Die Herzinsuffizienz ist eine der häufigsten chronischen Erkrankungen mit progressivem Krankheitsverlauf. Dieser ist verschiedenen Kompensationsmechanismen geschuldet, die zunächst zur Verbesserung, über einen längeren Zeitraum hinweg jedoch zur Verschärfung der Symptomatik führen. Durch erhöhte Konzentrationen inflammatorischer Zytokine im Rahmen dieser Krankheit kommt es unter anderem zu pathologischen Veränderungen in Muskel- als auch Fettgewebe. Das kürzlich in der Literatur als PGC-1α reguliert beschriebene Molekül FNDC5 (Spaltprodukt Irisin) wird als Myokin bezeichnet, welches zwischen Muskel- und Fettgewebe vermittelt. Bis dato ist jedoch ungeklärt, ob und inwiefern es einen Zusammenhang zwischen einer Herzinsuffizienz, erhöhten Konzentrationen proinflammatorischer Zytokine und dem Molekül FNDC5 in der Skelettmuskulatur gibt. Um diesen Fragestellungen nachzugehen, wurde in der vorliegenden Arbeit zum einen durch LAD-Ligatur in Ratten eine Herzinsuffizienz induziert, um die systemischen Verhältnisse dieser Erkrankung im Tiermodell bestmöglich nachzuempfinden. Zum anderen wurden Mäuse mit TNF-α oder Ang II behandelt und C2C12-Myotuben mit TNF-α, Ang II sowie einer Zytokinkombination inkubiert, um den Einfluss der Zytokine bzw. des Hormons auf die FNDC5-Expression zu untersuchen. Anschließend wurden die Expression von FNDC5 auf mRNA- und Proteinebene sowie die Expression der PGC-1α-mRNA in Skelettmuskelbiopsien bestimmt. Es konnte nachgewiesen werden, dass eine Herzinsuffizienz sowie der Einfluss inflammatorischer Zytokine zur signifikanten Expressionsverminderung von FNDC5 führt. Ang II hingegen bewirkte nicht in allen Versuchen eine deutliche Reduktion der FNDC5-Expression. Außerdem wurde gezeigt, dass die Signaltransduktionswege über p38 und p42/44 MAPK nicht für die Wirkung der Zytokinkombination auf die FNDC5-Expression verantwortlich sind.

Orientador: Cláudia Regina Cavaglieri / Dissertação (mestrado) - Universidade Estadual de Campinas, Faculdade de Educação Física / Made available in DSpace on 2018-08-26T14:02:01Z (GMT). No. of bitstreams: 1 Bonfante_IvanLuizPadilha_M.pdf: 2574050 bytes, checksum: d411734ffb669cd5db5c9f810ee6252b (MD5) Previous issue date: 2014 / Resumo: Introdução: A Irisina é um peptídeo que estimula a termogênese e a lipólise pelo browning do tecido adiposo branco e parece ter relação com homeostase metabólica. O exercício físico é tido como o seu principal estimulador, porém não são claros os protocolos que melhor promovem este efeito, ainda mais quando agregado as atividades que trabalhem a força muscular e a aptidão aeróbia, fatores esses recomendados para a manutenção e melhora da saúde. Embora em estudos com animais e in-vitro Irisina pareça estar relacionada com marcadores metabólicos, são escassos os trabalhos que investiguem em humanos quais as relações práticas entre exercícios físicos, Irisina e variáveis metabólicas. Objetivo: avaliar os efeitos do treinamento de força em conjunto com o aeróbio (treinamento combinado ¿ TC) sobre os níveis basais de Irisina circulante e marcadores relacionados a RI e SM em homens de meia idade com obesidade grau 1. Metodologia: Vinte e dois homens (Idade: 49,13±5,75 anos e IMC: 30,86±1,63 Kg/m²) foram distribuídos em grupo treinamento combinado (TC, n=12) e grupo controle (GC, n=10). O TC foi composto por treinamento de força (6 exercícios/3 séries/ 6-10 repetições /60-90seg de pausa entre as séries) e aeróbio (30 minutos de caminhada/corrida à 50-85% do VO2max) realizados na mesma sessão, com frequência de 3x por semana. O comportamento alimentar, teste de uma repetição máxima (1-RM), análise do volume máximo de oxigênio (VO2máx), circunferência de cintura (CC), composição corporal, colesterol, perfil lipídico, insulina, glicemia, hemoglobina glicada, HOMA-IR, HOMA-B, índice