercise-induced hyperpnea remain unresolved. Skeletal muscle acts as a secretory organ, releasing irisin (IR) during exercise. Irisin can cross the blood-brain barrier, influencing muscle and tissue metabolism, as well as signaling in the central nervous system (CNS). We evaluated the effect of intracerebroventricular or intraperitoneal injection of IR in adult male rats on the cardiorespiratory and metabolic function during sleep-wake cycle under room air, hypercapnia and hypoxia. Central IR injection caused an inhibition on ventilation (VE) during wakefulness under normoxia, while peripheral IR reduced VE during sleep. Additionally, central IR exacerbates hypercapnic hyperventilation by increasing VE and reducing oxygen consumption. As to cardiovascular regulation, central IR caused an increase in heart rate (HR) across all conditions, while no change was observed following peripheral administration. Finally, central IR attenuated the hypoxia-induced regulated hypothermia and increase sleep episodes, while peripheral IR augmented CO2-induced hypothermia, during wakefulness. Overall, our results suggest that IR act mostly on CNS exerting an inhibitory effect on breathing under resting conditions, while stimulating the hypercapnic ventilatory response and increasing HR. Therefore, IR seems not to be responsible for the exercise-induced hyperpnea, but contributes to the increase in HR.

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The identification of biomarkers for spinal muscular atrophy is crucial for predicting disease progression, severity, and response to new disease-modifying therapies. This study aimed to investigate the role of serum levels of myostatin and follistatin as biomarkers for spinal muscular atrophy, considering muscle atrophy secondary to denervation as the main clinical manifestation of the disease. The study evaluated the differential gene expression of myostatin and follistatin in a lesional model of gastrocnemius denervation in mice, as well as in a meta-analysis of three datasets in transgenic mice models of spinal muscular atrophy, and in two studies involving humans with spinal muscular atrophy. Subsequently, a case-control study involving 27 spinal muscular atrophy patients and 27 controls was conducted, followed by a 12-month cohort study with 25 spinal muscular atrophy cases. Serum levels of myostatin and follistatin were analysed using enzyme-linked immunosorbent assay at a single centre in southern Brazil. Skeletal muscle gene expression of myostatin decreased and of follistatin increased following lesional muscle denervation in mice, consistent with findings in the spinal muscular atrophy transgenic mice meta-analysis and in the iliopsoas muscle of five patients with spinal muscular atrophy type 1. Median serum myostatin levels were significantly lower in spinal muscular atrophy patients (98 pg/mL; 5-157) compared to controls (412 pg/mL; 299-730) (P < 0.001). Lower myostatin levels were associated with greater disease severity based on clinician-rated outcomes (Rho = 0.493-0.812; P < 0.05). After 12 months, there was a further reduction in myostatin levels among spinal muscular atrophy cases (P = 0.021). Follistatin levels did not differ between cases and controls, and no significant changes were observed over time. The follistatin:myostatin ratio was significantly increased in spinal muscular atrophy subjects and inversely correlated with motor severity. Serum myostatin levels show promise as a novel biomarker for evaluating the severity and progression of spinal muscular atrophy. The decrease in myostatin levels and the subsequent favourable environment for muscle growth may be attributed to denervation caused by motor neuron dysfunction.

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Chronic liver diseases are a group of pathologies affecting the liver with high prevalence worldwide. Among them, cholestatic chronic liver diseases (CCLD) are characterized by alterations in liver function and increased plasma bile acids. Secondary to liver disease, under cholestasis, is developed sarcopenia, a skeletal muscle dysfunction with decreased muscle mass, strength, and physical function. CCL5/RANTES is a chemokine involved in the immune and inflammatory response. Indeed, CCL5 is a myokine because it is produced by skeletal muscle. Several studies show that bile acids induce CCL5/RANTES expression in liver cells. However, it is unknown if the expression of CCL5/RANTES is changed in the skeletal muscle of mice with cholestatic liver disease. We used a murine model of cholestasis-induced sarcopenia by intake of hepatotoxin 3,5-diethoxycarbonyl-1,4-dihydrocollidine (DDC diet), in which we detected the mRNA levels for ccl5. We determined that mice fed the DDC diet presented high levels of serum bile acids and developed typical features of sarcopenia. Under these conditions, we detected the ccl5 gene expression in diaphragm muscle showing elevated mRNA levels compared to mice fed with a standard diet (chow diet). Our results collectively suggest an increased ccl5 gene expression in the diaphragm muscle concomitantly with elevated serum bile acids and the development of sarcopenia.

