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1.
J Proteome Res ; 16(2): 798-805, 2017 02 03.
Artigo em Inglês | MEDLINE | ID: mdl-27936752

RESUMO

Advancing age is associated with declines in maximal oxygen consumption. Declines in aerobic capacity not only contribute to the aging process but also are an independent risk factor for morbidity, cardiovascular disease, and all-cause mortality. Although statistically convincing, the relationships between aerobic capacity, aging, and disease risk remain largely unresolved. To this end, we employed sensitive, system-based metabolomics approach to determine whether enhanced aerobic capacity could mitigate some of the changes seen in the plasma metabolomic profile associated with aging. Metabolomic profiles of plasma samples obtained from young (13 month) and old (26 month) rats bred for low (LCR) or high (HCR) running capacity using proton nuclear magnetic resonance spectroscopy (1H NMR) were examined. Results demonstrated strong profile separation in old and low aerobic capacity rats, whereas young and high aerobic capacity rat models were less predictive. Significantly differential metabolites between the groups include taurine, acetone, valine, and trimethylamine-N-oxide among other metabolites, specifically citrate, succinate, isovalerate, and proline, were differentially increased in older HCR animals compared with their younger counterparts. When interactions between age and aerobic capacity were examined, results demonstrated that enhanced aerobic capacity could mitigate some but not all age-associated alterations in the metabolomic profile.


Assuntos
Envelhecimento/genética , Metaboloma/genética , Metabolômica , Consumo de Oxigênio/genética , Envelhecimento/metabolismo , Animais , Espectroscopia de Ressonância Magnética , Miocárdio/metabolismo , Ratos , Fatores de Risco , Corrida
2.
J Proteome Res ; 15(4): 1143-50, 2016 Apr 01.
Artigo em Inglês | MEDLINE | ID: mdl-26928523

RESUMO

The microbiota, the entirety of microorganisms residing in the gut, is increasingly recognized as an environmental factor in the maintenance of health and the development of disease. The objective of this analysis was to model in vivo interactions between gut microbiota and both serum and liver metabolites. Different genotypic models (C57BL/6 and BTBR(T+tf/j) mice) were studied in combination with significant dietary manipulations (chow vs ketogenic diets) to perturb the gut microbiota. Diet rather than genotype was the primary driver of microbial changes, with the ketogenic diet diminishing total bacterial levels. Fecal but not cecal microbiota profiles were associated with the serum and liver metabolomes. Modeling metabolome-microbiota interactions showed fecal Clostridium leptum to have the greatest impact on host metabolism, significantly correlating with 10 circulating metabolites, including 5 metabolites that did not correlate with any other microbes. C. leptum correlated negatively with serum ketones and positively with glucose and glutamine. Interestingly, microbial groups most strongly correlated with host metabolism were those modulating gut barrier function, the primary site of microbe-host interactions. These results show very robust relationships and provide a basis for future work wherein the compositional and functional associations of the microbiome can be modeled in the context of the metabolome.


Assuntos
Dieta Cetogênica , Microbioma Gastrointestinal/fisiologia , Metaboloma , Modelos Biológicos , Animais , Bacteroides/isolamento & purificação , Bacteroides/metabolismo , Bifidobacterium/isolamento & purificação , Bifidobacterium/metabolismo , Glicemia/metabolismo , Ceco/microbiologia , Clostridium/isolamento & purificação , Clostridium/metabolismo , Enterobacteriaceae/isolamento & purificação , Enterobacteriaceae/metabolismo , Fezes/microbiologia , Glutamina/sangue , Cetonas/sangue , Lactobacillus/isolamento & purificação , Lactobacillus/metabolismo , Fígado/metabolismo , Metabolômica , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos
3.
J Strength Cond Res ; 30(4): 1137-46, 2016 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-25647655

RESUMO

Preventing physical inactivity and weight gain during college is critical in decreasing lifelong obesity and associated disease risk. As such, we sought to compare cardiometabolic risk factors and lifestyle behaviors between college students enrolled in kinesiology and non-kinesiology degree programs to assess whether health and exercise degree programs may influence health behaviors and associated disease risk outcomes. Anthropometrics, fasting blood glucose, insulin, lipid profiles and HbA1c%, blood pressure, and peak oxygen consumption (V[Combining Dot Above]O2peak) were assessed in 247 healthy college students. The homeostasis model assessment of insulin sensitivity (HOMA) was calculated using glucose and insulin levels. Self-reported physical activity from the Paffenbarger questionnaire was collected to estimate the average caloric expenditure due to different types of physical activities. Despite no significant differences in body mass index or waist circumference between groups, kinesiology majors presented with ∼20% lower fasting insulin levels and HOMA (p = 0.01; p < 0.01, respectively) relative to nonmajors. Kinesiology majors reported increased weekly participation in vigorous-intensity sport and leisure activities and, on average, engaged in >300 metabolic equivalent-h·wk, whereas non-kinesiology majors engaged in <300 MET-h wk (p = 0.01). Our data suggest that students enrolled in kinesiology degree programs display improved healthy behaviors and associated outcomes (parameters of glucose homeostasis). Practical outcomes of this research indicate that implementing components of a comprehensive kinesiology curriculum encourages improved health behaviors and associated cardiometabolic risk factors.


