RESUMO
UNLABELLED: The majority of patients with nonalcoholic fatty liver disease (NAFLD) have "simple steatosis," which is defined by hepatic steatosis in the absence of substantial inflammation or fibrosis and is considered to be benign. However, 10%-30% of patients with NAFLD progress to fibrosing nonalcoholic steatohepatitis (NASH), which is characterized by varying degrees of hepatic inflammation and fibrosis, in addition to hepatic steatosis, and can lead to cirrhosis. The cause(s) of progression to fibrosing steatohepatitis are unclear. We aimed to test the relative contributions of dietary fat and dietary cholesterol and their interaction on the development of NASH. We assigned C57BL/6J mice to four diets for 30 weeks: control (4% fat and 0% cholesterol); high cholesterol (HC; 4% fat and 1% cholesterol); high fat (HF; 15% fat and 0% cholesterol); and high fat, high cholesterol (HFHC; 15% fat and 1% cholesterol). The HF and HC diets led to increased hepatic fat deposition with little inflammation and no fibrosis (i.e., simple hepatic steatosis). However, the HFHC diet led to significantly more profound hepatic steatosis, substantial inflammation, and perisinusoidal fibrosis (i.e., steatohepatitis), associated with adipose tissue inflammation and a reduction in plasma adiponectin levels. In addition, the HFHC diet led to other features of human NASH, including hypercholesterolemia and obesity. Hepatic and metabolic effects induced by dietary fat and cholesterol together were more than twice as great as the sum of the separate effects of each dietary component alone, demonstrating significant positive interaction. CONCLUSION: Dietary fat and dietary cholesterol interact synergistically to induce the metabolic and hepatic features of NASH, whereas neither factor alone is sufficient to cause NASH in mice.
Assuntos
Colesterol na Dieta/efeitos adversos , Dieta Hiperlipídica/efeitos adversos , Modelos Animais de Doenças , Fígado Gorduroso/etiologia , Adiponectina/sangue , Tecido Adiposo/imunologia , Animais , Ácidos e Sais Biliares/biossíntese , Ácidos Graxos/metabolismo , Fígado Gorduroso/patologia , Metabolismo dos Lipídeos , Lipídeos/sangue , Lipoproteínas VLDL/biossíntese , Fígado/metabolismo , Fígado/patologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Oxirredução , RNA Mensageiro/metabolismo , Aumento de PesoRESUMO
BACKGROUND: Multiple sclerosis is associated with gut microbiome alterations. The current study aimed to investigate the effect of home-based exercise on gut bacteria in people with multiple sclerosis (MS). We also examined the association of exercise-induced gut bacterial modulation with circulating levels of inflammatory and anti-inflammatory cytokines. MATERIALS AND METHODS: Forty-two people with MS (female/male: 31/11, expanded disability scale status <5) participated in this study and were divided into two groups: 6 months of home-based exercise (5 sessions per week) and controls. Before and after the intervention, the following parameters were assessed: gut microbiota, including faecalibacterium prausnitzii, akkermansia muciniphila, prevotella and bacteroides counts; cytokine levels including interleukin (IL)-10 and tumor necrosis factor-alpha (TNF-α); and psychosocial factors including anxiety, depression, and fatigue. RESULTS: Home-based exercise significantly increased prevotella counts, and decreased akkermansia muciniphila counts (p < 0.05); however, there were no significant effects on faecalibacterium prausnitzii and bacteroides counts (p > 0.05). There were no significant effects of home-based exercise on circulating cytokine levels (p > 0.05). Moreover, home-based exercise was associated with significant improvements in anxiety and depression (p < 0.05); however, fatigue revealed no significant change (p > 0.05). Akkermansia muciniphila, prevotella and bacteroides count changes in response to the intervention were correlated with changes in IL-10 (r = -0.052, r = 0.67, and r = -0.55, respectively). CONCLUSION: In general, our data revealed the effect of exercise on gut bacteria, especially prevotella, and akkermansia muciniphila counts, which can probably have a beneficial effect on MS disease pathology and course; however, the lack of changes in cytokines following exercise suggests the possible role of mechanisms other than modulation of circulating IL-10 and TNF- α levels.