QUICKI, Z score da síndrome metabólica (SM) e Irisina plasmática foram analisadas antes e após o período experimental (24 semanas, sendo as coletas pós realizadas ao menos 72 horas após a última sessão de treino). O teste t-Student foi utilizado para comparação entre as linhas de base, seguido da análise de modelo misto e do post-hoc de Tukey quando necessário. Foi aplicado ainda o teste de Pearson para analisar possíveis correlações de deltas. O nível de significância adotado foi de p<0,05. Para avaliar a magnitude dos efeitos sobre Irisina foi aplicado o d effect size, com o d '> ou =' 1,2 sendo considerado "large". Resultados: O TC apresentou aumento da força muscular, VO2máx., massa magra e índice QUICKI, além de diminuição da gordura corporal, CC, níveis de insulina, glicemia, colesterol total, LDL, HOMA-IR e Z-score da SM, além de manter os níveis de Irisina. Já o GC teve diminuição de Irisina e da força muscular no exercício supino, além de aumento do HOMA-IR. Foram encontradas correlações inversas entre os deltas de Irisina e glicemia, colesterol total e CC, além de relação positiva com a soma das cargas dos testes de 1RM. Conclusão: O programa de TC foi capaz de manter os níveis de Irisina e proporcionar melhoras funcionais, metabólicas e de composição corporal, diminuindo as chances do desenvolvimento de Diabetes tipo 2 e doenças cardiovasculares entre seus praticantes. Pelos resultados das correlações, além da diminuição de Irisina com similar aumento do HOMA-IR no GC, é possível observar também em humanos a relação entre este peptídeo e variáveis relacionadas a homeostase metabólica / Abstract: Introduction: Irisin is a peptide that stimulates thermogenesis and lipolysis in the white adipose tissue by browning it, and seems to be related with metabolic homeostasis. Physical exercise is considered its primary stimulator, but protocols that best promote this effect are not clear, even when activities working muscle strength and aerobic fitness are added, which are recommended factors for the improvement of health. Although in animal and in vitro studies, Irisin seems to be related to important metabolic markers. However, studies that investigate, in humans, the relations between exercise, Irisin and metabolic markers are scarce. Objective: To evaluate the effects of strength training combined to aerobic training (combined training - CT) on basal levels of circulating Irisin and markers related to insulin resistance (IR) and metabolic syndrome (MS) in middle-aged men with obesity. Methods: Twenty-two men (age: 49.13±5.75 years and BMI: 30.86±1.63 Kg/m²) were distributed in combined training group (CT, n=12) and control group (CG, n=10). The CT consisted of strength training (6 exercises/3 series/ 6-10 repetitions/60-90 second pause between sets) and aerobic (30 minutes of walking or running in 50-85% of VO2max), performed in the same session, with frequency of 3 times per week. The feeding behavior, one maximum repetition (1-RM), maximum volume of oxygen (VO2max), waist circumference (WC), body composition, lipid profile, insulin, glucose, glycated hemoglobin, HOMA-IR, HOMA-B, QUICKI index, metabolic syndrome (SM) Z score and Irisin plasma were evaluated before and after the trial period (24 weeks, with post samples taken at least 72 hours after the last training session). The t-Student test was used for comparison between groups at baseline, followed by mixed model analysis was used, and Tukey post-hoc when necessary. Pearson's test was further applied to analyze the correlation between the percentage changes of the variables. The significance level was p<0.05. To evaluate the magnitude of effects on Irisin the d effect size was applied. Results: The CT presented increase of muscle strenght, VO2max., lean mass and QUICKI index, and