RESUMO
Down syndrome (DS) is associated with congenital heart defects at birth, but cardiac function has not been assessed at older ages. We used the Ts65Dn mouse, a model of DS, to quantify heart structure and function with echocardiography in 18-mo male Ts65Dn and wild-type (WT) mice. Heart weight, nicotinamide adenine dinucleotide (NAD) signaling, and mitochondrial (citrate synthase) activity were investigated, as these pathways may be implicated in the cardiac pathology of DS. The left ventricle was smaller in Ts65Dn versus WT, as well as the anterior wall thickness of the left ventricle during both diastole (LVAW_d; mm) and systole (LVAW_s; mm) as assessed by echocardiography. Other functional metrics were similar between groups including left ventricular area end systole (mm2), left ventricular area end diastole (mm2), left ventricular diameter end systole (mm), left ventricular diameter end diastole (mm), isovolumetric relaxation time (ms), mitral valve atrial peak velocity (mm/s), mitral valve early peak velocity (mm/s), ratio of atrial and early peak velocities (E/A), heart rate (beats/min), ejection fraction (%), and fractional shortening (%). Nicotinamide phosphoribosyltransferase (NAMPT) protein expression, NAD concentration, and tissue weight were lower in the left ventricle of Ts65Dn versus WT mice. Sirtuin 3 (SIRT3) protein expression and citrate synthase activity were not different between groups. Although cardiac function was generally preserved in male Ts65Dn, the altered heart size and bioenergetic disturbances may contribute to differences in aging for DS.
Assuntos
NAD , Função Ventricular Esquerda , Masculino , Camundongos , Animais , Função Ventricular Esquerda/fisiologia , Citrato (si)-Sintase , Diástole/fisiologia , EcocardiografiaRESUMO
DICER is a key enzyme in microRNA (miRNA) biogenesis. Here we show that aerobic exercise training up-regulates DICER in adipose tissue of mice and humans. This can be mimicked by infusion of serum from exercised mice into sedentary mice and depends on AMPK-mediated signaling in both muscle and adipocytes. Adipocyte DICER is required for whole-body metabolic adaptations to aerobic exercise training, in part, by allowing controlled substrate utilization in adipose tissue, which, in turn, supports skeletal muscle function. Exercise training increases overall miRNA expression in adipose tissue, and up-regulation of miR-203-3p limits glycolysis in adipose under conditions of metabolic stress. We propose that exercise training-induced DICER-miR-203-3p up-regulation in adipocytes is a key adaptive response that coordinates signals from working muscle to promote whole-body metabolic adaptations.
Assuntos
Tecido Adiposo/metabolismo , RNA Helicases DEAD-box/metabolismo , Exercício Físico/fisiologia , Ribonuclease III/metabolismo , Proteínas Quinases Ativadas por AMP/metabolismo , Adaptação Fisiológica/fisiologia , Adipócitos/metabolismo , Animais , Células Cultivadas , RNA Helicases DEAD-box/deficiência , RNA Helicases DEAD-box/genética , Feminino , Glicólise , Humanos , Masculino , Camundongos , Camundongos Knockout , MicroRNAs/genética , MicroRNAs/metabolismo , Condicionamento Físico Animal , Ribonuclease III/deficiência , Ribonuclease III/genéticaRESUMO
Assessment methods vary widely across undergraduate physiology courses. Here, a cumulative oral examination was administered in two sections of a 300-level undergraduate physiology course. Student performance was quantified via instructor grading using a rubric, and self-perceptions (n = 55) were collected via survey. Overall, students affirmed that the oral examination assisted in their learning, specifically by leading them to begin preparation for their final written exam earlier than they otherwise would. The instructor considered the oral exam useful for student learning by providing a scaffold to the written final exam and a way to connect with students before a high-stakes final exam. Specific details of the examination format and suggestions and considerations for those considering this assessment approach are provided.
Assuntos
Avaliação Educacional , Fisiologia , Diagnóstico Bucal , Humanos , Aprendizagem , Percepção , Fisiologia/educação , EstudantesRESUMO
Deacetylases such as sirtuins (SIRTs) convert NAD to nicotinamide (NAM). Nicotinamide phosphoribosyl transferase (Nampt) is the rate-limiting enzyme in the NAD salvage pathway responsible for converting NAM to NAD to maintain cellular redox state. Activation of AMP-activated protein kinase (AMPK) increases SIRT activity by elevating NAD levels. As NAM directly inhibits SIRTs, increased Nampt activation or expression could be a metabolic stress response. Evidence suggests that AMPK regulates Nampt mRNA content, but whether repeated AMPK activation is necessary for increasing Nampt protein levels is unknown. To this end, we assessed whether exercise training- or 5-amino-1-ß-D-ribofuranosyl-imidazole-4-carboxamide (AICAR)-mediated increases in skeletal muscle Nampt abundance are AMPK dependent. One-legged knee-extensor exercise training in humans increased Nampt protein by 16% (P < 0.05) in the trained, but not the untrained leg. Moreover, increases in Nampt mRNA following acute exercise or AICAR treatment (P < 0.05 for both) were maintained in mouse skeletal muscle lacking a functional AMPK α2 subunit. Nampt protein was reduced in skeletal muscle of sedentary AMPK α2 kinase dead (KD), but 6.5 weeks of endurance exercise training increased skeletal muscle Nampt protein to a similar extent in both wild-type (WT) (24%) and AMPK α2 KD (18%) mice. In contrast, 4 weeks of daily AICAR treatment increased Nampt protein in skeletal muscle in WT mice (27%), but this effect did not occur in AMPK α2 KD mice. In conclusion, functional α2-containing AMPK heterotrimers are required for elevation of skeletal muscle Nampt protein, but not mRNA induction. These findings suggest AMPK plays a post-translational role in the regulation of skeletal muscle Nampt protein abundance, and further indicate that the regulation of cellular energy charge and nutrient sensing is mechanistically related.
