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1.
J Endocr Soc ; 6(9): bvac111, 2022 Sep 01.
Artículo en Inglés | MEDLINE | ID: mdl-35935071

RESUMEN

Context and objective: Obesity and inactivity are risk factors for developing impaired glucose tolerance characterized by insulin resistance and reduced beta-cell function. The stimulatory effect of glucagon-like peptide 1 (GLP-1) on insulin secretion is also impaired in obese, inactive individuals. The aim of this study was to investigate whether endurance training influences beta-cell sensitivity to GLP-1. Participants and intervention: Twenty-four female participants, age 46 ±â€…2 years, body mass index 32.4 ±â€…0.9 kg/m2, and maximal oxygen consumption 24.7 ±â€…0.8 mL/kg/min participated in a 10-week exercise training study. Methods: Beta-cell sensitivity to GLP-1 was assessed in a subset of participants (n = 6) during a 120-minute hyperglycemic glucose clamp (8.5 mM) including a 1-hour GLP-1 (7-36 amide) infusion (0.4 pmol/kg/min). Changes in glucose tolerance, body composition, and cardiorespiratory fitness were assessed by oral glucose tolerance tests (OGTTs), dual-energy X-ray absorptiometry scans, magnetic resonance scans, and maximal oxygen consumption (VO2max) tests, respectively. Results: The c-peptide response to infusion of GLP-1 increased 28 ±â€…3% (P < 0.05) toward the end of the hyperglycemic clamp. The insulin response remained unchanged. Training improved glucose tolerance and reduced GLP-1, insulin, and glucagon levels during the OGTTs. Training increased VO2max (from 24.7 ±â€…0.8 to 27.0 ±â€…0.7 mL/kg/min; P < 0.05) and reduced visceral fat volume (from 4176 ±â€…265 to 3888 ±â€…266 cm3; P < 0.01). Conclusion: Along with improved glycemic control, endurance training improved beta-cell sensitivity to GLP-1 in overweight women. The study was deemed not to constitute a clinical trial and was not registered as such.

2.
J Diabetes Res ; 2020: 9626398, 2020.
Artículo en Inglés | MEDLINE | ID: mdl-32832565

RESUMEN

INTRODUCTION: Current clinical guidelines for management of diabetic peripheral neuropathy (DPN) emphasize good glycemic control. However, this has limited effect on prevention of DPN in type 2 diabetic (T2D) patients. This study investigates the effect of insulin treatment on development of DPN in a rat model of T2D to assess the underlying causes leading to DPN. METHODS: Twelve-week-old male Sprague-Dawley rats were allocated to a normal chow diet or a 45% kcal high-fat diet. After eight weeks, the high-fat fed animals received a mild dose of streptozotocin to induce hyperglycemia. Four weeks after diabetes induction, the diabetic animals were allocated into three treatment groups receiving either no insulin or insulin-releasing implants in a high or low dose. During the 12-week treatment period, blood glucose and body weight were monitored weekly, whereas Hargreaves' test was performed four, eight, and 12 weeks after treatment initiation. At study termination, several blood parameters, body composition, and neuropathy endpoints were assessed. RESULTS: Insulin treatment lowered blood glucose in a dose-dependent manner. In addition, both doses of insulin lowered lipids and increased body fat percentage. High-dose insulin treatment attenuated small nerve fiber damage assessed by Hargreaves' test and intraepidermal nerve fiber density compared to untreated diabetes and low-dose insulin; however, neuropathy was not completely prevented by tight glycemic control. Linear regression analysis revealed that glycemic status, circulating lipids, and sciatic nerve sorbitol level were all negatively associated with the small nerve fiber damage observed. CONCLUSION: In summary, our data suggest that high-dose insulin treatment attenuates small nerve fiber damage. Furthermore, data also indicate that both poor glycemic control and dyslipidemia are associated with disease progression. Consequently, this rat model of T2D seems to fit well with progression of DPN in humans and could be a relevant preclinical model to use in relation to research investigating treatment opportunities for DPN.