Assuntos
Comportamentos Relacionados com a Saúde , Cinesiologia Aplicada/educação , Estilo de Vida , Estudantes , Exercício Físico/fisiologia , Feminino , Humanos , Insulina/sangue , Resistência à Insulina , Masculino , Universidades , Adulto Jovem
4.
J Proteome Res ; 13(11): 5063-70, 2014 Nov 07.
Artigo em Inglês | MEDLINE | ID: mdl-25182463

RESUMO

Metabolite profiles of individuals possessing either the cardiovascular risk or protective variants of the low-density lipoprotein cholesterol (LDL-C) associated 1p13.3 locus of the SORT1 gene (rs646776) were analyzed. Serum metabolites and lipids were assessed using LC-MS-based metabolomics in a healthy young population (n = 138: 95 males, 43 females). Although no significant differences were observed in the combined cohort, divergent sex effects were identified. Females carrying the protective allele showed increased phosphatidylcholines, very long chain fatty acids (>C20), and unsaturated fatty acids. Unsaturated fatty acids are considered to be protective against cardiovascular disease. In contrast, males carrying the protective allele exhibited decreased long-chain fatty acids (≤C20) and sphingomyelins, which is similarly considered to decrease cardiovascular disease risk. No significant changes in clinically assessed lipids such as LDL-C, high-density lipoprotein (HDL-C), total cholesterol, or triglycerides were observed in females, whereas only LDL-C was significantly changed in males. This indicates that, apart from reducing LDL-C, other mechanisms may contribute to the protective effect of the SORT1 locus. Thus, the analysis of metabolic biomarkers might reveal early disease development that may be overlooked by relying on standard clinical parameters.


Assuntos
Proteínas Adaptadoras de Transporte Vesicular/genética , Sangue/metabolismo , LDL-Colesterol/sangue , Lipídeos/sangue , Metabolômica/métodos , Adulto , Doenças Cardiovasculares/sangue , Doenças Cardiovasculares/genética , LDL-Colesterol/genética , Ácidos Graxos/sangue , Ácidos Graxos/genética , Feminino , Predisposição Genética para Doença , Heterozigoto , Humanos , Masculino , Fatores Sexuais , Adulto Jovem
5.
Biochem Cell Biol ; 92(3): 226-34, 2014 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-24882465

RESUMO

Although myostatin functions primarily as a negative regulator of skeletal muscle growth and development, accumulating biological and epidemiological evidence indicates an important contributing role in liver disease. In this study, we demonstrate that myostatin suppresses the proliferation of mouse Hepa-1c1c7 murine-derived liver cells (50%; p < 0.001) in part by reducing the expression of the cyclins and cyclin-dependent kinases that elicit G1-S phase transition of the cell cycle (p < 0.001). Furthermore, real-time PCR-based quantification of the long noncoding RNA metastasis associated lung adenocarcinoma transcript 1 (Malat1), recently identified as a myostatin-responsive transcript in skeletal muscle, revealed a significant downregulation (25% and 50%, respectively; p < 0.05) in the livers of myostatin-treated mice and liver cells. The importance of Malat1 in liver cell proliferation was confirmed via arrested liver cell proliferation (p < 0.05) in response to partial Malat1 siRNA-mediated knockdown. Myostatin also significantly blunted insulin-stimulated glucose uptake and Akt phosphorylation in liver cells while increasing the phosphorylation of myristoylated alanine-rich C-kinase substrate (MARCKS), a protein that is essential for cancer cell proliferation and insulin-stimulated glucose transport. Together, these findings reveal a plausible mechanism by which circulating myostatin contributes to the diminished regenerative capacity of the liver and diseases characterized by liver insulin resistance.


Assuntos
Antineoplásicos/farmacologia , Glucose/metabolismo , Insulina/metabolismo , Fígado/efeitos dos fármacos , Fígado/metabolismo , Miostatina/farmacologia , RNA Longo não Codificante/antagonistas & inibidores , Animais , Antineoplásicos/química , Proliferação de Células/efeitos dos fármacos , Relação Dose-Resposta a Droga , Ensaios de Seleção de Medicamentos Antitumorais , Fígado/patologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Miostatina/química , Fosforilação/efeitos dos fármacos , Proteínas Proto-Oncogênicas c-akt/antagonistas & inibidores , Proteínas Proto-Oncogênicas c-akt/metabolismo , RNA Longo não Codificante/genética , RNA Longo não Codificante/metabolismo , Relação Estrutura-Atividade , Células Tumorais Cultivadas
6.
Am J Physiol Cell Physiol ; 304(10): C995-1001, 2013 May 15.
Artigo em Inglês | MEDLINE | ID: mdl-23485710