Assuntos
Músculo Esquelético/metabolismo , Nicotinamida Fosforribosiltransferase/metabolismo , Adenilato Quinase/genética , Adenilato Quinase/metabolismo , Adulto , Aminoimidazol Carboxamida/análogos & derivados , Aminoimidazol Carboxamida/farmacologia , Animais , Exercício Físico , Células HEK293 , Humanos , Masculino , Camundongos , Músculo Esquelético/efeitos dos fármacos , Músculo Esquelético/fisiologia , Nicotinamida Fosforribosiltransferase/genética , Esforço Físico , Ribonucleotídeos/farmacologiaRESUMO
The purpose of this study was to determine the effects of an acute oral dose of 3 mg·kg(-1) of Rhodiola rosea on endurance exercise performance, perceived exertion, mood, and cognitive function. Subjects (n = 18) ingested either R. rosea or a carbohydrate placebo 1 hour before testing in a double-blind, random crossover manner. Exercise testing consisted of a standardized 10-minute warm-up followed by a 6-mile time trial (TT) on a bicycle ergometer. Rating of perceived exertion (RPE) was measured every 5 minutes during the TT using a 10-point Borg scale. Blood lactate concentration, salivary cortisol, and salivary alpha amylase were measured before warm-up, 2 minutes after warm-up, and 2 minutes after TT (n = 15). A Profile of Mood States questionnaire and a Stroop Color Test were completed before warm-up and after TT. Testing was repeated 2-7 days later with the other condition. Rhodiola rosea ingestion significantly decreased heart rate during the standardized warm-up (R. rosea = 136 ± 17 b·min(-1); placebo = 140 ± 17 b·min(-1); mean ± SD; p = 0.001). Subjects completed the TT significantly faster after R. rosea ingestion (R. rosea = 25.4 ± 2.7 minutes; placebo = 25.8 ± 3.0 minutes; p = 0.037). The mean RPE was lower in the R. rosea trial (R. rosea = 6.0 ± 0.9; placebo = 6.6 ± 1.0; p = 0.04). This difference was even more pronounced when a ratio of the RPE relative to the workload was calculated (R. rosea = 0.048 ± 0.01; placebo = 0.057 ± 0.02; p = 0.007). No other statistically significant differences were observed. Acute R. rosea ingestion decreases heart rate response to submaximal exercise and appears to improve endurance exercise performance by decreasing the perception of effort.
Assuntos
Teste de Esforço/efeitos dos fármacos , Resistência Física/efeitos dos fármacos , Fitoterapia , Rhodiola , Afeto , Análise de Variância , Estudos Cross-Over , Método Duplo-Cego , Feminino , Frequência Cardíaca/efeitos dos fármacos , Humanos , Hidrocortisona/análise , Ácido Láctico/sangue , Esforço Físico/fisiologia , Saliva/química , Inquéritos e Questionários , Adulto Jovem , alfa-Amilases/análiseRESUMO
Regular physical activity improves glucose tolerance and decreases adiposity. Our aim was to investigate the effects of exercise training on subcutaneous (inguinal) and visceral (parametrial) adipose tissue in rats that were fed a chow diet (13% fat) or made insulin resistant by a high-fat diet (60% fat). Sprague-Dawley rats performed 4 wk of voluntary wheel running or were kept as sedentary controls. The training groups fed chow and the high-fat diet achieved similar running distances (8.8 +/- 1.8 and 9.3 +/- 1.9 km/day, respectively). Training improved oral glucose tolerance in chow-fed rats and prevented the glucose intolerance that occurred in sedentary rats fed the high-fat diet. In both subcutaneous and visceral adipose tissue, the high-fat diet-induced increases in fat pad weight (67% and 133%, respectively), adipocyte size (20% and 43%), and cell number (36% and 65%) were completely prevented by exercise training. Cytokine mRNA expression in visceral fat did not change with exercise training. However, in subcutaneous fat, training actually increased mRNA expression of several cytokines [IL-6: 80% (P < 0.05); TNF-alpha: 100% (P < 0.05); IL-1 receptor antagonist (IL-1Ra): 57% (P = 0.08)] with no detectable increases in serum cytokine concentrations. In summary, exercise training can overcome high-fat diet-induced impairments in glucose tolerance and increases in adipocyte size, cell number, and fat pad mass. Improved glucose tolerance was accompanied by an increase in cytokine gene expression in subcutaneous fat. This finding raises the possibility of a specific role of subcutaneous adipose tissue in adaptive responses to exercise training.