also the decrease of body fat, WC, insulin, glucose, total cholesterol, LDL, HOMA-IR and Z-score SM. The Irisin levels were maintained. The CG had decreased Irisin levels and muscle strength in the bench press exercise, besides an increase of HOMA-IR. Inverse correlation between the change in levels of Irisina and glucose, total cholesterol and WC were found, besides positive relations with the sum of 1 RM loads. Conclusion: The combined training was able to maintain the Irisin levels and provide functional, metabolic and body composition improvements, decreasing the chances of developing type 2 diabetes and cardiovascular disease. Through the results found in the correlations, as well as Irisin decrease and HOMA-IR increase in CG, it is possible to observe, in humans, the relation between this peptide and variables related to metabolic homeostasis / Mestrado / Atividade Fisica Adaptada / Mestre em Educação Física

Die Herzinsuffizienz ist eine der häufigsten chronischen Erkrankungen mit progressivem Krankheitsverlauf. Dieser ist verschiedenen Kompensationsmechanismen geschuldet, die zunächst zur Verbesserung, über einen längeren Zeitraum hinweg jedoch zur Verschärfung der Symptomatik führen. Durch erhöhte Konzentrationen inflammatorischer Zytokine im Rahmen dieser Krankheit kommt es unter anderem zu pathologischen Veränderungen in Muskel- als auch Fettgewebe. Das kürzlich in der Literatur als PGC-1α reguliert beschriebene Molekül FNDC5 (Spaltprodukt Irisin) wird als Myokin bezeichnet, welches zwischen Muskel- und Fettgewebe vermittelt. Bis dato ist jedoch ungeklärt, ob und inwiefern es einen Zusammenhang zwischen einer Herzinsuffizienz, erhöhten Konzentrationen proinflammatorischer Zytokine und dem Molekül FNDC5 in der Skelettmuskulatur gibt. Um diesen Fragestellungen nachzugehen, wurde in der vorliegenden Arbeit zum einen durch LAD-Ligatur in Ratten eine Herzinsuffizienz induziert, um die systemischen Verhältnisse dieser Erkrankung im Tiermodell bestmöglich nachzuempfinden. Zum anderen wurden Mäuse mit TNF-α oder Ang II behandelt und C2C12-Myotuben mit TNF-α, Ang II sowie einer Zytokinkombination inkubiert, um den Einfluss der Zytokine bzw. des Hormons auf die FNDC5-Expression zu untersuchen. Anschließend wurden die Expression von FNDC5 auf mRNA- und Proteinebene sowie die Expression der PGC-1α-mRNA in Skelettmuskelbiopsien bestimmt. Es konnte nachgewiesen werden, dass eine Herzinsuffizienz sowie der Einfluss inflammatorischer Zytokine zur signifikanten Expressionsverminderung von FNDC5 führt. Ang II hingegen bewirkte nicht in allen Versuchen eine deutliche Reduktion der FNDC5-Expression. Außerdem wurde gezeigt, dass die Signaltransduktionswege über p38 und p42/44 MAPK nicht für die Wirkung der Zytokinkombination auf die FNDC5-Expression verantwortlich sind.

Excessive alcohol consumption is a leading cause of death and disability globally and can lead to diseases such as alcoholic skeletal myopathy. Skeletal muscle is the largest organ in the human body and functions to regulate whole-body energy homeostasis. Additionally, skeletal muscle can function as an endocrine organ via secretion of myokines. Two myokines, myonectin and irisin, present a wide range of effects upon metabolism, inflammation, and tissue survival- signaling. We hypothesized that chronic alcohol consumption will result in reduced circulating myonectin and irisin levels. Mice were fed an ethanol-containing or control diet for 10 days or 6 weeks. Tissues and serum were collected from mice and immunoblotting was used to quantify myonectin and irisin levels. Our data demonstrated that neither a 10 day nor 6-week ethanol diet was effective in altering myonectin levels, whereas irisin was undetectable. Therefore, we conclude that these myokines are not affected by alcohol consumption.