Asunto(s)
Diabetes Mellitus Experimental/tratamiento farmacológico , Neuropatías Diabéticas/prevención & control , Insulina/uso terapéutico , Neuropatía de Fibras Pequeñas/prevención & control , Animales , Glucemia/efectos de los fármacos , Glucemia/metabolismo , Diabetes Mellitus Experimental/complicaciones , Diabetes Mellitus Experimental/patología , Diabetes Mellitus Tipo 2/complicaciones , Diabetes Mellitus Tipo 2/tratamiento farmacológico , Diabetes Mellitus Tipo 2/patología , Dieta Alta en Grasa , Progresión de la Enfermedad , Humanos , Masculino , Fibras Nerviosas/efectos de los fármacos , Fibras Nerviosas/fisiología , Obesidad/complicaciones , Obesidad/tratamiento farmacológico , Obesidad/patología , Ratas , Ratas Sprague-Dawley , Nervio Ciático/efectos de los fármacos , Nervio Ciático/fisiología
4.
Microcirculation ; 27(2): e12593, 2020 02.
Artículo en Inglés | MEDLINE | ID: mdl-31605649

RESUMEN

OBJECTIVE: The effect of insulin on blood flow distribution within muscle microvasculature has been suggested to be important for glucose metabolism. However, the "capillary recruitment" hypothesis is still controversial and relies on studies using indirect contrast-enhanced ultrasound (CEU) methods. METHODS: We studied how hyperinsulinemia effects capillary blood flow in rat extensor digitorum longus (EDL) muscle during euglycemic hyperinsulinemic clamp using intravital video microscopy (IVVM). Additionally, we modeled blood flow and microbubble distribution within the vascular tree under conditions observed during euglycemic hyperinsulinemic clamp experiments. RESULTS: Euglycemic hyperinsulinemia caused an increase in erythrocyte (80 ± 25%, P < .01) and plasma (53 ± 12%, P < .01) flow in rat EDL microvasculature. We found no evidence of de novo capillary recruitment within, or among, capillary networks supplied by different terminal arterioles; however, erythrocyte flow became slightly more homogenous. Our computational model predicts that a decrease in asymmetry at arteriolar bifurcations causes redistribution of microbubble flow among capillaries already perfused with erythrocytes and plasma, resulting in 25% more microbubbles flowing through capillaries. CONCLUSIONS: Our model suggests increase in CEU signal during hyperinsulinemia reflects a redistribution of arteriolar flow and not de novo capillary recruitment. IVVM experiments support this prediction showing increases in erythrocyte and plasma flow and not capillary recruitment.


Asunto(s)
Capilares , Hiperinsulinismo , Microcirculación , Músculo Esquelético , Animales , Capilares/metabolismo , Capilares/fisiopatología , Hiperinsulinismo/metabolismo , Hiperinsulinismo/fisiopatología , Masculino , Músculo Esquelético/irrigación sanguínea , Músculo Esquelético/fisiopatología , Ratas , Ratas Sprague-Dawley
5.
J Physiol ; 595(16): 5557-5571, 2017 08 15.
Artículo en Inglés | MEDLINE | ID: mdl-28620941

RESUMEN

KEY POINTS: Mechanotransduction in endothelial cells is a central mechanism in the regulation of vascular tone and vascular remodelling Mechanotransduction and vascular function may be affected by high sugar levels in plasma because of a resulting increase in oxidative stress and increased levels of advanced glycation end-products (AGE). In healthy young subjects, 2 weeks of daily supplementation with 3 × 75 g of sucrose was found to reduce blood flow in response to passive lower leg movement and in response to 12 W of knee extensor exercise. This vascular impairment was paralleled by up-regulation of platelet endothelial cell adhesion molecule (PECAM)-1, endothelial nitric oxide synthase, NADPH oxidase and Rho family GTPase Rac1 protein expression, an increased basal phosphorylation status of vascular endothelial growth factor receptor 2 and a reduced phosphorylation status of PECAM-1. There were no measurable changes in AGE levels. The findings of the present study demonstrate that daily high sucrose intake markedly affects mechanotransduction proteins and has a detrimental effect on vascular function. ABSTRACT: Endothelial mechanotransduction is important for vascular function but alterations and activation of vascular mechanosensory proteins have not been investigated in humans. In endothelial cell culture, simple sugars effectively impair mechanosensor proteins. To study mechanosensor- and vascular function in humans, 12 young healthy male subjects supplemented their diet with 3 × 75 g sucrose day-1 for 14 days in a randomized cross-over design. Before and after the intervention period, the hyperaemic response to passive lower leg movement and active knee extensor exercise was determined by ultrasound doppler. A muscle biopsy was obtained from the thigh muscle before and after acute passive leg movement to allow assessment of protein amounts and the phosphorylation status of mechanosensory proteins and NADPH oxidase. The sucrose intervention led to a reduced flow response to passive movement (by 17 ± 2%) and to 12 W of active exercise (by 9 ± 1%), indicating impaired vascular function. A reduced flow response to passive and active exercise was paralleled by a significant up-regulation of platelet endothelial cell adhesion molecule (PECAM-1), endothelial nitric oxide synthase, NADPH oxidase and the Rho family GTPase Rac1 protein expression in the muscle tissue, as well as an increased basal phosphorylation status of vascular endothelial growth factor receptor 2 and a reduced phosphorylation status of PECAM-1. The phosphorylation status was not acutely altered with passive leg movement. These findings indicate that a regular intake of high levels of sucrose can impair vascular mechanotransduction and increase the oxidative stress potential, and suggest that dietary excessive sugar intake may contribute to the development of vascular disease.