Assuntos
Microbioma Gastrointestinal , Esclerose Múltipla , Exercício Físico , Faecalibacterium prausnitzii , Feminino , Humanos , Masculino , Esclerose Múltipla/terapia , VerrucomicrobiaRESUMO
OBJECTIVES: Physical exercise decreases the incidence of breast cancer and also improves survival in breast cancer patients. However, the mechanistic basis of these protective effects of exercise is not well known. Changes in tumor cytokines, such as oncostatin-M (OSM), have been associated with modulation of antitumor immune responses in breast cancer. Exercise and antioxidants such as selenium affect both antitumor immune responses as well as tumor cytokine expression. Thus, the aim of this study was to determine the effects of aerobic exercise training (AET) and selenium nanoparticle (SeNP) administration on T-helper 1 and 2 and tumor tissue cytokines in mice bearing the 4 T1 mammary carcinoma. METHODS: We examined the effects of 6 wk of AET and SeNP administration (100 µg three times/wk) on tumor size, concentration of tumor necrosis factor (TNF)-α, interleukin (IL)-6, interferon (IFN)-γ, IL-4 and OSM in tumor tissue and INF-γ and IL-4 in splenocytes of 64 mice bearing the 4 T1 mammary carcinoma. RESULTS: AET increased OSM levels in tumor tissue. Moreover, AET increased levels of TNF-α in tumor tissue, whereas SeNP supplementation decreased IL-4 levels tumor tissue. Also, the combination of AET and SeNP administration decreased tumor volume and increased T-helper 1 cytokines in the splenocytes of tumor-bearing mice. CONCLUSION: These findings suggest that the combination of AET and SeNP supplementation effects antitumor immune responses in splenocytes, whereas AET induced antitumor cytokines, such as OSM and TNF-α in tumor tissue.
Assuntos
Neoplasias da Mama/metabolismo , Citocinas/metabolismo , Suplementos Nutricionais , Condicionamento Físico Animal/fisiologia , Selênio/farmacologia , Células Th1/metabolismo , Células Th2/metabolismo , Animais , Neoplasias da Mama/terapia , Feminino , Interferon gama/metabolismo , Interleucina-4/metabolismo , Interleucina-6/metabolismo , Neoplasias Mamárias Experimentais/metabolismo , Camundongos Endogâmicos BALB C , Nanopartículas , Selênio/administração & dosagem , Fator de Necrose Tumoral alfa/metabolismoRESUMO
IL-15 is a cytokine that is part of the innate immune system, as well as a proposed myokine released from skeletal muscle during physical exercise that mediates many of the positive physiological effects of exercise. Many of the immune functions of IL-15 are mediated by juxtacrine signaling via externalized IL-15 bound to membrane-associated IL-15 receptor-α (IL-15Rα). Serum and plasma samples also contain measurable concentrations of IL-15, believed to arise from proteolytic cleavage of membrane-associated IL-15/IL-15Rα complexes to generate soluble IL-15/IL-15Rα species. Here, we validate commercial assays that can distinguish the free form of IL-15 and IL-15/IL-15Rα complexes. These assays showed that most (86%) IL-15 in mouse serum resides in the free state, with a minor proportion (14%) residing in complex with IL-15Rα. Given the much shorter half-life of free IL-15 compared with IL-15/IL-15Rα complexes, these findings cast doubt on the currently accepted model for IL-15 secretion from cleavage of membrane-bound IL-15/IL-15Rα and suggest that IL-15 is released as a free molecule by an unknown mechanism.
Assuntos
Membrana Celular/metabolismo , Interleucina-15/sangue , Animais , Meia-Vida , Interleucina-15/imunologia , Interleucina-15/metabolismo , Camundongos , Ligação Proteica , Receptores de Interleucina-15/sangue , Receptores de Interleucina-15/imunologiaRESUMO
In vivo studies have shown that cancer-associated skeletal muscle wasting (cachexia) is mediated by two cytokines, tumor necrosis factor-alpha (TNF) and interleukin-6 (IL-6). It has been unclear from these studies whether TNF exerts direct effects on skeletal muscle and/or whether these effects are mediated via IL-6. Previous studies from our laboratory have shown that TNF induces IL-6 mRNA expression in cultured skeletal muscle cells. To further investigate the relationship between TNF and IL-6, the effects of TNF and IL-6 on protein and DNA dynamics in murine C2C12 skeletal myotube cultures were determined. At 1000 U/ml, TNF induced 30% increases in protein and DNA content. The effects of TNF on protein accumulation were inhibited by aphidicolin, an inhibitor of DNA synthesis. IL-6 mimicked the effects of TNF on C2C12 cultures, inducing a 32% increase in protein accumulation and a 71% increase in the rate of protein synthesis. IL-6 also decreased expression of mRNA for several proteolytic system components, including ubiquitin 2.4 kb (51%) and 1.2 kb (63%), cathepsin B (39%) and m-calpain (47%), indicating that IL-6 acts on both protein synthesis and degradation. Incubation of murine C2C12 myotube cultures with TNF (1000 U/ml) in the presence of a polyclonal mouse anti-IL-6 antibody resulted in an abolishment of the effects of TNF on protein synthesis, but did not inhibit TNF-induced stimulation of DNA synthesis. These findings indicate that the effects of TNF on muscle protein synthesis are mediated by IL-6, but that TNF exerts IL-6-independent effects on proliferation of murine skeletal myoblasts.