Assuntos
Dieta Aterogênica , Gorduras na Dieta/farmacologia , Gordura Intra-Abdominal/fisiologia , Condicionamento Físico Animal/fisiologia , Gordura Subcutânea/fisiologia , Animais , Glicemia/fisiologia , Peso Corporal/fisiologia , Ingestão de Alimentos/fisiologia , Feminino , Gordura Intra-Abdominal/anatomia & histologia , Gordura Intra-Abdominal/efeitos dos fármacos , Gordura Intra-Abdominal/metabolismo , Fígado/metabolismo , Músculo Esquelético/metabolismo , Tamanho do Órgão , Ratos , Ratos Sprague-Dawley , Corrida , Gordura Subcutânea/anatomia & histologia , Gordura Subcutânea/efeitos dos fármacos , Gordura Subcutânea/metabolismo , Triglicerídeos/metabolismoRESUMO
Aging decreases skeletal muscle mass and strength, but aerobic and resistance exercise training maintains skeletal muscle function. NAD+ is a coenzyme for ATP production and a required substrate for enzymes regulating cellular homeostasis. In skeletal muscle, NAD+ is mainly generated by the NAD+ salvage pathway in which nicotinamide phosphoribosyltransferase (NAMPT) is rate-limiting. NAMPT decreases with age in human skeletal muscle, and aerobic exercise training increases NAMPT levels in young men. However, whether distinct modes of exercise training increase NAMPT levels in both young and old people is unknown. We assessed the effects of 12 weeks of aerobic and resistance exercise training on skeletal muscle abundance of NAMPT, nicotinamide riboside kinase 2 (NRK2), and nicotinamide mononucleotide adenylyltransferase (NMNAT) 1 and 3 in young (≤35 years) and older (≥55 years) individuals. NAMPT in skeletal muscle correlated negatively with age (r2 = 0.297, P < 0.001, n = 57), and VO2 peak was the best predictor of NAMPT levels. Moreover, aerobic exercise training increased NAMPT abundance 12% and 28% in young and older individuals, respectively, whereas resistance exercise training increased NAMPT abundance 25% and 30% in young and in older individuals, respectively. None of the other proteins changed with exercise training. In a separate cohort of young and old people, levels of NAMPT, NRK1, and NMNAT1/2 in abdominal subcutaneous adipose tissue were not affected by either age or 6 weeks of high-intensity interval training. Collectively, exercise training reverses the age-dependent decline in skeletal muscle NAMPT abundance, and our findings highlight the value of exercise training in ameliorating age-associated deterioration of skeletal muscle function.
Assuntos
Envelhecimento/fisiologia , Terapia por Exercício/métodos , Músculo Esquelético/fisiologia , NAD/metabolismo , Tecido Adiposo/enzimologia , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Antropometria/métodos , Glicemia/metabolismo , Citocinas/metabolismo , Feminino , Humanos , Insulina/sangue , Peptídeos e Proteínas de Sinalização Intracelular/metabolismo , Masculino , Pessoa de Meia-Idade , Músculo Esquelético/metabolismo , Nicotinamida Fosforribosiltransferase/metabolismo , Nicotinamida-Nucleotídeo Adenililtransferase/metabolismo , Fosfotransferases (Aceptor do Grupo Álcool)/metabolismo , Treinamento Resistido , Adulto JovemRESUMO
Performance on the Sternberg working memory task, and MEG cortical response on a variation of the Sternberg task were examined in middle-aged carriers and non-carriers of the APOE epsilon4 allele. Physical activity was also assessed to examine whether exercise level modifies the relationship between APOE genotype and neurocognitive function. Regression revealed that high physical activity was associated with faster RT in the six- and eight-letter conditions of the Sternberg in epsilon4 carriers, but not in the non-carriers after controlling for age, gender, and education (N=54). Furthermore, the MEG analysis revealed that sedentary epsilon4 carriers exhibited lower right temporal lobe activation on matching probe trials relative to high-active epsilon4 carriers, while physical activity did not distinguish non-carriers (N=23). The M170 peak was identified as a potential marker for pre-clinical decline as epsilon4 carriers exhibited longer M170 latency, and highly physically active participants exhibited greater M170 amplitude to matching probe trials.