Asunto(s)
Sacarosa en la Dieta/farmacología , Adulto , Antígenos CD/fisiología , Cadherinas/fisiología , Estudios Cruzados , Epoprostenol/fisiología , Ejercicio Físico/fisiología , Arteria Femoral/fisiología , Productos Finales de Glicación Avanzada/sangre , Humanos , Pierna/fisiología , Masculino , Músculo Esquelético/citología , Músculo Esquelético/fisiología , Óxido Nítrico Sintasa de Tipo III/fisiología , Óxidos de Nitrógeno/sangre , Fosforilación , ARN Mensajero/metabolismo , Receptor para Productos Finales de Glicación Avanzada/sangre , Flujo Sanguíneo Regional , Transducción de Señal , Receptor 2 de Factores de Crecimiento Endotelial Vascular/fisiología , Adulto Joven
6.
Sci Transl Med ; 8(334): 334ra54, 2016 Apr 13.
Artículo en Inglés | MEDLINE | ID: mdl-27075628

RESUMEN

Impaired estrogen receptor α (ERα) action promotes obesity and metabolic dysfunction in humans and mice; however, the mechanisms underlying these phenotypes remain unknown. Considering that skeletal muscle is a primary tissue responsible for glucose disposal and oxidative metabolism, we established that reduced ERα expression in muscle is associated with glucose intolerance and adiposity in women and female mice. To test this relationship, we generated muscle-specific ERα knockout (MERKO) mice. Impaired glucose homeostasis and increased adiposity were paralleled by diminished muscle oxidative metabolism and bioactive lipid accumulation in MERKO mice. Aberrant mitochondrial morphology, overproduction of reactive oxygen species, and impairment in basal and stress-induced mitochondrial fission dynamics, driven by imbalanced protein kinase A-regulator of calcineurin 1-calcineurin signaling through dynamin-related protein 1, tracked with reduced oxidative metabolism in MERKO muscle. Although muscle mitochondrial DNA (mtDNA) abundance was similar between the genotypes, ERα deficiency diminished mtDNA turnover by a balanced reduction in mtDNA replication and degradation. Our findings indicate the retention of dysfunctional mitochondria in MERKO muscle and implicate ERα in the preservation of mitochondrial health and insulin sensitivity as a defense against metabolic disease in women.


Asunto(s)
Receptor alfa de Estrógeno/metabolismo , Homeostasis/efectos de los fármacos , Mitocondrias Musculares/metabolismo , Músculo Esquelético/metabolismo , Animales , Autofagia/efectos de los fármacos , Proteínas de Unión al Calcio , Replicación del ADN/efectos de los fármacos , ADN Mitocondrial/genética , Dinaminas/metabolismo , Femenino , Eliminación de Gen , Glucosa/metabolismo , Humanos , Insulina/farmacología , Péptidos y Proteínas de Señalización Intracelular/metabolismo , Metabolismo de los Lípidos/efectos de los fármacos , Ratones , Ratones Noqueados , Mitocondrias Musculares/efectos de los fármacos , Dinámicas Mitocondriales/efectos de los fármacos , Proteínas Musculares/metabolismo , Músculo Esquelético/efectos de los fármacos , Especificidad de Órganos/efectos de los fármacos , Oxidación-Reducción/efectos de los fármacos , Estrés Oxidativo/efectos de los fármacos , Especies Reactivas de Oxígeno/metabolismo , Transducción de Señal/efectos de los fármacos
8.
Biochem Biophys Rep ; 4: 342-350, 2015 Dec.
Artículo en Inglés | MEDLINE | ID: mdl-29124223