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Myonectin has shown beneficial effects on lipid regulation in murine models; therefore, it may have implications in the pathophysiology of metabolic syndrome (MS). We evaluated the relationship between serum myonectin and serum lipids, global and regional fat mass, intramuscular lipid content, and insulin resistance (IR) in adults with metabolic risk factors. This was a cross-sectional study in sedentary adults who were diagnosed with MS or without MS (NMS). Serum myonectin was quantified by enzyme-linked immunosorbent assay, lipid profile by conventional techniques, and free fatty acids (FFA) by gas chromatography. Body composition was assessed by dual-energy X-ray absorptiometry and intramuscular lipid content through proton nuclear magnetic resonance spectroscopy in the right vastus lateralis muscle. IR was estimated with the homeostatic model assessment (HOMA-IR). The MS (n = 61) and NMS (n = 29) groups were comparable in age (median (interquartile range): 51.0 (46.0-56.0) vs. 53.0 (45.5-57.5) years, p > 0.05) and sex (70.5% men vs. 72.4% women). MS subjects had lower serum levels of myonectin than NMS subjects (1.08 (0.87-1.35) vs. 1.09 (0.93-4.05) ng·mL-1, p < 0.05). Multiple linear regression models adjusted for age, sex, fat mass index and lean mass index showed that serum myonectin was negatively correlated with the android/gynoid fat mass ratio (R2 = 0.48, p < 0.01), but not with the lipid profile, FFA, intramuscular lipid content or HOMA-IR. In conclusion, serum myonectin is lower in subjects with MS. Myonectin negatively correlates with a component relevant to the pathophysiology of MS, such as the android/gynoid fat mass ratio, but not with other components such as FFA, intramuscular fat or IR.

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The brain-derived neurotrophic factor (BDNF) is a member of the nerve growth factor family which is generated mainly by the brain. Its main role involve synaptic modulation, neurogenesis, neuron survival, immune regulation, myocardial contraction, and angiogenesis in the brain. Together with the encephalon, some peripheral tissues synthesize BDNF like skeletal muscle. On this tissue, this neurotrophin participates on cellular mechanisms related to muscle function maintenance and plasticity as reported on recent scientific works. Moreover, during exercise stimuli the BDNF contributes directly to strengthening neuromuscular junctions, muscle regeneration, insulin-regulated glucose uptake and ß-oxidation processes in muscle tissue. Given its vital relevance on many physiological mechanisms, the current mini-review focuses on discussing up-to-date knowledge about BDNF production in skeletal muscle and how this neurotrophin impacts skeletal muscle biology.

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BACKGROUND AND AIMS: Chronic heart failure (CHF) represents a significant cause of morbidity and mortality globally. Metabolic maladaptation has proven to be critical in the progression of this condition. Preclinical studies have shown that irisin, an adipomyokine involved in metabolic regulations, can induce positive cardioprotective effects by improving cardiac remodeling, cardiomyocyte viability, calcium delivery, and reducing inflammatory mediators. However, data on clinical studies identifying the associations between irisin levels and functional imaging parameters are scarce in CHF patients. The objective of this study was to determine the association of irisin levels with cardiac imaging measurements through cardiac magnetic resonance, inflammatory markers, and biochemical parameters in patients with CHF compared with control subjects. METHODS AND RESULTS: Thirty-two subjects diagnosed with CHF and thirty-two healthy controls were evaluated in a cross-sectional study. Serum irisin levels were significantly lower in patients with CHF than in controls. This is the first study to report a significant positive correlation between irisin levels and cardiac magnetic resonance parameters such as left ventricular ejection fraction, fraction shortening, and global radial strain. A negative correlation was demonstrated between irisin levels and brain natriuretic peptide, insulin levels, and Homeostatic model assessment for insulin resistance index. We did not observe significant correlations between irisin levels and inflammatory cytokines. CONCLUSIONS: Given the importance of fraction shortening and global radial strain as accurate markers of ventricular wall motion, these results support the hypothesis that irisin may play an essential role in maintaining an adequate myocardial wall architecture, deformation, and thickness.