Assuntos
Interleucina-6/metabolismo , Músculo Esquelético/efeitos dos fármacos , Fator de Necrose Tumoral alfa/farmacologia , Animais , Divisão Celular/efeitos dos fármacos , Células Cultivadas , Interleucina-6/biossíntese , Interleucina-6/farmacologia , Camundongos , Proteínas Musculares/biossíntese , Proteínas Musculares/genética , Músculo Esquelético/metabolismo , RNA Mensageiro/análise , Fatores de TempoRESUMO
Interleukin-15 (IL-15) is a proinflammatory cytokine with multifunctional effects outside the immune system. Previous studies have indicated that treatment of normal rats with IL-15 reduces white adipose tissue (WAT) mass, but it was unclear if these effects were direct or indirect. In the present study, the effects of IL-15 on WAT mass and lipid metabolism were studied in two genetic models of obesity: the leptin receptor-negative fa/fa Zucker rat and the leptin-deficient ob/ob mouse. Lean Zucker rats, lean (+/+), and obese mice (ob/ob) responded to IL-15 with reductions in WAT mass and lipoprotein lipase activity (LPL), with no decreases in food intake. In contrast, fa/fa Zucker rats did not respond to IL-15 administration by any of the above measures of fat mass or lipid metabolism. In addition, ribonuclease protection assays (RPAs) were used to demonstrate that all three subunits (gamma(c), beta and alpha) of the IL-15 receptor complex are expressed by rat and mouse WAT, suggesting that the effects of IL-15 on adipose tissue metabolism could be direct. Additionally, the fa/fa rats expressed 84% lower levels of the gamma(c) signaling receptor subunit than lean Zucker rats, suggesting this decrease may play a role in the lack of adipose tissue response to IL-15 in the fa/fa genotype and lending further support for a direct action of IL-15 on adipose tissue.
Assuntos
Tecido Adiposo/efeitos dos fármacos , Interleucina-15/farmacologia , Obesidade/patologia , Tecido Adiposo/metabolismo , Tecido Adiposo/patologia , Animais , Modelos Animais de Doenças , Regulação para Baixo , Lipase Lipoproteica/análise , Camundongos , Camundongos Obesos , Obesidade/genética , Obesidade/metabolismo , Tamanho do Órgão/efeitos dos fármacos , RNA Mensageiro/análise , Ratos , Ratos Zucker , Receptores de Interleucina/análise , Receptores de Interleucina/genéticaRESUMO
Incubation of rat isolated skeletal muscles (extensor digitorum longus) in the presence of 100 ng/ml of human recombinant interleukin-15 (IL-15) resulted in a significant decrease in total proteolytic rate, while it had no effect on total protein synthesis as measured by the incorporation of (14)C-phenylalanine into muscle protein. In addition, IL-15 had no effect on either amino acid uptake (as determined by the tissue uptake of labelled [1-(14)C]MeAIB) or alanine utilization by incubated skeletal muscles. Similarly, a single injection of IL-15 (100 microg/kg) in vivo did not result in any changes in amino acid uptake (as measured by the tissue uptake of alpha-[1-(14)C]AIB) or alanine metabolism, with the exception of alanine carbon incorporation into lipids, which was significantly increased in adipose tissue as a result of IL-15 administration. The results suggest that the main mechanism involved in the anabolic effects of IL-15 in skeletal muscle relies on a decrease in the proteolytic rate.