RESUMEN

Transfection of rat skeletal muscle in vivo is a widely used research model. However, gene electrotransfer protocols have been developed for mice and yield variable results in rats. We investigated whether changes in hyaluronidase pre-treatment and plasmid DNA delivery can improve transfection efficiency in rat skeletal muscle. We found that pre-treating the muscle with a hyaluronidase dose suitable for rats (0.56 U/g b.w.) prior to plasmid DNA injection increased transfection efficiency by >200% whereas timing of the pre-treatment did not affect efficiency. Uniformly distributing plasmid DNA delivery across the muscle by increasing the number of plasmid DNA injections further enhanced transfection efficiency whereas increasing plasmid dose from 0.2 to 1.6 µg/g b.w. or vehicle volume had no effect. The optimized protocol resulted in ~80% (CI95%: 79-84%) transfected muscle fibers with a homogenous distribution. We also show that transfection was stable over five weeks of regular exercise or inactivity. Our findings show that species-specific plasmid DNA delivery and hyaluronidase pre-treatment greatly improves transfection efficiency in rat skeletal muscle.

9.
Am J Physiol Endocrinol Metab ; 307(12): E1105-16, 2014 Dec 15.
Artículo en Inglés | MEDLINE | ID: mdl-25352432

RESUMEN

Increased skeletal muscle capillarization is associated with improved glucose tolerance and insulin sensitivity. However, a possible causal relationship has not previously been identified. Therefore, we investigated whether increased skeletal muscle capillarization increases insulin sensitivity. Skeletal muscle-specific angiogenesis was induced by adding the α1-adrenergic receptor antagonist prazosin to the drinking water of Sprague-Dawley rats (n = 33), whereas 34 rats served as controls. Insulin sensitivity was measured ≥40 h after termination of the 3-wk prazosin treatment, which ensured that prazosin was cleared from the blood stream. Whole body insulin sensitivity was measured in conscious, unrestrained rats by hyperinsulinemic euglycemic clamp. Tissue-specific insulin sensitivity was assessed by administration of 2-deoxy-[(3)H]glucose during the plateau phase of the clamp. Whole body insulin sensitivity increased by ∼24%, and insulin-stimulated skeletal muscle 2-deoxy-[(3)H]glucose disposal increased by ∼30% concomitant with an ∼20% increase in skeletal muscle capillarization. Adipose tissue insulin sensitivity was not affected by the treatment. Insulin-stimulated muscle glucose uptake was enhanced independent of improvements in skeletal muscle insulin signaling to glucose uptake and glycogen synthesis, suggesting that the improvement in insulin-stimulated muscle glucose uptake could be due to improved diffusion conditions for glucose in the muscle. The prazosin treatment did not affect the rats on any other parameters measured. We conclude that an increase in skeletal muscle capillarization is associated with increased insulin sensitivity. These data point toward the importance of increasing skeletal muscle capillarization for prevention or treatment of type 2 diabetes.


Asunto(s)
Resistencia a la Insulina , Músculo Esquelético/irrigación sanguínea , Músculo Esquelético/metabolismo , Animales , Antihipertensivos/farmacología , Glucosa/metabolismo , Técnica de Clampeo de la Glucosa , Insulina/farmacología , Masculino , Microcirculación/efectos de los fármacos , Músculo Esquelético/efectos de los fármacos , Prazosina/farmacología , Ratas , Ratas Sprague-Dawley , Regulación hacia Arriba
10.
Am J Physiol Heart Circ Physiol ; 307(8): H1111-9, 2014 Oct 15.
Artículo en Inglés | MEDLINE | ID: mdl-25128170