Assuntos
Doença de Alzheimer , Apolipoproteína E4/genética , Exercício Físico , Magnetoencefalografia , Memória de Curto Prazo/fisiologia , Tempo de Reação/fisiologia , Idoso , Doença de Alzheimer/genética , Doença de Alzheimer/fisiopatologia , Doença de Alzheimer/reabilitação , Análise de Variância , Mapeamento Encefálico , Estimulação Elétrica/métodos , Feminino , Lateralidade Funcional , Genótipo , Humanos , Masculino , Pessoa de Meia-Idade , Testes Neuropsicológicos , Tempo de Reação/efeitos da radiaçãoRESUMO
CONTEXT: Intramuscular lipid content increases with aging and obesity and is directly related to impaired glucose tolerance and insulin resistance. OBJECTIVE: Our purpose was to determine the effects of aerobic exercise training (AEX) with and without weight loss (WL) on midthigh low-density muscle (LDM; a measure of im lipid) and whether changes in LDM impact glucose tolerance in sedentary older men. DESIGN: Forty-six men (60.4 +/- 1.1 yr) completed 6 months of AEX (n = 34) or AEX + WL (n = 12) and had oral glucose tolerance tests (OGTTs) and computed tomography measures of LDM and regional abdominal and thigh fat depot areas. RESULTS: At baseline, LDM area directly correlated with fasting plasma glucose (FPG), 120-min glucose (G(120)), and glucose area under the curve (G(AUC)) during an OGTT (r = 0.44, r = 0.51, and r = 0.54, respectively, P < 0.01). After the interventions, the AEX + WL group had greater decreases in LDM (-13.5 vs. +1.3%, respectively), FPG (-8.3 vs. +2.1%, respectively), G(120) (-22.5 vs. -3.6%, respectively), and G(AUC) (-17.3 vs. - 3.1%, respectively) than the AEX group. In the entire sample, the decreases in LDM correlated with reductions in FPG, G(120), and G(AUC) during an OGTT (r = 0.31, r = 0.34, and r = 0.41, P < 0.05). Changes in other regional fat depots did not independently correlate with glucose tolerance or insulin responses. CONCLUSION: AEX + WL is more efficacious than AEX for reducing LDM and glucose tolerance. The improvement in glucose tolerance may be partially mediated by decreases in LDM in older men.
Assuntos
Glicemia/análise , Exercício Físico/fisiologia , Músculo Esquelético/anatomia & histologia , Coxa da Perna/anatomia & histologia , Redução de Peso/fisiologia , Composição Corporal , Distribuição da Gordura Corporal , Teste de Tolerância a Glucose , Humanos , Insulina/sangue , Resistência à Insulina , Masculino , Pessoa de Meia-IdadeRESUMO
BACKGROUND: A common functional missense mutation [Ala54Thr of the fatty acid-binding protein 2 gene (FABP2)] has previously been studied for associations with glucoregulation, postprandial lipemia, and lipid oxidation rates. However, most of those studies have not accounted for the interactive and potentially confounding effects of habitual physical activity and diet. OBJECTIVE: We tested the hypothesis that, in sedentary nondiabetic subjects following a low-fat diet, Thr54 FABP2 carriers have lower glucoregulatory function, greater postprandial lipemia, and greater lipid oxidation rates than do their Ala54 FABP2-homozygous counterparts. DESIGN: Men and women (n = 122) aged 50-75 y who were following a low-fat diet were genotyped and underwent oral-glucose-tolerance tests. A subgroup (n = 36) also underwent postprandial lipemia tests with lipid oxidation rate measurements. RESULTS: Thr54 carriers were less likely to have normal glucose tolerance (P = 0.05) and had higher fasting glucose concentrations (P = 0.003) than did Ala54 homozygotes. In Thr54 carriers, the insulin sensitivity index was lower (P = 0.02), and the fasting insulin and the oral-glucose-tolerance test insulin area under the curve were higher (P = 0.05 and 0.03, respectively) than in Ala54 homozygotes. FABP2 genotype was not associated with fasting or postprandial lipemia test triacylglycerol or free fatty acids (P > or = 0.22 for all), but postprandial lipid oxidation rates were higher (P = 0.01), which suggests that fat absorption is higher in Thr54 carriers than in Ala54 homozygotes. CONCLUSIONS: In sedentary nondiabetic persons following a low-fat diet, FABP2 Thr54 carriers have lower glucose tolerance and lower insulin action than do Ala54-homozygous persons. Furthermore, FABP Thr54 carriers have higher lipid oxidation rates, which may be the mechanism of glucoregulatory dysfunction.