Assuntos
Interleucina-15/farmacologia , Proteínas Musculares/metabolismo , Músculo Esquelético/efeitos dos fármacos , Alanina/metabolismo , Ácidos Aminoisobutíricos/farmacocinética , Animais , Radioisótopos de Carbono , Linhagem Celular , Humanos , Técnicas In Vitro , Masculino , Modelos Biológicos , Fibras Musculares Esqueléticas/citologia , Fibras Musculares Esqueléticas/efeitos dos fármacos , Fibras Musculares Esqueléticas/metabolismo , Músculo Esquelético/citologia , Músculo Esquelético/metabolismo , Biossíntese de Proteínas/efeitos dos fármacos , Ratos , Ratos Wistar , Proteínas Recombinantes/farmacologiaRESUMO
Interleukin-15 (IL-15) and irisin are exercise-induced myokines that exert favorable effects on energy expenditure and metabolism. IL-15 can induce PGC-1α expression, which in turn induces expression of irisin and its precursor, FNDC5. Therefore, the present study tested the hypothesis that increases in circulating irisin levels and muscle FNDC5 mRNA expression are dependent on IL-15. Circulating irisin levels and gastrocnemius muscle FNDC5 mRNA expression were examined following acute exercise in control and IL-15-deleted (IL-15 KO) mice, following injection of IL-15 into IL-15 KO mice, and in transgenic mice with elevated circulating IL-15 levels (IL-15 Tg mice). Circulating IL-15 levels and muscle PGC-1α and PPARδ mRNA expressions were determined as positive controls. No effect of IL-15 deletion on post-exercise serum irisin levels or muscle FNDC5 mRNA expression was detected. While serum IL-15 levels and muscle PGC-1α expression were elevated post-exercise in control mice, both serum irisin levels and muscle FNDC5 expression decreased shortly after exercise in both control and IL-15 KO mice. A single injection of recombinant IL-15 into IL-15 KO mice that significantly increased muscle PPARδ and PGC-1α mRNA expressions had no effect on circulating irisin release, but modestly induced muscle FNDC5 expression. Additionally, serum irisin and gastrocnemius muscle FNDC5 expression in IL-15 Tg mice were similar to those of control mice. Muscle FNDC5 mRNA expression and irisin release are not IL-15-dependent in mice.
Assuntos
Fibronectinas/metabolismo , Interleucina-15/metabolismo , Atividade Motora/fisiologia , Músculo Esquelético/metabolismo , Receptores Citoplasmáticos e Nucleares/metabolismo , Fatores de Transcrição/metabolismo , Animais , Fibronectinas/sangue , Interleucina-15/sangue , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Camundongos Transgênicos , Coativador 1-alfa do Receptor gama Ativado por Proliferador de Peroxissomo , RNA Mensageiro/metabolismoRESUMO
Type 1 diabetes is associated with skeletal muscle atrophy. Skeletal muscle is an endocrine organ producing myokines such as interleukin-15 (IL-15) and interleukin-6 (IL-6) in response to contraction. These factors may mediate the effects of exercise on skeletal muscle metabolism and anabolic pathways. Lack of correlation between muscle IL-15 mRNA and protein levels after exercise training has been observed, while regulatory effects of IL-6 on IL-15 expression have also been suggested. This study determined post-exercise changes in muscle IL-15 and IL-6 mRNA expression and IL-15 protein levels in healthy and streptozotocin-induced diabetic rats in both the fast flexor hallucis longus (FHL) and slow soleus muscles. Resistance training preserved FHL muscle weight in diabetic rats and increased IL-15 protein levels in both the soleus and FHL muscles. However, the temporal pattern of this response was distinct in normal and diabetic rats. Moreover, discordance between post-exercise muscle IL-15 mRNA and protein expression was observed in our study, and diabetes suppressed post-exercise increases in FHL muscle IL-6 mRNA expression. Our study indicates that training, skeletal muscle phenotype, and metabolic status all influence the temporal pattern of post-exercise changes in IL-15 expression. Muscle IL-15 protein levels increase following training, suggesting this may be an adaptation contributing to increased capacity for secretion of this myokine that is not depressed by the diabetic state.