RESUMO

Myostatin, a member of the transforming growth factor-ß (TGF-ß) superfamily of secreted proteins, is a potent negative regulator of myogenesis. Free myostatin induces the phosphorylation of the Smad family of transcription factors, which, in turn, regulates gene expression, via the canonical TGF-ß signaling pathway. There is, however, emerging evidence that myostatin can regulate gene expression independent of Smad signaling. As such, we acquired global gene expression data from the gastrocnemius muscle of C57BL/6 mice following a 6-day treatment with recombinant myostatin compared with vehicle-treated animals. Of the many differentially expressed genes, the myostatin-associated decrease (-11.20-fold; P < 0.05) in the noncoding metastasis-associated lung adenocarcinoma transcript 1 (Malat1) was the most significant and the most intriguing because of numerous reports describing its novel role in regulating cell growth. We therefore sought to further characterize the role of Malat1 expression in skeletal muscle myogenesis. RT-PCR-based quantification of C2C12 and primary human skeletal muscle cells revealed a significant and persistent upregulation (4- to 7-fold; P < 0.05) of Malat1 mRNA during the differentiation of myoblasts into myotubes. Conversely, targeted knockdown of Malat1 using siRNA suppressed myoblast proliferation by arresting cell growth in the G(0)/G(1) phase. These results reveal Malat1 as novel downstream target of myostatin with a considerable ability to regulate myogenesis. The identification of new targets of myostatin will have important repercussions for regenerative biology through inhibition and/or reversal of muscle atrophy and wasting diseases.


Assuntos
Desenvolvimento Muscular , Miostatina/metabolismo , RNA Longo não Codificante/metabolismo , Animais , Diferenciação Celular , Proliferação de Células , Células Cultivadas , Feminino , Pontos de Checagem da Fase G1 do Ciclo Celular , Expressão Gênica , Humanos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Fibras Musculares Esqueléticas , Músculo Esquelético/metabolismo , Mioblastos/metabolismo , Miostatina/farmacologia , Interferência de RNA , RNA Longo não Codificante/antagonistas & inibidores , RNA Longo não Codificante/genética , RNA Mensageiro/biossíntese , RNA Interferente Pequeno , Proteínas Recombinantes/farmacologia
7.
Physiol Genomics ; 45(1): 17-25, 2013 Jan 07.
Artigo em Inglês | MEDLINE | ID: mdl-23132757

RESUMO

O-linked ß-N-acetyl glucosamine (O-GlcNAc) is a posttranslational modification consisting of a single N-acetylglucosamine moiety attached by an O-ß-glycosidic linkage to serine and threonine residues of both nuclear and cytosolic proteins. Analogous to phosphorylation, the modification is reversible and dynamic, changing in response to stress, nutrients, hormones, and exercise. Aims of this study were to examine differences in O-GlcNAc protein modification in the cardiac tissue of rats artificially selected for low (LCR) or high (HCR) running capacity. Hyperinsulinemic-euglycemic clamps in conscious animals assessed insulin sensitivity while 2-[(14)C] deoxyglucose tracked both whole body and tissue-specific glucose disposal. Immunoblots of cardiac muscle examined global O-GlcNAc modification, enzymes that control its regulation (OGT, OGA), and specific proteins involved in mitochondrial oxidative phosphorylation. LCR rats were insulin resistant disposing of 65% less glucose than HCR. Global tissue O-GlcNAc, OGT, OGA, and citrate synthase were similar between groups. Analysis of cardiac proteins revealed enhanced O-GlcNAcylation of mitochondrial Complex I, Complex IV, VDAC, and SERCA in LCR compared with HCR. These results are the first to establish an increase in specific protein O-GlcNAcylation in LCR animals that may contribute to progressive mitochondrial dysfunction and the pathogenesis of insulin resistance observed in the LCR phenotype.


Assuntos
Resistência à Insulina/fisiologia , Proteínas Mitocondriais/genética , Proteínas Mitocondriais/metabolismo , Modelos Animais , Miocárdio/metabolismo , Corrida/fisiologia , Absorciometria de Fóton , Análise de Variância , Animais , Radioisótopos de Carbono/metabolismo , Citrato (si)-Sintase/metabolismo , Ácidos Graxos não Esterificados/sangue , Glucose/metabolismo , Técnica Clamp de Glucose/métodos , Glicosilação , Immunoblotting , Cinética , N-Acetilglucosaminiltransferases/metabolismo , Fosforilação Oxidativa , Ratos , Ratos Endogâmicos
8.
Cardiovasc Diabetol ; 12: 128, 2013 Sep 04.
Artigo em Inglês | MEDLINE | ID: mdl-24007410