Assuntos
Glicemia/metabolismo , Gorduras na Dieta/administração & dosagem , Proteínas de Ligação a Ácido Graxo/genética , Hiperlipidemias/genética , Metabolismo dos Lipídeos/genética , Idoso , Área Sob a Curva , Composição Corporal , Diabetes Mellitus Tipo 2/genética , Diabetes Mellitus Tipo 2/metabolismo , Dieta com Restrição de Gorduras , Exercício Físico/fisiologia , Feminino , Predisposição Genética para Doença , Genótipo , Teste de Tolerância a Glucose , Humanos , Hiperlipidemias/metabolismo , Metabolismo dos Lipídeos/fisiologia , Masculino , Pessoa de Meia-Idade , Mutação de Sentido Incorreto , Oxirredução , Consumo de Oxigênio , Cooperação do Paciente , Período Pós-PrandialRESUMO
Chronic hypertriglyceridemia is thought to be atherogenic and is associated with an elevated thrombotic potential, both of which may be improved with aerobic exercise training. Eight subjects were tested for aerobic capacity, body composition, and postprandial lipemia (PPL), followed by 6 mo of exercise training and final testing. Blood samples were obtained for measurement of free fatty acid (FFA), triglycerides (TG), insulin (Ins), and glucose (Glu). Hemostatic variables including factor VII activity (FVIIa), tissue factor pathway inhibitor-factor Xa complex (TFPI/Xa), and plasminogen activator inhibitor-1 (PAI-1) antigen/activity as well as leukocyte tumor necrosis factor-alpha (TNF-alpha) gene expression were determined among four subjects. We found that the exercise training was of sufficient intensity to increase aerobic capacity (P < 0.0001) and improve body composition (P = 0.04). There were no differences between tests among PPL responses of FFA, TG, Ins, or Glu; however, the mean TG response and fat oxidation rate improved. PAI-1 antigen/activity, FVIIa, TFPI/Xa, and TNF-alpha gene expression were all improved after exercise training after adjusting for confounders. We conclude that aerobic exercise training reduces the potential for coagulation, improves fibrinolytic potential, and reduces leukocyte TNF-alpha gene expression after the ingestion of a high-fat meal.
Assuntos
Exercício Físico/fisiologia , Hemostasia/fisiologia , Lipídeos/sangue , Período Pós-Prandial/fisiologia , Idoso , Coagulação Sanguínea/efeitos dos fármacos , Coagulação Sanguínea/fisiologia , Gorduras na Dieta/farmacologia , Fator VII/análise , Fator VII/genética , Fator VII/fisiologia , Fator Xa/análise , Fator Xa/genética , Fator Xa/fisiologia , Feminino , Fibrinólise/efeitos dos fármacos , Fibrinólise/fisiologia , Regulação da Expressão Gênica/efeitos dos fármacos , Regulação da Expressão Gênica/fisiologia , Hemostasia/efeitos dos fármacos , Humanos , Lipoproteínas/sangue , Lipoproteínas/genética , Lipoproteínas/fisiologia , Masculino , Pessoa de Meia-Idade , Inibidor 1 de Ativador de Plasminogênio/sangue , Inibidor 1 de Ativador de Plasminogênio/genética , Inibidor 1 de Ativador de Plasminogênio/fisiologia , RNA Mensageiro/sangue , Fator de Necrose Tumoral alfa/análise , Fator de Necrose Tumoral alfa/genética , Fator de Necrose Tumoral alfa/fisiologiaRESUMO
The present study sought to investigate, in sedentary men and women, (a) whether a common functional gene variant (peroxisome proliferator-activated receptor-gamma2 [PPARgamma2] Pro12Ala) predicts insulin action and (b) whether improvements in insulin action in response to endurance exercise training are associated with PPARgamma2 Pro12Ala. Sedentary, 50- to 75-year-old men and women (N = 73) were genotyped and underwent oral glucose tolerance tests (OGTTs) before and after 6 months of endurance training. At baseline, men heterozygous for the Pro12Ala variant had a greater OGTT insulin area under the curve (AUC) as compared with Pro12 homozygous men (P = .009). Endurance training resulted in a significantly greater improvement in insulin AUC in Pro12Ala heterozygous men as compared with Pro12 homozygous men (P = .003) despite no genotype-specific differences with respect to training-induced changes in body weight, body mass index, and percent body fat. No differences between genotype groups were present at baseline or in response to training in women. Training did not alter the OGTT glucose AUC for the group as a whole, and the baseline, final, and change in glucose AUC were not dependent on PPARgamma2 genotype and/or sex. In conclusion, these findings suggest that sedentary men with the PPARgamma2 Pro12Ala variant have lower insulin action on glucose disposal as compared with their counterparts. However, these men are particularly responsive with respect to the magnitude of endurance training-induced improvement in insulin action.
Assuntos
Exercício Físico , Glucose/farmacologia , Insulina/metabolismo , PPAR gama/genética , Idoso , Índice de Massa Corporal , Feminino , Genótipo , Teste de Tolerância a Glucose , Humanos , Secreção de Insulina , Masculino , Pessoa de Meia-Idade , Consumo de Oxigênio , Resistência Física , Caracteres SexuaisRESUMO
The mitochondrial protein deacetylase sirtuin (SIRT) 3 may mediate exercise training-induced increases in mitochondrial biogenesis and improvements in reactive oxygen species (ROS) handling. We determined the requirement of AMP-activated protein kinase (AMPK) for exercise training-induced increases in skeletal muscle abundance of SIRT3 and other mitochondrial proteins. Exercise training for 6.5 weeks increased SIRT3 (p < 0.01) and superoxide dismutase 2 (MnSOD; p < 0.05) protein abundance in quadriceps muscle of wild-type (WT; n = 13-15), but not AMPK α2 kinase dead (KD; n = 12-13) mice. We also observed a strong trend for increased MnSOD abundance in exercise-trained skeletal muscle of healthy humans (p = 0.051; n = 6). To further elucidate a role for AMPK in mediating these effects, we treated WT (n = 7-8) and AMPK α2 KD (n = 7-9) mice with 5-amino-1-ß-D-ribofuranosyl-imidazole-4-carboxamide (AICAR). Four weeks of daily AICAR injections (500 mg/kg) resulted in AMPK-dependent increases in SIRT3 (p < 0.05) and MnSOD (p < 0.01) in WT, but not AMPK α2 KD mice. We also tested the effect of repeated AICAR treatment on mitochondrial protein levels in mice lacking the transcriptional coactivator peroxisome proliferator-activated receptor γ-coactivator 1α (PGC-1α KO; n = 9-10). Skeletal muscle SIRT3 and MnSOD protein abundance was reduced in sedentary PGC-1α KO mice (p < 0.01) and AICAR-induced increases in SIRT3 and MnSOD protein abundance was only observed in WT mice (p < 0.05). Finally, the acetylation status of SIRT3 target lysine residues on MnSOD (K122) or oligomycin-sensitivity conferring protein (OSCP; K139) was not altered in either mouse or human skeletal muscle in response to acute exercise. We propose an important role for AMPK in regulating mitochondrial function and ROS handling in skeletal muscle in response to exercise training.