Assuntos
Diabetes Mellitus Experimental/metabolismo , Interleucina-15/metabolismo , Interleucina-6/metabolismo , Músculo Esquelético/metabolismo , Treinamento Resistido , Animais , Masculino , Fenótipo , RNA Mensageiro/metabolismo , Ratos , Ratos Wistar , Fatores de TempoRESUMO
Interleukin-15 (IL-15) is a putative myokine hypothesized to induce an oxidative skeletal muscle phenotype. The specific IL-15 receptor alpha subunit (IL-15Rα) has also been implicated in specifying this contractile phenotype. The purposes of this study were to determine the muscle-specific effects of IL-15Rα functional deficiency on skeletal muscle isometric contractile properties, fatigue characteristics, spontaneous cage activity, and circulating IL-15 levels in male and female mice. Muscle creatine kinase (MCK)-driven IL-15Rα knockout mice (mIl15ra(fl/fl)/Cre(+)) were generated using the Cre-loxP system. We tested the hypothesis that IL-15Rα functional deficiency in skeletal muscle would increase resistance to contraction-induced fatigue, cage activity, and circulating IL-15 levels. There was a significant effect of genotype on the fatigue curves obtained in extensor digitorum longus (EDL) muscles from female mIl15ra(fl/fl)/Cre(+) mice, such that force output was greater during the repeated contraction protocol compared with mIl15ra(fl/fl)/Cre(-) control mice. Muscles from female mIl15ra(fl/fl)/Cre(+) mice also had a twofold greater amount of the mitochondrial genome-specific COXII gene compared with muscles from mIl15ra(fl/fl)/Cre(-) control mice, indicating a greater mitochondrial density in these skeletal muscles. There was a significant effect of genotype on the twitch:tetanus ratio in EDL and soleus muscles from mIl15ra(fl/fl)/Cre(+) mice, such that the ratio was lower in these muscles compared with mIl15ra(fl/fl)/Cre(-) control mice, indicating a pro-oxidative shift in muscle phenotype. However, spontaneous cage activity was not different and IL-15 protein levels were lower in male and female mIl15ra(fl/fl)/Cre(+) mice compared with control. Collectively, these data support a direct effect of muscle IL-15Rα deficiency in altering contractile properties and fatigue characteristics in skeletal muscles.
Assuntos
Éxons/genética , Contração Muscular/fisiologia , Fibras Musculares de Contração Rápida/fisiologia , Fibras Musculares de Contração Lenta/fisiologia , Animais , Feminino , Interleucina-15/genética , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Camundongos Transgênicos/genética , Camundongos Transgênicos/fisiologia , Mitocôndrias/genética , Mitocôndrias/fisiologia , Contração Muscular/genética , Fadiga Muscular/genética , Fadiga Muscular/fisiologia , Receptores de Interleucina-15/genéticaRESUMO
Incubation of C2C12 differentiated myotubes in the presence of 1000 units/ml (100 ng/ml) of recombinant murine tumor necrosis factor-alpha (TNF-alpha) for up 6 h caused an important increase in mRNA content of the cytokine (10-fold at 6 h). The levels of expression of the two cytokine receptors were not changed by the cytokine at short-time intervals, but 48 h of treatment resulted in a decreased expression of TNFR1 (33%). Interestingly, the presence of the cytokine resulted in significant increases in mRNA content for the catabolic pro-inflammatory cytokines IL-6 (17-fold) and IFN-gamma (8-fold). Similarly, TNF-alpha also caused a moderate increased expression of different anti-inflammatory cytokines such as IL-9 (104%), IL-10 (24%) and IL-15 (47%). The results suggest that other cytokines may be involved in mediating TNF-alpha action in skeletal muscle and that anti-inflammatory cytokines may be released as a counter-regulatory mechanism.