RESUMEN

In animal studies, the polyphenol resveratrol has been shown to influence several pathways of importance for angiogenesis in skeletal muscle. The aim of the present study was to examine the angiogenic effect of resveratrol supplementation with parallel exercise training in aged men. Forty-three healthy physically inactive aged men (65 ± 1 yr) were divided into 1) a training group that conducted 8 wk of intense exercise training where half of the subjects received a daily intake of either 250 mg trans-resveratrol (n = 14) and the other half received placebo (n = 13) and 2) a nontraining group that received either 250 mg trans-resveratrol (n = 9) or placebo (n = 7). The group that trained with placebo showed a ~20% increase in the capillary-to-fiber ratio, an increase in muscle protein expression of VEGF, VEGF receptor-2, and tissue inhibitor of matrix metalloproteinase (TIMP-1) but unaltered thrombospodin-1 levels. Muscle interstitial VEGF and thrombospodin-1 protein levels were unchanged after the training period. The group that trained with resveratrol supplementation did not show an increase in the capillary-to-fiber ratio or an increase in muscle VEGF protein. Muscle TIMP-1 protein levels were lower in the training and resveratrol group than in the training and placebo group. Both training groups showed an increase in forkhead box O1 protein. In nontraining groups, TIMP-1 protein was lower in the resveratrol-treated group than the placebo-treated group after 8 wk. In conclusion, these data show that exercise training has a strong angiogenic effect, whereas resveratrol supplementation may limit basal and training-induced angiogenesis.


Asunto(s)
Ejercicio Físico , Músculo Esquelético/fisiología , Neovascularización Fisiológica , Estilbenos/farmacología , Anciano , Estudios de Casos y Controles , Suplementos Dietéticos , Proteína Forkhead Box O1 , Factores de Transcripción Forkhead/genética , Factores de Transcripción Forkhead/metabolismo , Humanos , Masculino , Persona de Mediana Edad , Músculo Esquelético/irrigación sanguínea , Músculo Esquelético/efectos de los fármacos , Músculo Esquelético/metabolismo , Resveratrol , Estilbenos/administración & dosificación , Trombospondina 1/genética , Trombospondina 1/metabolismo , Inhibidor Tisular de Metaloproteinasa-1/genética , Inhibidor Tisular de Metaloproteinasa-1/metabolismo , Factor A de Crecimiento Endotelial Vascular/genética , Factor A de Crecimiento Endotelial Vascular/metabolismo , Receptor 2 de Factores de Crecimiento Endotelial Vascular/genética , Receptor 2 de Factores de Crecimiento Endotelial Vascular/metabolismo
11.
PLoS One ; 9(2): e87308, 2014.
Artículo en Inglés | MEDLINE | ID: mdl-24586268

RESUMEN

MiRNAs are potent intracellular posttranscriptional regulators and are also selectively secreted into the circulation in a cell-specific fashion. Global changes in miRNA expression in skeletal muscle in response to endurance exercise training have been reported. Therefore, our aim was to establish the miRNA signature in human plasma in response to acute exercise and chronic endurance training by utilizing a novel methodological approach. RNA was isolated from human plasma collected from young healthy men before and after an acute endurance exercise bout and following 12 weeks of endurance training. Global miRNA (742 miRNAs) measurements were performed as a screening to identify detectable miRNAs in plasma. Using customized qPCR panels we quantified the expression levels of miRNAs detected in the screening procedure (188 miRNAs). We demonstrate a dynamic regulation of circulating miRNA (ci-miRNA) levels following 0 hour (miR-106a, miR-221, miR-30b, miR-151-5p, let-7i, miR-146, miR-652 and miR-151-3p), 1 hour (miR-338-3p, miR-330-3p, miR-223, miR-139-5p and miR-143) and 3 hours (miR-1) after an acute exercise bout (P<0.00032). Where ci-miRNAs were all downregulated immediately after an acute exercise bout (0 hour) the 1 and 3 hour post exercise timepoints were followed by upregulations. In response to chronic training, we identified seven ci-miRNAs with decreased levels in plasma (miR-342-3p, let-7d, miR-766, miR-25, miR-148a, miR-185 and miR-21) and two miRNAs that were present at higher levels after the training period (miR-103 and miR-107) (P<0.00032). In conclusion, acute exercise and chronic endurance training, likely through specific mechanisms unique to each stimulus, robustly modify the miRNA signature of human plasma.