RESUMO
High-fat meal consumption alters the circulating cytokine profile and contributes to cardiometabolic diseases. A prior bout of exercise can ameliorate the triglyceride response to a high-fat meal, but the interactive effects of exercise and high-fat meals on cytokines that mediate cardiometabolic risk are not fully understood. We investigated the effects of prior exercise on the responses of circulating tumor necrosis factor-α (TNF-α), interleukin-6 (IL-6), IL-8, leptin, retinol-binding protein 4 (RBP4), vascular endothelial growth factor (VEGF), basic fibroblast growth factor (bFGF), placental growth factor (PlGF), and soluble fms-like tyrosine kinase-1 (sFlt-1) to a high-fat meal. Ten healthy men were studied before and 4 h after ingestion of a high-fat meal either with or without â¼50 min of endurance exercise at 70% of VO2 max on the preceding day. In response to the high-fat meal, lower leptin and higher VEGF, bFGF, IL-6, and IL-8 concentrations were evident (P < 0.05 for all). There was no effect of the high-fat meal on PlGF, TNF-α, or RBP4 concentrations. We found lower leptin concentrations with prior exercise (P < 0.05) and interactive effects of prior exercise and the high-fat meal on sFlt-1 (P < 0.05). The high-fat meal increased IL-6 by 59% without prior exercise and 218% with prior exercise (P < 0.05). In conclusion, a prior bout of endurance exercise does not affect all high-fat meal-induced changes in circulating cytokines, but does affect fasting or postprandial concentrations of IL-6, leptin, and sFlt-1. These data may reflect a salutary effect of prior exercise on metabolic responses to a high-fat meal.
RESUMO
Chronic exercise training results in numerous skeletal muscle adaptations, including increases in insulin sensitivity and glycogen content. To understand the mechanism leading to increased muscle glycogen, we studied the effects of exercise training on glycogen regulatory proteins in rat skeletal muscle. Female Sprague Dawley rats performed voluntary wheel running for 1, 4 or 7 weeks. After 7 weeks of training, insulin-stimulated glucose uptake was increased in epitrochlearis muscle. As compared with sedentary control rats, muscle glycogen did not change after 1 week of training, but increased significantly after 4 and 7 weeks. The increases in muscle glycogen were accompanied by elevated glycogen synthase activity and protein expression. To assess the regulation of glycogen synthase, we examined its major activator, protein phosphatase 1 (PP1), and its major deactivator, glycogen synthase kinase (GSK)-3. Consistent with glycogen synthase activity, PP1 activity was unchanged after 1 week of training but significantly increased after 4 and 7 weeks of training. Protein expression of R(GL)(G(M)), another regulatory PP1 subunit, significantly decreased after 4 and 7 weeks of training. Unlike PP1 activity, GSK-3 phosphorylation did not follow the pattern of glycogen synthase activity. The ~ 40% decrease in GSK-3α phosphorylation after 1 week of exercise training persisted until 7 weeks, and may function as a negative feedback mechanism in response to elevated glycogen. Our findings suggest that exercise training-induced increases in muscle glycogen content could be regulated by multiple mechanisms, including enhanced insulin sensitivity, glycogen synthase expression, allosteric activation of glycogen synthase, and PP1 activity.