Assuntos
Antígenos CD/genética , Citocinas/metabolismo , Regulação da Expressão Gênica/efeitos dos fármacos , Músculo Esquelético/metabolismo , Receptores de Citocinas/metabolismo , Receptores do Fator de Necrose Tumoral/genética , Fator de Necrose Tumoral alfa/farmacologia , Animais , Antígenos CD/efeitos dos fármacos , Linhagem Celular , Citocinas/efeitos dos fármacos , Cinética , Camundongos , Músculo Esquelético/efeitos dos fármacos , Receptores de Citocinas/efeitos dos fármacos , Receptores do Fator de Necrose Tumoral/efeitos dos fármacos , Receptores Tipo I de Fatores de Necrose Tumoral , Fator de Necrose Tumoral alfa/genéticaRESUMO
Using laboratory mouse models, the molecular pathways responsible for the metabolic benefits of endurance exercise are beginning to be defined. The most common method for assessing exercise endurance in mice utilizes forced running on a motorized treadmill equipped with a shock grid. Animals who quit running are pushed by the moving treadmill belt onto a grid that delivers an electric foot shock; to escape the negative stimulus, the mice return to running on the belt. However, avoidance behavior and psychological stress due to use of a shock apparatus can interfere with quantitation of running endurance, as well as confound measurements of postexercise serum hormone and cytokine levels. Here, we demonstrate and validate a refined method to measure running endurance in naïve C57BL/6 laboratory mice on a motorized treadmill without utilizing a shock grid. When mice are preacclimated to the treadmill, they run voluntarily with gait speeds specific to each mouse. Use of the shock grid is replaced by gentle encouragement by a human operator using a tongue depressor, coupled with sensitivity to the voluntary willingness to run on the part of the mouse. Clear endpoints for quantifying running time-to-exhaustion for each mouse are defined and reflected in behavioral signs of exhaustion such as splayed posture and labored breathing. This method is a humane refinement which also decreases the confounding effects of stress on experimental parameters.
Assuntos
Teste de Esforço/instrumentação , Teste de Esforço/métodos , Resistência Física/fisiologia , Bem-Estar do Animal , Animais , Masculino , Camundongos , Camundongos Endogâmicos C57BLRESUMO
Physical exercise induces transient upregulation of the pro-oxidative mediators peroxisome proliferator-activated receptor-δ (PPARδ), silent information regulator of transcription (sirtuin)-1 (SIRT1), PPARγ coactivator 1α (PGC-1α), and PGC-1ß in skeletal muscle. To determine the role of the cytokine IL-15 in acute postexercise induction of these molecules, expression of these factors after a bout of exhaustive treadmill running was examined in the gastrocnemius muscle of untrained control and IL-15-knockout (KO) mice. Circulating IL-15 levels increased transiently in control mice after exercise. Control mice, but not IL-15-KO mice, upregulated muscle PPARδ and SIRT1 protein after exercise, accompanied by a complex pattern of mRNA expression for these factors. However, in exhaustive exercise, control mice ran significantly longer than IL-15-KO mice. Therefore, in a second experiment, mice were limited to a 20-minute run, after which a similar pattern of induction of muscle PPARδ and SIRT1 protein by control mice only was observed. In a separate experiment, IL-15-KO mice injected systemically with recombinant IL-15 upregulated muscle PPARδ and SIRT1 mRNA within 30 minutes and also exhibited increased muscle PPARδ protein levels by 3 hours. After exercise, both control and IL-15-KO mice downregulated IL-15 receptor-α (IL-15Rα) mRNA, whereas IL-15Rα-deficient mice exhibited constitutively elevated circulating IL-15 levels. These observations indicate IL-15 release after exercise is necessary for induction of PPARδ and SIRT1 at the protein level in muscle tissue and suggest that exercise releases IL-15 normally sequestered by the IL-15Rα in the resting state. These findings could be used to develop an IL-15-based strategy to induce many of the metabolic benefits of physical exercise.
Assuntos
Interleucina-15/fisiologia , Músculo Esquelético/fisiologia , Condicionamento Físico Animal , Receptores Citoplasmáticos e Nucleares/metabolismo , Sirtuína 1/metabolismo , Animais , Composição Corporal , Regulação da Expressão Gênica , Masculino , Camundongos , Camundongos Knockout , Oxigênio/fisiologia , Coativador 1-alfa do Receptor gama Ativado por Proliferador de Peroxissomo , RNA Mensageiro/metabolismo , Reação em Cadeia da Polimerase em Tempo Real , Fatores de Transcrição/metabolismoRESUMO
Endurance exercise initiates a pattern of gene expression that promotes fat oxidation, which in turn improves endurance, body composition, and insulin sensitivity. The signals from exercise that initiate these pathways have not been completely characterized. IL-15 is a cytokine that is up-regulated in skeletal muscle after exercise and correlates with leanness and insulin sensitivity. To determine whether IL-15 can induce any of the metabolic adaptations associated with exercise, substrate metabolism, endurance, and molecular expression patterns were examined in male transgenic mice with constitutively elevated muscle and circulating IL-15 levels. IL-15 transgenic mice ran twice as long as littermate control mice in a run-to-exhaustion trial and preferentially used fat for energy metabolism. Fast muscles in IL-15 transgenic mice exhibited high expression of intracellular mediators of oxidative metabolism that are induced by exercise, including sirtuin 1, peroxisome proliferator-activated receptor (PPAR)-δ, PPAR-γ coactivator-1α, and PPAR-γ coactivator-1ß. Muscle tissue in IL-15 transgenic mice exhibited myosin heavy chain and troponin I mRNA isoform expression patterns indicative of a more oxidative phenotype than controls. These findings support a role for IL-15 in induction of exercise endurance, oxidative metabolism, and skeletal muscle molecular adaptations induced by physical training.