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Endothelial dysfunction is a crucial physiopathological mechanism for cardiovascular diseases that results from the harmful impact of metabolic disorders. Irisin, a recently discovered adipomyokine, has been shown to exert beneficial metabolic effects by increasing energy consumption, improving insulin sensitivity, and reducing the proinflammatory milieu. Multiple preclinical models have assessed irisin's possible role in the development of endothelial dysfunction, displaying that treatment with exogenous irisin can decrease the production of oxidative stress mediators by up-regulating Akt/mTOR/Nrf2 pathway, promote endothelial-dependent vasodilatation through the activation of AMPK-PI3K-AkteNOS pathway, and increase the endothelial cell viability by activation of ERK proliferation pathway and downregulation of Bad/Bax/Caspase 3 pro-apoptotic pathway. However, there is scarce evidence of these mechanisms in clinical studies, and available results are controversial. Some have shown negative correlations of irisin levels with the burden of coronary atherosclerosis and leukocyte adhesion molecules' expression. Others have demonstrated associations between irisin levels and increased atherosclerosis risk and higher carotid intima-media thickness. Since the role of irisin in endothelial damage remains unclear, in this review, we compare, contrast, and integrate the current knowledge from preclinical and clinical studies to elucidate the potential preventive role and the underlying mechanisms and pathways of irisin in endothelial dysfunction. This review also comprises original figures to illustrate these mechanisms.

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Long-distance running is an exhausting effort for the whole organism. Prolonged aerobic exercise induces changes in inflammatory markers. However, predicting muscle damage in response has limitations in terms of selecting biomarkers used to measure inflammatory status. The present study conducts a systematic review and meta-analysis of articles focusing in ultra-marathon, marathon, and half-marathon and levels of cytokines. The search was conducted in PubMed, Web of Science, and Scopus databases, resulting in the inclusion of 76 articles. IL-6 was highlighted, evaluated in 62 studies and show increase in the standard mean difference (SMD): half-marathon (SMD -1.36; IC 95%: -1.82, -0.89, Ch2:0.58; tau2:0.00; p < 0.0001), marathon (SMD -6.81; IC 95%: -9.26, -4.37; Ch2:481.37 tau2:11.88; p < 0.0001) and ultra-marathon (SMD -8.00 IC 95%: -10.47, -5.53; Ch2:328.40; tau2:14.19; p < 0.0001). In contrast meta-regression analysis did not show relationship to the running distance (p = 0.864). The meta-analysis evidenced increase in the concentration of IL-1ra (p < 0.0001), IL-1B (p < 0.0001), IL-8 (p < 0.0001), IL-10 (p < 0.0001) and TNF-α (p < 0.0001). Reduction in IL-2 (p < 0.0001) and INF-y (p < 0.03) and no change in the IL-4 (p < 0.56). The number of studies evaluating the effect of adipokines was limited, however Leptin and Resistin were recurrent. The effects of an acute bout of prolonged aerobic exercise will protect against chronic systemic inflammation. The time to return to baseline values showed a substantial and dose-dependent relationship with run volume. The concentration of IL-6 was robustly studied and the marathon running was the most explored. Network of endocrine interactions in which circulating factors, released in extreme exercises, interplay through inter-organ crosstalk and physiologic changes were expressed. The running volume variability was able to modulate compounds that play a fundamental role in the maintenance of homeostasis and cell signaling.