Assuntos
Adaptação Fisiológica/fisiologia , Glicogênio/metabolismo , Músculo Esquelético/metabolismo , Condicionamento Físico Animal/fisiologia , Animais , Glicemia/metabolismo , Peso Corporal/fisiologia , Feminino , Glucose/metabolismo , Glucose/farmacocinética , Transportador de Glucose Tipo 4/metabolismo , Glicogênio Fosforilase/metabolismo , Glicogênio Sintase/metabolismo , Quinase 3 da Glicogênio Sintase/metabolismo , Immunoblotting , Insulina/sangue , Insulina/farmacologia , Músculo Esquelético/efeitos dos fármacos , Proteína Fosfatase 1/metabolismo , Ratos , Ratos Sprague-Dawley , Fatores de TempoRESUMO
Recent studies suggest that interleukin 6 (IL-6) is released from contracting skeletal muscles; however, the cellular origin, secretion kinetics, and signaling mechanisms regulating IL-6 secretion are unknown. To address these questions, we developed imaging methodology to study IL-6 in fixed mouse muscle fibers and in live animals in vivo. Using confocal imaging to visualize endogenous IL-6 protein in fixed muscle fibers, we found IL-6 in small vesicle structures distributed throughout the fibers under basal (resting) conditions. To determine the kinetics of IL-6 secretion, intact quadriceps muscles were transfected with enhanced green fluorescent protein (EGFP)-tagged IL-6 (IL-6-EGFP), and 5 days later anesthetized mice were imaged before and after muscle contractions in situ. Contractions decreased IL-6-EGFP-containing vesicles and protein by 62% (P < 0.05), occurring rapidly and progressively over 25 min of contraction. However, contraction-mediated IL-6-EGFP reduction was normal in muscle-specific AMP-activated protein kinase (AMPK) α2-inactive transgenic mice. In contrast, the AMPK activator AICAR decreased IL-6-EGFP vesicles, an effect that was inhibited in the transgenic mice. In conclusion, resting skeletal muscles contain IL-6-positive vesicles that are expressed throughout myofibers. Contractions stimulate the rapid reduction of IL-6 in myofibers, occurring through an AMPKα2-independent mechanism. This novel imaging methodology clearly establishes IL-6 as a contraction-stimulated myokine and can be used to characterize the secretion kinetics of other putative myokines.
Assuntos
Aminoimidazol Carboxamida/análogos & derivados , Interleucina-6/metabolismo , Fibras Musculares Esqueléticas/efeitos dos fármacos , Fibras Musculares Esqueléticas/metabolismo , Ribonucleotídeos/farmacologia , Aminoimidazol Carboxamida/farmacologia , Animais , Proteínas de Fluorescência Verde/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Microscopia Confocal , Contração Muscular/efeitos dos fármacosRESUMO
PURPOSE: To determine the effects of 6wk of supplementation with fish oil (FO) on blood pressure and the morning salivary cortisol concentration in normotensive adults. METHODS: Testing was performed following an overnight fast. Subjects (n=40; 35+/-13y, mean+/-SD) rested supine for 40min, at which time blood pressure and heart rate were measured. Saliva was collected and analyzed for cortisol. Subjects were then randomly assigned to either: 4g/d of Safflower Oil (SO); or 4g/d of FO supplying 1,600mg/d eicosapentaenoic acid and 800mg/d docosahexaenoic acid. Testing was repeated following 6wk of treatment. RESULTS: Compared to SO, there was a significant decrease in systolic blood pressure with FO (SO=1.3+/-5.8 mmHg; FO=-6.8+/-10.2 mmHg; p=0.004), a significant reduction in pulse pressure (SO=0.2+/-7.8 mmHg; FO=-6.4+/-8.8 mmHg; p=0.02), and a tendency for a decrease in mean arterial pressure (SO=1.2+/-5.3 mmHg; FO=-2.5+/-7.3 mmHg; p=0.08). There was a tendency for salivary cortisol to decrease with FO (SO=0.005+/-0.129 µg/dL; FO=-0.068+/-0.148 µg/dL; p=0.072), however, this change was not significantly correlated with the change in systolic blood pressure (r=0.021, p=0.929). CONCLUSION: 6wk of supplementation with FO significantly decreases systolic blood pressure in normotensive adults and this change was not significantly correlated with a reduction in salivary cortisol.
Assuntos
Pressão Sanguínea/efeitos dos fármacos , Suplementos Nutricionais , Óleos de Peixe/farmacologia , Hidrocortisona/metabolismo , Adulto , Biomarcadores/metabolismo , Ácidos Docosa-Hexaenoicos/administração & dosagem , Ácidos Docosa-Hexaenoicos/farmacologia , Esquema de Medicação , Ácido Eicosapentaenoico/administração & dosagem , Ácido Eicosapentaenoico/farmacologia , Feminino , Óleos de Peixe/administração & dosagem , Humanos , Masculino , Pessoa de Meia-Idade , Projetos Piloto , Óleo de Cártamo/administração & dosagem , Óleo de Cártamo/farmacologia , Saliva/metabolismoRESUMO
Insulin-like growth factor binding protein-1 (IGFBP-1) has metabolic effects throughout the body, and its expression is regulated in part by insulin. Circulating IGFBP-1 predicts development of cardiometabolic diseases in longitudinal studies, and low IGFBP-1 concentrations are associated with insulin resistance and consumption of a high-fat diet. Because of the favorable metabolic effects of regular aerobic exercise, we hypothesized that aerobic exercise training would increase plasma IGFBP-1 concentrations and attenuate the reduction in IGFBP-1 after a high-fat meal. Ten overweight (body mass index = 28.7 ± 0.9 kg/m(2)), older (61 ± 2 years) men and women underwent high-fat feeding and oral glucose tolerance tests at baseline and after 6 months of aerobic exercise training. In response to aerobic exercise training, subjects increased cardiorespiratory fitness by 13% (P < .05) and insulin sensitivity index by 28% (P < .05). Basal plasma concentrations of IGFBP-1 increased by 41% after aerobic exercise training (P < .05). The insulin response to an oral glucose tolerance test was a significant predictor of fasting plasma IGFBP-1 concentrations at baseline and after exercise training (P = .02). In response to the high-fat meal at baseline, plasma IGFBP-1 concentrations decreased by 58% (P < .001); a 61% decrease to similar postprandial concentrations was observed after exercise training (P < .001). Plasma insulin response to the high-fat meal was inversely associated with postprandial IGFBP-1 concentrations at baseline and after exercise training (P = .06 and P < .05, respectively). Although aerobic exercise training did not attenuate the response to a high-fat meal, the increase in IGFBP-1 concentrations after exercise training may be one mechanism by which exercise reduces risk for cardiometabolic diseases in older adults.