Asunto(s)
Ejercicio Físico/fisiología , MicroARNs/sangre , Resistencia Física/fisiología , Adulto , Regulación hacia Abajo , Humanos , Masculino , MicroARNs/genética , Factores de Tiempo , Regulación hacia Arriba
12.
Endocrine ; 45(2): 271-8, 2014 Mar.
Artículo en Inglés | MEDLINE | ID: mdl-23649460

RESUMEN

Regular endurance exercise promotes metabolic and oxidative changes in skeletal muscle. Overexpression of interleukin-15 (IL-15) in mice exerts similar metabolic changes in muscle as seen with endurance exercise. Muscular IL-15 production has been shown to increase in mice after weeks of regular endurance running. With the present study we aimed to determine if muscular IL-15 production would increase in human male subjects following 12 weeks of endurance training. In two different studies we obtained plasma and muscle biopsies from young healthy subjects performing: (1) 12 weeks of ergometer cycling exercise five times per week with plasma and biopsies before and after the intervention, and (2) 3 h of ergometer cycling exercise with plasma and biopsies before and after the exercise bout and well into recovery. We measured changes in plasma IL-15, muscle IL-15 mRNA and IL-15 protein. Twelve weeks of regular endurance training induced a 40% increase in basal skeletal muscle IL-15 protein content (p < 0.01), but with no changes in either muscle IL-15 mRNA or plasma IL-15 levels. However, an acute bout of 3-h exercise did not show significant changes in muscle IL-15 or plasma IL-15 levels. The induction of muscle IL-15 protein in humans following a regular training period supports previous findings in mice and emphasizes the hypothesis of IL-15 taking part in skeletal muscle adaptation during training.


Asunto(s)
Ejercicio Físico/fisiología , Interleucina-15/metabolismo , Músculo Esquelético/metabolismo , Resistencia Física/fisiología , Regulación hacia Arriba/fisiología , Adaptación Fisiológica/fisiología , Adulto , Biopsia , Prueba de Esfuerzo , Humanos , Masculino , Músculo Esquelético/patología , ARN Mensajero/metabolismo , Factores de Tiempo
13.
J Appl Physiol (1985) ; 112(6): 990-1000, 2012 Mar.
Artículo en Inglés | MEDLINE | ID: mdl-22207723

RESUMEN

Vitamin C and E supplementation has been shown to attenuate the acute exercise-induced increase in plasma interleukin-6 (IL-6) concentration. Here, we studied the effect of antioxidant vitamins on the regulation of IL-6 expression in muscle and the circulation in response to acute exercise before and after high-intensity endurance exercise training. Twenty-one young healthy men were allocated into either a vitamin (VT; vitamin C and E, n = 11) or a placebo (PL, n = 10) group. A 1-h acute bicycling exercise trial at 65% of maximal power output was performed before and after 12 wk of progressive endurance exercise training. In response to training, the acute exercise-induced IL-6 response was attenuated in PL (P < 0.02), but not in VT (P = 0.82). However, no clear difference between groups was observed (group × training: P = 0.13). Endurance exercise training also attenuated the acute exercise-induced increase in muscle-IL-6 mRNA in both groups. Oxidative stress, assessed by plasma protein carbonyls concentration, was overall higher in the VT compared with the PL group (group effect: P < 0.005). This was accompanied by a general increase in skeletal muscle mRNA expression of antioxidative enzymes, including catalase, copper-zinc superoxide dismutase, and glutathione peroxidase 1 mRNA expression in the VT group. However, skeletal muscle protein content of catalase, copper-zinc superoxide dismutase, or glutathione peroxidase 1 was not affected by training or supplementation. In conclusion, our results indicate that, although vitamin C and E supplementation may attenuate exercise-induced increases in plasma IL-6 there is no clear additive effect when combined with endurance training.