RESUMO

BACKGROUND: This study aimed to evaluate the efficacy of mesenchymal stem cell (MSC) transplantation to mitigate abnormalities in cardiac-specific and systemic metabolism mediated by a combination of a myocardial infarction and diet-induced insulin resistance. METHODS: C57BL/6 mice were high-fat fed for eight weeks prior to induction of a myocardial infarction via chronic ligation of the left anterior descending coronary artery. MSCs were administered directly after myocardial infarction induction through a single intramyocardial injection. Echocardiography was performed prior to the myocardial infarction as well as seven and 28 days post-myocardial infarction. Hyperinsulinemic-euglycemic clamps coupled with 2-[14C]deoxyglucose were employed 36 days post-myocardial infarction (13 weeks of high-fat feeding) to assess systemic insulin sensitivity and insulin-mediated, tissue-specific glucose uptake in the conscious, unrestrained mouse. High-resolution respirometry was utilized to evaluate cardiac mitochondrial function in saponin-permeabilized cardiac fibers. RESULTS: MSC administration minimized the decline in ejection fraction following the myocardial infarction. The greater systolic function in MSC-treated mice was associated with increased in vivo cardiac glucose uptake and enhanced mitochondrial oxidative phosphorylation efficiency. MSC therapy promoted reductions in fasting arterial glucose and fatty acid concentrations. Additionally, glucose uptake in peripheral tissues including skeletal muscle and adipose tissue was elevated in MSC-treated mice. Enhanced glucose uptake in these tissues was associated with improved insulin signalling as assessed by Akt phosphorylation and prevention of a decline in GLUT4 often associated with high-fat feeding. CONCLUSIONS: These studies provide insight into the utility of MSC transplantation as a metabolic therapy that extends beyond the heart exerting beneficial systemic effects on insulin action.


Assuntos
Dieta Hiperlipídica , Metabolismo Energético , Resistência à Insulina , Transplante de Células-Tronco Mesenquimais , Infarto do Miocárdio/cirurgia , Miocárdio/metabolismo , Tecido Adiposo/metabolismo , Animais , Glicemia/metabolismo , Células Cultivadas , Modelos Animais de Doenças , Ácidos Graxos/sangue , Transportador de Glucose Tipo 4/metabolismo , Humanos , Insulina/sangue , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Mitocôndrias Cardíacas/metabolismo , Músculo Esquelético/metabolismo , Infarto do Miocárdio/sangue , Infarto do Miocárdio/fisiopatologia , Fosforilação Oxidativa , Fosforilação , Proteínas Proto-Oncogênicas c-akt/metabolismo , Recuperação de Função Fisiológica , Volume Sistólico , Sístole , Fatores de Tempo
9.
Am J Physiol Endocrinol Metab ; 302(2): E163-72, 2012 Jan 15.
Artigo em Inglês | MEDLINE | ID: mdl-21971524

RESUMO

Intense interest has been focused on cell-based therapy for the infarcted heart given that stem cells have exhibited the ability to reduce infarct size and mitigate cardiac dysfunction. Despite this, it is unknown whether mesenchymal stem cell (MSC) therapy can prevent metabolic remodeling following a myocardial infarction (MI). This study examines the ability of MSCs to rescue the infarcted heart from perturbed substrate uptake in vivo. C57BL/6 mice underwent chronic ligation of the left anterior descending coronary artery to induce a MI. Echocardiography was performed on conscious mice at baseline as well as 7 and 23 days post-MI. Twenty-eight days following the ligation procedure, hyperinsulinemic euglycemic clamps assessed in vivo insulin sensitivity. Isotopic tracer administration evaluated whole body, peripheral tissue, and cardiac-specific glucose and fatty acid utilization. To gain insight into the mechanisms by which MSCs modulate metabolism, mitochondrial function was assessed by high-resolution respirometry using permeabilized cardiac fibers. Data show that MSC transplantation preserves insulin-stimulated fatty acid uptake in the peri-infarct region (4.25 ± 0.64 vs. 2.57 ± 0.34 vs. 3.89 ± 0.54 µmol·100 g(-1)·min(-1), SHAM vs. MI + PBS vs. MI + MSC; P < 0.05) and prevents increases in glucose uptake in the remote left ventricle (3.11 ± 0.43 vs. 3.81 ± 0.79 vs. 6.36 ± 1.08 µmol·100 g(-1)·min(-1), SHAM vs. MI + PBS vs. MI + MSC; P < 0.05). This was associated with an enhanced efficiency of mitochondrial oxidative phosphorylation with a respiratory control ratio of 3.36 ± 0.18 in MSC-treated cardiac fibers vs. 2.57 ± 0.14 in the infarct-only fibers (P < 0.05). In conclusion, MSC therapy exhibits the potential to rescue the heart from metabolic aberrations following a MI. Restoration of metabolic flexibility is important given the metabolic demands of the heart and the role of energetics in the progression to heart failure.