Assuntos
Metabolismo Energético/fisiologia , Interleucina-15/metabolismo , Músculo Esquelético/metabolismo , PPAR delta/genética , Sirtuína 1/genética , Transativadores/genética , Animais , Metabolismo Energético/genética , Interleucina-15/genética , Masculino , Camundongos , Camundongos Transgênicos , Cadeias Pesadas de Miosina/genética , Coativador 1-alfa do Receptor gama Ativado por Proliferador de Peroxissomo , Fatores de Transcrição , Troponina I/genéticaRESUMO
Human aging is characterized by both physical and physiological frailty. A key feature of frailty, sarcopenia is the age-associated decline in skeletal muscle mass, strength, and endurance that characterize even the healthy elderly. Increases in adiposity, particularly in visceral adipose tissue, are almost universal in aging individuals and can contribute to sarcopenia and insulin resistance by increasing levels of inflammatory cytokines known collectively as adipokines. Aging also is associated with declines in adaptive and innate immunity, known as immune senescence, which are risk factors for cancer and all-cause mortality. The cytokine interleukin-15 (IL-15) is highly expressed in skeletal muscle tissue and declines in aging rodent models. IL-15 inhibits fat deposition and insulin resistance, is anabolic for skeletal muscle in certain situations, and is required for the development and survival of natural killer (NK) lymphocytes. We review the effect that adipokines and myokines have on NK cells, with special emphasis on IL-15. We posit that increased adipokine and decreased IL-15 levels during aging constitute a common mechanism for sarcopenia, obesity, and immune senescence.
Assuntos
Adipocinas/imunologia , Senescência Celular/imunologia , Inflamação/imunologia , Interleucina-15/fisiologia , Células Matadoras Naturais/fisiologia , Obesidade/imunologia , Sarcopenia/imunologia , Adiposidade/imunologia , Idoso , Envelhecimento/metabolismo , Citocinas , Humanos , Músculo Esquelético/imunologia , Obesidade/fisiopatologia , Sarcopenia/fisiopatologiaRESUMO
Interleukin-15 (IL-15) is a cytokine which inhibits lipid deposition in cultured adipocytes and decreases adipose tissue deposition in laboratory rodents. In human subjects, negative correlations between circulating IL-15 levels and both total and abdominal fat have been demonstrated. Deletions of IL15 in humans and mice are associated with obesity, while gain-of-function IL-15 overexpressing mice are resistant to diet-induced obesity. IL-15 is highly (but not exclusively) expressed at the mRNA level in skeletal muscle tissue, and the regulation of IL-15 translation and secretion is complex. Conflicting evidence exists concerning whether circulating IL-15 is released from skeletal muscle tissue in response to exercise or other physiological stimuli. The IL-15 receptor-alpha (IL-15Rα) subunit has a complex biochemistry, encoding both membrane-bound and soluble forms which can modulate IL-15 secretion and bioactivity. The gene encoding this receptor, IL15RA, resides on human chromosome 10p, a location linked to obesity and type-2 diabetes. Several single-nucleotide polymorphisms (SNPs) in human IL15RA and IL15 correlate with adiposity and markers of the metabolic syndrome. Genetic variation in IL15RA may modulate IL-15 bioavailability, which in turn regulates adiposity. Thus, IL-15 and the IL-15Rα may be novel targets for pharmacologic control of obesity in the human population.