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BACKGROUND: Myokines are a group of protein mediators produced by skeletal muscle under stress or physical exertion. Even though their discovery and effects in cell culture and animal models of disease have elicited great enthusiasm, very little is known about their role in human metabolism. We assessed whether plasma concentrations of three known myokines [myonectin, myostatin, and fibroblast-derived growth factor 21 (FGF-21)] would be associated with direct and indirect indicators of insulin resistance (IR) in individuals who did not have a diagnosis of diabetes. METHODS: We studied 81 adults of both sexes comprising a wide range of body adiposity and insulin sensitivity. All participants underwent a thorough clinical assessment and a 5-point oral glucose tolerance test with calculation of multiple IR and insulin sensitivity indices. Twenty-one of them additionally underwent a hyperinsulinemic-euglycemic clamp with determination of steady-state whole-body insulin-stimulated glucose disposal ("M"). We compared plasma myokine concentrations across quartiles of IR indices and clinical IR surrogates, and explored the correlation of each myokine with the M-value. RESULTS: Plasma myonectin levels increased monotonically across quartiles of the incremental area under the insulin curve (higher values indicate more IR) (p-trend = 0.021) and decreased monotonically across quartiles of the insulin sensitivity index (ISI - higher values indicate less IR) (p-trend = 0.012). After multivariate adjustment for other relevant determinants of IR (body mass index, age, and sex), the negative association of myonectin with ISI persisted (standardized beta = -0.235, p = 0.023). Myostatin was not associated with any clinical IR indicator or direct IR index measure. In multivariate analyses, FGF-21 showed a trend toward a positive correlation with glucose disposal that did not reach statistical significance (standardized beta = 0.476, p = 0.091). CONCLUSION: The secretion of myonectin may constitute an attempt at a compensatory mechanism against IR in humans.

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In the continuous search of researchers to find an effective method to control obesity, a myokine called Irisin was found. Irisin is secreted mainly by skeletal muscle in response to exercise, either resistance, strength or high intensity, where High Intensity Interval Training (HIIT) is included. This polypeptide hormone acts mainly on subcutaneous adipose cells, turning white fat into brown fat. Brown fat is highly thermogenic, which enhance raising of total energy expenditure and helps maintaining or loosing corporal weight. Plasmatic Irisin levels are related positively with insulin sensitivity and weight loss. It has been also discovered that a greater plasmatic level of Irisin is related to the lengthening of telomeres, to a greater concentration of free tyrosine (T4) and it has been recently found that is related to an antitumoral effect on some types of cancer. All of the functions mediated by Irisin, have given it a protective action against different diseases, especially metabolic ones. The aim of this review was to update the knowledge about Irisin, and to show the effects that exercise has on its plasmatic levels, as well as comprehend how does the release of irisin influences different body systems. Counting with more information will allow the arising of new lines of investigation that will bring up non pharmacological therapeutic strategies for the treatment of non-communicable diseases.

En la búsqueda continua de los investigadores por combatir de manera más efectiva la obesidad, se descubre una mioquina llamada Irisina. La Irisina es secretada principalmente por el músculo esquelético en respuesta al ejercicio, ya sea aeróbico, de fuerza o de alta intensidad, donde se incluyen, ejercicios de intervalo de alta intensidad (HIIT). Esta hormona polipeptídica actúa principalmente sobre células adiposas subcutáneas, transformando grasa blanca en grasa parda. La grasa parda es altamente termogénica, lo que favorece el aumento del gasto energético total y ayuda a mantener o incluso a perder peso corporal. La concentración de Irisina plasmática se relaciona positivamente con la sensibilidad a la insulina y la pérdida de peso. Además, se ha descubierto que una mayor concentración de Irisina plasmática se relaciona con el alargamiento de los telómeros, y también, con una mayor concentración de T4 libre y con un recién descubierto efecto antitumoral en algunos tipos de cáncer. Todas las funciones mediadas por la Irisina, le atribuyen una acción protectora contra distintas enfermedades, especialmente metabólicas. El objetivo de esta revisión fue actualizar el conocimiento sobre la Irisina, evidenciando los efectos que tiene la realización de ejercicio sobre los niveles plasmáticos de ésta, así como también comprender como su liberación influye en distintos sistemas corporales. El contar con mayor información dará paso a nuevas líneas de investigación y permitirá contar con estrategias terapéuticas no farmacológicas que contribuyan en el tratamiento de enfermedades crónicas no transmisibles.

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