Assuntos
Metabolismo Energético/fisiologia , Transplante de Células-Tronco Mesenquimais , Mitocôndrias/metabolismo , Infarto do Miocárdio/terapia , Miocárdio/metabolismo , Remodelação Ventricular/fisiologia , Animais , Coração/fisiopatologia , Camundongos , Mitocôndrias/patologia , Infarto do Miocárdio/metabolismo , Infarto do Miocárdio/patologia , Infarto do Miocárdio/fisiopatologia , Miocárdio/patologia , Fosforilação/fisiologia
10.
Am J Physiol Endocrinol Metab ; 301(1): E31-9, 2011 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-21386062

RESUMO

Substrate imbalance is a well-recognized feature of diabetic cardiomyopathy. Insulin resistance effectively limits carbohydrate oxidation, resulting in abnormal cardiac glycogen accumulation. Aims of the present study were to 1) characterize the role of glycogen-associated proteins involved in excessive glycogen accumulation in type 2 diabetic hearts and 2) determine if exercise training can attenuate abnormal cardiac glycogen accumulation. Control (db(+)) and genetically diabetic (db/db) C57BL/KsJ-lepr(db)/lepr(db) mice were subjected to sedentary or treadmill exercise regimens. Exercise training consisted of high-intensity/short-duration (10 days) and low-intensity/long-duration (6 wk) protocols. Glycogen levels were elevated by 35-50% in db/db hearts. Exercise training further increased (2- to 3-fold) glycogen levels in db/db hearts. Analysis of soluble and insoluble glycogen pools revealed no differential accumulation of one glycogen subspecies. Phosphorylation (Ser(640)) of glycogen synthase, an indicator of enzymatic fractional activity, was greater in db/db mice subjected to sedentary and exercise regimens. Elevated glycogen levels were accompanied by decreased phosphorylation (Thr(172)) of 5'-AMP-activated kinase and phosphorylation (Ser(79)) of its downstream substrate acetyl-CoA carboxylase. Glycogen concentration was not associated with increases in other glycogen-associated proteins, including malin and laforin. Novel observations show that exercise training does not correct diabetes-induced elevations in cardiac glycogen but, rather, precipitates further accumulation.


Assuntos
Diabetes Mellitus Experimental/metabolismo , Diabetes Mellitus Tipo 2/metabolismo , Cardiomiopatias Diabéticas/metabolismo , Glicogênio/metabolismo , Miocárdio/metabolismo , Condicionamento Físico Animal/fisiologia , Animais , Peso Corporal/fisiologia , Diabetes Mellitus Experimental/genética , Diabetes Mellitus Experimental/terapia , Diabetes Mellitus Tipo 2/genética , Diabetes Mellitus Tipo 2/terapia , Cardiomiopatias Diabéticas/genética , Cardiomiopatias Diabéticas/terapia , Terapia por Exercício , Doença de Depósito de Glicogênio Tipo IIb/genética , Doença de Depósito de Glicogênio Tipo IIb/metabolismo , Doença de Depósito de Glicogênio Tipo IIb/terapia , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Miocárdio/patologia , Receptores para Leptina/genética
11.
Endocr Pract ; 22(7): 897-8, 2016 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-27018623
12.
Nutrients ; 12(12)2020 Dec 16.
Artigo em Inglês | MEDLINE | ID: mdl-33339359

RESUMO

Caffeine-containing, nutritionally fortified energy shots are consumed at high rates by adolescents, yet little is known about their metabolic impact. The purpose of this study was to examine the consequences of small format, caffeinated energy shots on glucose metabolism and gastrointestinal hormone secretion in adolescents. Twenty participants aged 13-19 years participated in a double-blind, randomized cross-over study consisting of two trials separated by 1-4 weeks. Participants consumed a volume-matched caffeinated energy shot (CAF, 5 mg/kg) or a decaffeinated energy shot (DECAF) followed by a 2 h oral glucose tolerance test. Blood samples were collected and area under the curve (AUC) calculated for glucose, insulin and gut and metabolic hormones. Consumption of CAF resulted in a 25% increase in glucose and a 26% increase in insulin area under the curve (AUC, p = 0.037; p < 0.0001) compared to DECAF. No impact on gut hormones was observed. To further characterize responses, individuals were classified as either slow or fast caffeine metabolizers based on an allele score. Glucose intolerance was greater in genetically fast vs. slow caffeine metabolizers and differences between groups were supported by distinct serum metabolomics separation. Consumption of caffeine-containing energy shots results in acute impaired glucoregulation in healthy adolescents as characterized by hyperinsulinemia following an oral glucose challenge.


Assuntos
Glicemia/metabolismo , Cafeína/efeitos adversos , Bebidas Energéticas , Hormônios Gastrointestinais/sangue , Intolerância à Glucose/induzido quimicamente , Doença Aguda , Adolescente , Área Sob a Curva , Estudos Cross-Over , Método Duplo-Cego , Feminino , Teste de Tolerância a Glucose , Humanos , Hiperinsulinismo/induzido quimicamente , Insulina/sangue , Masculino , Adulto Jovem
13.
PLoS One ; 14(1): e0209913, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30653534