Asunto(s)
Ácido Ascórbico/administración & dosificación , Ejercicio Físico/fisiología , Interleucina-6/metabolismo , Resistencia Física/efectos de los fármacos , Resistencia Física/fisiología , Vitamina E/administración & dosificación , Adulto , Antioxidantes/farmacología , Ácido Ascórbico/sangre , Índice de Masa Corporal , Catalasa/metabolismo , Suplementos Dietéticos , Método Doble Ciego , Glutatión Peroxidasa/metabolismo , Humanos , Hidrocortisona/sangre , Hidrocortisona/metabolismo , Proteína Antagonista del Receptor de Interleucina 1/sangre , Proteína Antagonista del Receptor de Interleucina 1/metabolismo , Interleucina-6/sangre , Masculino , Proteínas Musculares/metabolismo , Músculo Esquelético/efectos de los fármacos , Músculo Esquelético/metabolismo , Músculo Esquelético/fisiología , Estrés Oxidativo/efectos de los fármacos , Estrés Oxidativo/fisiología , Superóxido Dismutasa/metabolismo , Vitamina E/sangre , Glutatión Peroxidasa GPX1
14.
Am J Physiol Endocrinol Metab ; 300(5): E761-70, 2011 May.
Artículo en Inglés | MEDLINE | ID: mdl-21325105

RESUMEN

While production of reactive oxygen and nitrogen species (RONS) is associated with some of the beneficial adaptations to regular physical exercise, it is not established whether RONS play a role in the improved insulin-stimulated glucose uptake in skeletal muscle obtained by endurance training. To assess the effect of antioxidant supplementation during endurance training on insulin-stimulated glucose uptake, 21 young healthy (age 29 ± 1 y, BMI 25 ± 3 kg/m(2)) men were randomly assigned to either an antioxidant [AO; 500 mg vitamin C and 400 IU vitamin E (α-tocopherol) daily] or a placebo (PL) group that both underwent a supervised intense endurance-training program 5 times/wk for 12 wk. A 3-h euglycemic-hyperinsulinemic clamp, a maximal oxygen consumption (Vo(2max)) and maximal power output (P(max)) test, and body composition measurements (fat mass, fat-free mass) were performed before and after the training. Muscle biopsies were obtained for determination of the concentration and activity of proteins regulating glucose metabolism. Although plasma levels of vitamin C (P < 0.05) and α-tocopherol (P < 0.05) increased markedly in the AO group, insulin-stimulated glucose uptake increased similarly in both the AO (17.2%, P < 0.05) and the PL (18.9%, P < 0.05) group in response to training. Vo(2max) and P(max) also increased similarly in both groups (time effect, P < 0.0001 for both) as well as protein content of GLUT4, hexokinase II, and total Akt (time effect, P ≤ 0.05 for all). Our results indicate that administration of antioxidants during strenuous endurance training has no effect on the training-induced increase in insulin sensitivity in healthy individuals.


Asunto(s)
Antioxidantes/farmacología , Composición Corporal , Suplementos Dietéticos , Resistencia Física/fisiología , Aptitud Física/fisiología , Absorciometría de Fotón , Adulto , Umbral Anaerobio/efectos de los fármacos , Ácido Ascórbico/farmacología , Western Blotting , Método Doble Ciego , Prueba de Tolerancia a la Glucosa , Humanos , Resistencia a la Insulina/fisiología , Luminiscencia , Masculino , Persona de Mediana Edad , Músculo Esquelético/metabolismo , Oxígeno/sangre , ARN/biosíntesis , ARN/genética , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa , Vitamina E/farmacología , Adulto Joven
15.
J Physiol ; 588(Pt 20): 4029-37, 2010 Oct 15.
Artículo en Inglés | MEDLINE | ID: mdl-20724368

RESUMEN

Muscle specific miRNAs, myomiRs, have been shown to control muscle development in vitro and are differentially expressed at rest in diabetic skeletal muscle. Therefore, we investigated the expression of these myomiRs, including miR-1, miR-133a, miR-133b and miR-206 in muscle biopsies from vastus lateralis of healthy young males (n = 10) in relation to a hyperinsulinaemic­euglycaemic clamp as well as acute endurance exercise before and after 12 weeks of endurance training. The subjects increased their endurance capacity, VO2max (l min−1) by 17.4% (P < 0.001), and improved insulin sensitivity by 19% (P < 0.01). While myomiR expression remained stable during a hyperinsulinaemic­euglycaemic clamp, an acute bout of exercise increased mir-1 (P < 0.05) and mir-133a (P < 0.05) expression before, but not after, training. In resting biopsies, endurance training for 12 weeks decreased basal expression of all four myomiRs (P < 0.05). Interestingly, all myomiRs reverted to their pre-training expression levels 14 days after ceasing the training programme. Components of major pathways involved in endurance adaptation such as MAPK and TGF-ß were predicted to be targeted by the myomiRs examined. Tested predicted target proteins included Cdc42 and ERK 1/2. Although these proteins were downregulated between post-training period and 2 weeks of cessation, an inverse correlation between myomiR and target proteins was not found. In conclusion, our data suggest myomiRs respond to physiological stimuli, but their role in regulating human skeletal muscle adaptation remains unknown.