Assuntos
Gorduras na Dieta/farmacologia , Exercício Físico/fisiologia , Proteína 1 de Ligação a Fator de Crescimento Semelhante à Insulina/sangue , Educação Física e Treinamento , Idoso , Área Sob a Curva , Análise Química do Sangue , Glicemia/análise , Glicemia/metabolismo , Composição Corporal/fisiologia , Depressão Química , Feminino , Teste de Tolerância a Glucose , Humanos , Insulina/sangue , Masculino , Pessoa de Meia-Idade , Aptidão Física/fisiologiaRESUMO
BACKGROUND: To determine the effects of supplemental fish oil (FO) on resting metabolic rate (RMR), body composition, and cortisol production in healthy adults. METHODS: A total of 44 men and women (34 ± 13y, mean+SD) participated in the study. All testing was performed first thing in the morning following an overnight fast. Baseline measurements of RMR were measured using indirect calorimetry using a facemask, and body composition was measured using air displacement plethysmography. Saliva was collected via passive drool and analyzed for cortisol concentration using ELISA. Following baseline testing, subjects were randomly assigned in a double blind manner to one of two groups: 4 g/d of Safflower Oil (SO); or 4 g/d of FO supplying 1,600 mg/d eicosapentaenoic acid (EPA) and 800 mg/d docosahexaenoic acid (DHA). All tests were repeated following 6 wk of treatment. Pre to post differences were analyzed using a treatment X time repeated measures ANOVA, and correlations were analyzed using Pearson's r. RESULTS: Compared to the SO group, there was a significant increase in fat free mass following treatment with FO (FO = +0.5 ± 0.5 kg, SO = -0.1 ± 1.2 kg, p = 0.03), a significant reduction in fat mass (FO = -0.5 ± 1.3 kg, SO = +0.2 ± 1.2 kg, p = 0.04), and a tendency for a decrease in body fat percentage (FO = -0.4 ± 1.3% body fat, SO = +0. 3 ± 1.5% body fat, p = 0.08). No significant differences were observed for body mass (FO = 0.0 ± 0.9 kg, SO = +0.2 ± 0.8 kg), RMR (FO = +17 ± 260 kcal, SO = -62 ± 184 kcal) or respiratory exchange ratio (FO = -0.02 ± 0.09, SO = +0.02 ± 0.05). There was a tendency for salivary cortisol to decrease in the FO group (FO = -0.064 ± 0.142 µg/dL, SO = +0.016 ± 0.272 µg/dL, p = 0.11). There was a significant correlation in the FO group between change in cortisol and change in fat free mass (r = -0.504, p = 0.02) and fat mass (r = 0.661, p = 0.001). CONCLUSION: 6 wk of supplementation with FO significantly increased lean mass and decreased fat mass. These changes were significantly correlated with a reduction in salivary cortisol following FO treatment.
RESUMO
PURPOSE OF REVIEW: To address the role of LKB1 and AMP-activated protein kinase (AMPK) in glucose transport, fatty acid oxidation, and metabolic adaptations in skeletal muscle. RECENT FINDINGS: Contraction-mediated skeletal muscle glucose transport is decreased in muscle-specific LKB1 knockout mice, but not in whole body AMPKalpha2 knockout mice or AMPKalpha2 inactive transgenic mice. Chronic activation of AMPK by 5-aminoimidazole-4-carboxamide-1-beta-D-ribofuranoside (AICAR) and beta-guanadinopropionic acid enhances mitochondrial function in skeletal muscle, but AICAR or exercise-induced increases in mitochondrial markers are preserved in skeletal muscles from whole body AMPKalpha2 or muscle-specific LKB1 knockout mice. Pharmacological activation of AMPK increases glucose transport and fatty acid oxidation in skeletal muscle. Therefore, chronic activation of AMPK may be beneficial in the treatment of obesity and type 2 diabetes. SUMMARY: LKB1 and AMPK play important roles in regulating metabolism in resting and contracting skeletal muscle.