RESUMO

Over the past decade, there has been a substantial increase in the number of beverage products containing added vitamins and minerals. Often viewed as a healthier choice by consumers, the metabolic impacts of excessive vitamin consumption are relatively unknown, especially in children. The aim of this study was to examine the effects of a widely available, vitamin fortified beverage (5h Energy Decaffeinated) on insulin sensitivity, metabolic hormones and serum metabolomic responses in adolescents. Twenty adolescents (13-19y, 10M/10F) completed two randomized trials, consuming either coloured water as placebo (PL) or a vitamin fortified, sugar free beverage (FB, 1.5ml/kg) 40min prior to a modified oral glucose tolerance test (OGTT, 1.75g/kg glucose). Samples were collected at baseline and at 30, 45, 60, 90 and 120min during the OGTT. No differences in blood glucose response were observed between the treatments. However, compared to PL, postprandial plasma C-peptide and insulin excursion was significantly greater with FB, resulting in a 28% decline in the insulin sensitivity index. This was accompanied by elevated GLP-1, glucagon and PYY responses with FB compared to PL. Serum metabolomics (1H-NMR) analysis also revealed perturbations to vitamin B-linked one carbon metabolism flux with FB consumption that became more pronounced over time. These included a transient reduction in homocysteine flux accompanied by increases in betaine, vitamin B6, vitamin B12, choline, folate and taurine. Although these impacts are likely short-lived, results show that beverages fortified with excessive amounts of vitamins are not metabolically inert, but likely result in greater insulin secretion, differential gut hormone secretion and elevated one-carbon flux to process the excessive vitamin loads.


Assuntos
Bebidas , Alimentos Fortificados , Complexo Vitamínico B , Adolescente , Adulto , Glicemia/metabolismo , Estudos Cross-Over , Feminino , Teste de Tolerância a Glucose , Humanos , Resistência à Insulina , Masculino , Período Pós-Prandial , Complexo Vitamínico B/administração & dosagem , Complexo Vitamínico B/farmacocinética
14.
Front Physiol ; 9: 1572, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30555336

RESUMO

Mesenchymal stem cells (MSCs) are the most commonly used cells in tissue engineering and regenerative medicine. MSCs can promote host tissue repair through several different mechanisms including donor cell engraftment, release of cell signaling factors, and the transfer of healthy organelles to the host. In the present study, we examine the specific impacts of MSCs on mitochondrial morphology and function in host tissues. Employing in vitro cell culture of inherited mitochondrial disease and an in vivo animal experimental model of low-grade inflammation (high fat feeding), we show human-derived MSCs to alter mitochondrial function. MSC co-culture with skin fibroblasts from mitochondrial disease patients rescued aberrant mitochondrial morphology from a fission state to a more fused appearance indicating an effect of MSC co-culture on host cell mitochondrial network formation. In vivo experiments confirmed mitochondrial abundance and mitochondrial oxygen consumption rates were elevated in host tissues following MSC treatment. Furthermore, microarray profiling identified 226 genes with differential expression in the liver of animals treated with MSC, with cellular signaling, and actin cytoskeleton regulation as key upregulated processes. Collectively, our data indicate that MSC therapy rescues impaired mitochondrial morphology, enhances host metabolic capacity, and induces widespread host gene shifting. These results highlight the potential of MSCs to modulate mitochondria in both inherited and pathological disease states.

15.
Appl Physiol Nutr Metab ; 42(3): 278-284, 2017 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-28177749

RESUMO

Studies of physical activity behaviours have increasingly shown the importance of heritable factors such as genetic variation. Nonsynonymous polymorphisms of alpha-actinin 3 (ACTN3) and the ß-adrenergic receptors 1 and 3 (ADRB1 and ADRB3) have been previously associated with exercise capacity and cardiometabolic health. We thus hypothesized that these polymorphisms are also related to physical activity behaviours in young adults. To test this hypothesis we examined relationships between ACTN3 (R577X), ARDB1 (Arg389Gly), ADRB3 (Trp64Arg), and physical activity behaviours in university students. We stratified for student enrollment in kinesiology degree programs compared with nonmajors as we previously found this to be a predictor of physical activity. We did not identify novel associations between physical activity and ACTN3. However, the minor alleles of ADRB1 and ADRB3 were significantly underrepresented in kinesiology students compared with nonmajors. Furthermore, carriers of the ADRB1 minor allele reported reduced participation in moderate physical activity and increased afternoon fatigue compared with ancestral allele homozygotes. Together, these findings suggest that the heritability of physical activity behaviours in young adults may be linked to nonsynonymous polymorphisms within ß-adrenergic receptors.


Assuntos
Actinina/genética , Exercício Físico , Comportamentos Relacionados com a Saúde , Cinesiologia Aplicada/educação , Receptores Adrenérgicos beta 1/genética , Receptores Adrenérgicos beta 3/genética , Adolescente , Adulto , Alelos , Glicemia/metabolismo , Colesterol/sangue , Estudos de Coortes , Dieta , Feminino , Loci Gênicos , Marcadores Genéticos , Técnicas de Genotipagem , Hemoglobinas Glicadas/metabolismo , Humanos , Masculino , Síndrome Metabólica/sangue , Síndrome Metabólica/diagnóstico , Síndrome Metabólica/genética , Polimorfismo de Nucleotídeo Único , Estudantes , Inquéritos e Questionários , Triglicerídeos/sangue , Adulto Jovem
16.
Diabetes ; 54(5): 1283-8, 2005 May.
Artigo em Inglês | MEDLINE | ID: mdl-15855311