RESUMO
Interleukin-15 (IL-15) is a cytokine that is highly expressed in skeletal muscle. In addition to its well-characterized effects on innate immunity, IL-15 has been proposed to modulate skeletal muscle and adipose tissue mass, as well as insulin sensitivity. In the present study, an IL-15 gain-of-function model, transgenic mice with skeletal muscle-specific oversecretion of IL-15 (IL-15 Tg mice), was utilized to test the hypotheses that IL-15 promotes insulin sensitivity and resistance to diet-induced obesity (DIO) by increasing circulating adiponectin levels, and that IL-15 regulates skeletal muscle metabolism without inducing overt muscle hypertrophy. Compared to closely related control mice, IL-15 Tg mice exhibited lower total body fat following high-fat feeding, lower intra-abdominal fat following both low- and high-fat feeding, and greater insulin sensitivity. However, this was not accompanied by increased total or high molecular weight serum adiponectin levels in IL-15 Tg mice. While overall lean body mass did not differ, IL-15 Tg mice exhibited increased mass of the oxidative soleus muscle, and increased expression of mRNA encoding the slow isoform of troponin I (TnnI 1) in the predominately glycolytic extensor digitorum longus muscle. Skeletal muscle tissue from IL-15 Tg mice also exhibited alterations in the expression of several genes associated with fatty acid metabolism, such as SIRT1, SIRT4, and uncoupling protein 2 (UCP2). These findings suggest changes in oxidative metabolism, rather than induction of adiponectin expression, appear to be responsible for the DIO-resistant and more insulin-sensitive phenotype of IL-15 Tg mice.
RESUMO
IL-15 receptor α (IL-15Rα) is a component of the heterotrimeric plasma membrane receptor for the pleiotropic cytokine IL-15. However, IL-15Rα is not merely an IL-15 receptor subunit, as mice lacking either IL-15 or IL-15Rα have unique phenotypes. IL-15 and IL-15Rα have been implicated in muscle phenotypes, but a role in muscle physiology has not been defined. Here, we have shown that loss of IL-15Rα induces a functional oxidative shift in fast muscles, substantially increasing fatigue resistance and exercise capacity. IL-15Rα-knockout (IL-15Rα-KO) mice ran greater distances and had greater ambulatory activity than controls. Fast muscles displayed fatigue resistance and a slower contractile phenotype. The molecular signature of these muscles included altered markers of mitochondrial biogenesis and calcium homeostasis. Morphologically, fast muscles had a greater number of muscle fibers, smaller fiber areas, and a greater ratio of nuclei to fiber area. The alterations of physiological properties and increased resistance to fatigue in fast muscles are consistent with a shift toward a slower, more oxidative phenotype. Consistent with a conserved functional role in humans, a genetic association was found between a SNP in the IL15RA gene and endurance in athletes stratified by sport. Therefore, we propose that IL-15Rα has a role in defining the phenotype of fast skeletal muscles in vivo.
Assuntos
Subunidade alfa de Receptor de Interleucina-15/genética , Fibras Musculares de Contração Rápida/patologia , Músculo Esquelético/patologia , Animais , Cálcio/metabolismo , Homeostase , Humanos , Interleucina-15/metabolismo , Contração Isométrica , Masculino , Camundongos , Camundongos Knockout , Fadiga Muscular , Fibras Musculares de Contração Rápida/metabolismo , Músculo Esquelético/metabolismo , Oxigênio/química , Fenótipo , Resistência Física , Polimorfismo de Nucleotídeo ÚnicoRESUMO
Interleukin-15 (IL-15) is a skeletal muscle-derived cytokine with favorable effects on muscle mass and body composition. Modulation of IL-15 levels has been suggested as a treatment for sarcopenia and age-associated increases in adiposity. However, it is unclear whether IL-15 levels change during aging, as measurement of IL-15 at physiological concentrations in mice has been technically difficult, and translational regulation of IL-15 is complex. Moreover, the IL-15 receptor alpha (IL-15Ralpha) can comprise part of a membrane-associated receptor complex, or appear as a soluble form which stabilizes IL-15 and facilitates IL-15 secretion. Here, we report measurement of physiological levels of murine IL-15, and determine that muscle and serum IL-15 levels decline progressively with age. However, expression of IL-15 mRNA and membrane-associated subunits of the IL-15 receptor did not change with age in muscle. Expression of soluble IL-15Ralpha (sIL-15Ralpha) mRNA declined 5-fold with age, and serum IL-15 levels correlated highly with muscle sIL-15 mRNA expression, suggesting declines in sIL-15Ralpha expression lead to decreased circulating IL-15 levels during aging. These findings complement studies which described several single-nucleotide polymorphisms in the human IL-15Ralpha gene which impact muscularity and adiposity, and provide a technical basis for further investigation of IL-15 and the sIL-15Ralpha in determining body composition in aging mice, as a model for humans.