RESUMO

Obesity-related diseases such as the metabolic syndrome and type 2 diabetes originate, in part, from the progressive metabolic deterioration of skeletal muscle. A preliminary proteomic survey of rectus abdominus muscle detected a statistically significant increase in adenylate kinase (AK)1, glyceraldehyde-3-phosphate dehydrogenase (GAPDH), and aldolase A in obese/overweight and morbidly obese women relative to lean control subjects. AK1 is essential for the maintenance of cellular energy charge, and GAPDH and aldolase A are well known glycolytic enzymes. We found that muscle AK1 protein and enzymatic activity increased 2.9 and 90%, respectively, in obese women and 9.25 and 100%, respectively, in morbidly obese women. The total enzymatic activity of creatine kinase, which also regulates energy metabolism in muscle, was shown to increase 30% in obese/overweight women only. We propose that increased protein and enzymatic activity of AK1 is representative of a compensatory glycolytic drift to counteract reduced muscle mitochondrial function with the progression of obesity. This hypothesis is supported by increased abundance of the glycolytic enzymes GAPDH and aldolase A in obese and morbidly obese muscle. In summary, proteome analysis of muscle has helped us better describe the molecular etiology of obesity-related disease.


Assuntos
Proteínas Musculares/metabolismo , Obesidade Mórbida/metabolismo , Obesidade/metabolismo , Proteoma , Adenilato Quinase/metabolismo , Índice de Massa Corporal , Creatina Quinase/metabolismo , Digitonina , Eletroforese em Gel Bidimensional , Feminino , Humanos , Pessoa de Meia-Idade , Espectrometria de Massas por Ionização e Dessorção a Laser Assistida por Matriz
17.
Mol Autism ; 7(1): 37, 2016.
Artigo em Inglês | MEDLINE | ID: mdl-27594980

RESUMO

BACKGROUND: Gastrointestinal dysfunction and gut microbial composition disturbances have been widely reported in autism spectrum disorder (ASD). This study examines whether gut microbiome disturbances are present in the BTBR(T + tf/j) (BTBR) mouse model of ASD and if the ketogenic diet, a diet previously shown to elicit therapeutic benefit in this mouse model, is capable of altering the profile. FINDINGS: Juvenile male C57BL/6 (B6) and BTBR mice were fed a standard chow (CH, 13 % kcal fat) or ketogenic diet (KD, 75 % kcal fat) for 10-14 days. Following diets, fecal and cecal samples were collected for analysis. Main findings are as follows: (1) gut microbiota compositions of cecal and fecal samples were altered in BTBR compared to control mice, indicating that this model may be of utility in understanding gut-brain interactions in ASD; (2) KD consumption caused an anti-microbial-like effect by significantly decreasing total host bacterial abundance in cecal and fecal matter; (3) specific to BTBR animals, the KD counteracted the common ASD phenotype of a low Firmicutes to Bacteroidetes ratio in both sample types; and (4) the KD reversed elevated Akkermansia muciniphila content in the cecal and fecal matter of BTBR animals. CONCLUSIONS: Results indicate that consumption of a KD likely triggers reductions in total gut microbial counts and compositional remodeling in the BTBR mouse. These findings may explain, in part, the ability of a KD to mitigate some of the neurological symptoms associated with ASD in an animal model.


Assuntos
Transtorno do Espectro Autista/microbiologia , Dieta Cetogênica , Microbioma Gastrointestinal , Animais , Bactérias/isolamento & purificação , Comportamento Animal , Ceco/microbiologia , Modelos Animais de Doenças , Fezes/microbiologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Comportamento Social
18.
Front Physiol ; 7: 654, 2016.
Artigo em Inglês | MEDLINE | ID: mdl-28082920

RESUMO

The ketogenic diet (KD) has been utilized as a dietary therapeutic for nearly a century. One experimental model particularly responsive to the KD is the BTBRT+tf/j (BTBR) mouse, which displays phenotypic characteristics of autism spectrum disorder (ASD) and insulin resistance. Recently, the study of impaired mitochondrial function has become a focal point of research investigating the pathophysiology of ASD. As highly dynamic organelles, mitochondria undergo constant fluctuations in morphology, biogenesis, and quality control in order to maintain cellular homeostasis. An important modifier of mitochondrial dynamics is energy availability. Therefore, the aim of this study was to examine the impact of a KD on mitochondrial dynamics in the liver and brain (prefrontal cortex) of the BTBR mouse model of ASD. Juvenile male C57Bl/6 (B6) and BTBR mice were age-matched to 5 weeks of age before being fed standard chow (CD, 13% kcal fat) or a KD (75% kcal fat) for 10-14 days. Analysis of brain tissue identified differences in mitochondrial gene expression but no correlation with protein levels. Unlike in the brain, KD led to decreased levels of mitochondrial proteins in the liver, despite increased gene expression. Consistent with decreased mitochondrial proteins, we also observed decreased mtDNA for all mice on the KD, demonstrating that the KD reduces the total amount of mitochondria in the liver. In order to explain the discrepancy between protein levels and gene expression, we investigated whether mitochondrial turnover via mitophagy was increased. To this end, we examined expression levels of the mitophagy regulator BNIP3 (BCL2/adenovirus E1B 19 kd-interacting protein 3). BNIP3 gene and protein expression were significantly elevated in liver of KD animals (p < 0.05), indicating the potential activation of mitophagy. Therefore, consumption of a KD exerts highly tissue-specific effects, ultimately increasing mitochondrial turnover in the liver, while gene and protein expression in the brain remaining tightly regulated.

19.
J Appl Physiol (1985) ; 98(1): 168-79, 2005 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-15347626

RESUMO

Aerobic conditioned muscle shows increased oxidative metabolism or glucose relative to untrained muscle at a given absolute exercise intensity. The studies of a targeted risk reduction intervention through defined exercise (STRRIDE) study is an aerobic exercise intervention in men and women with features of metabolic syndrome (Kraus WE, Torgan CE, Duscha BD, Norris J, Brown SA, Cobb FR, Bales CW, Annex BH, Samsa GP, Houmard JA, and Slentz CA, Med Sci Sports Exerc 33: 1774-1784, 2001), with four muscle biopsies taken during training and detraining time points. Here, we expanded a previous study (Hittel DS, Kraus WE, and Hoffman EP, J Physiol 548: 401-410, 2003) and used mRNA profiling to investigate gene transcripts associated with energy and substrate metabolism in STRRIDE participants. We found coordinate regulation of key metabolic enzymes with aerobic training in metabolic syndrome (aspartate aminotransferase 1, lactate dehydrogenase B, and pyruvate dehydrogenase-alpha(1)). All were also quickly downregulated by detraining, although the induction was not an acute response to activity. Protein and enzymatic assays were used to validate mRNA induction with aerobic training and loss with detraining (96 h to 2 wk) in 10 male and 10 female STRRIDE subjects. We propose that training coordinately increases the levels of aspartate aminotransferase 1, lactate dehydrogenase B, and pyruvate dehydrogenase-alpha(1) subunit, increasing glucose metabolism in muscle by liberating pyruvate for oxidative metabolism and, therefore, limiting lactate efflux. Serial measurement of fasting plasma lactate from 62 subjects from the same exercise group demonstrated a significant decrease of circulating lactate with training. We also found evidence for sex-specific molecular remodeling of muscle with ubiquinol-cytochrome c reductase core protein II, a component of mitochondrial respiratory complex III, which showed an increase after training that was specific to women. These biochemical adaptations complement existing molecular models for improved glucose tolerance with exercise intervention in prediabetic individuals.


Assuntos
Glicemia/análise , Exercício Físico , Ácido Láctico/sangue , Síndrome Metabólica/fisiopatologia , Proteínas Musculares/metabolismo , Músculo Esquelético/fisiopatologia , Obesidade/fisiopatologia , Oxirredutases/metabolismo , Adulto , Feminino , Regulação da Expressão Gênica , Humanos , Masculino , Síndrome Metabólica/genética , Pessoa de Meia-Idade , Proteínas Musculares/genética , Obesidade/genética , Oxirredutases/genética , Fatores Sexuais
20.
PLoS One ; 10(6): e0130644, 2015.
Artigo em Inglês | MEDLINE | ID: mdl-26107372

RESUMO

Homozygosity for a premature stop codon (X) in the ACTN3 "sprinter" gene is common in humans despite the fact that it reduces muscle size, strength and power. Because of the close relationship between skeletal muscle function and cardiometabolic health we examined the influence of ACTN3 R577X polymorphism over cardiovascular and metabolic characteristics of young adults (n = 98 males, n = 102 females; 23 ± 4.2 years) from our Assessing Inherent Markers for Metabolic syndrome in the Young (AIMMY) study. Both males and females with the RR vs XX genotype achieved higher mean VO2 peak scores (47.8 ± 1.5 vs 43.2 ±1.8 ml/O2/min, p = 0.002) and exhibited higher resting systolic (115 ± 2 vs 105 ± mmHg, p = 0.027) and diastolic (69 ± 3 vs 59 ± 3 mmHg, p = 0.005) blood pressure suggesting a role for ACTN3 in the maintenance of vascular tone. We subsequently identified the expression of alpha-actinin 3 protein in pulmonary artery smooth muscle, which may explain the genotype-specific differences in cardiovascular adaptation to acute exercise. In addition, we utilized targeted serum metabolomics to distinguish between RR and XX genotypes, suggesting an additional role for the ACTN3 R577X polymorphism in human metabolism. Taken together, these results identify significant cardiometabolic effects associated with possessing one or more functional copies of the ACTN3 gene.


Assuntos
Actinina/genética , Desempenho Atlético/fisiologia , Músculo Liso/fisiologia , Resistência Física/genética , Polimorfismo de Nucleotídeo Único , Actinina/metabolismo , Adulto , Pressão Sanguínea/fisiologia , Exercício Físico/fisiologia , Feminino , Expressão Gênica , Genótipo , Humanos , Masculino , Contração Muscular/fisiologia , Músculo Esquelético/fisiologia , Artéria Pulmonar/fisiologia , Testes de Função Respiratória
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