Asunto(s)
Ejercicio Físico/fisiología , MicroARNs/fisiología , Músculo Esquelético/fisiología , Resistencia Física/fisiología , Adulto , Análisis de Varianza , Western Blotting , Composición Corporal/fisiología , Técnica de Clampeo de la Glucosa , Humanos , Masculino , Consumo de Oxígeno/fisiología , Transducción de Señal/fisiología
16.
J Appl Physiol (1985) ; 108(6): 1487-96, 2010 Jun.
Artículo en Inglés | MEDLINE | ID: mdl-20133430

RESUMEN

A low maximal oxygen consumption (VO2max) is a strong risk factor for premature mortality. Supervised endurance exercise training increases VO2max with a very wide range of effectiveness in humans. Discovering the DNA variants that contribute to this heterogeneity typically requires substantial sample sizes. In the present study, we first use RNA expression profiling to produce a molecular classifier that predicts VO2max training response. We then hypothesized that the classifier genes would harbor DNA variants that contributed to the heterogeneous VO2max response. Two independent preintervention RNA expression data sets were generated (n=41 gene chips) from subjects that underwent supervised endurance training: one identified and the second blindly validated an RNA expression signature that predicted change in VO2max ("predictor" genes). The HERITAGE Family Study (n=473) was used for genotyping. We discovered a 29-RNA signature that predicted VO2max training response on a continuous scale; these genes contained approximately 6 new single-nucleotide polymorphisms associated with gains in VO2max in the HERITAGE Family Study. Three of four novel candidate genes from the HERITAGE Family Study were confirmed as RNA predictor genes (i.e., "reciprocal" RNA validation of a quantitative trait locus genotype), enhancing the performance of the 29-RNA-based predictor. Notably, RNA abundance for the predictor genes was unchanged by exercise training, supporting the idea that expression was preset by genetic variation. Regression analysis yielded a model where 11 single-nucleotide polymorphisms explained 23% of the variance in gains in VO2max, corresponding to approximately 50% of the estimated genetic variance for VO2max. In conclusion, combining RNA profiling with single-gene DNA marker association analysis yields a strongly validated molecular predictor with meaningful explanatory power. VO2max responses to endurance training can be predicted by measuring a approximately 30-gene RNA expression signature in muscle prior to training. The general approach taken could accelerate the discovery of genetic biomarkers, sufficiently discrete for diagnostic purposes, for a range of physiological and pharmacological phenotypes in humans.


Asunto(s)
Proteínas Musculares/genética , Consumo de Oxígeno/genética , Resistencia Física/genética , Esfuerzo Físico/fisiología , Aptitud Física/fisiología , Polimorfismo de Nucleótido Simple/genética , Humanos , Masculino , Fenotipo , Adulto Joven
17.
Med Sci Sports Exerc ; 42(7): 1388-95, 2010 Jul.
Artículo en Inglés | MEDLINE | ID: mdl-20019626

RESUMEN

BACKGROUND: There is a considerable commercial market, especially within the sports community, claiming the need for antioxidant supplementation. One argument for antioxidant supplementation in sports is that physical exercise is associated with increased reactive oxygen and nitrogen species (RONS) production, which may cause cell damage. However, RONS production may also activate redox-sensitive signaling pathways and transcription factors, which subsequently, may promote training adaptation. PURPOSE: Our aim was to investigate the effects of combined vitamin C and E supplementation to healthy individuals on different measures of exercise performance after endurance training. METHODS: Using a double-blinded placebo-controlled design, moderately trained young men received either oral supplementation with vitamins C and E (n = 11) or placebo (n = 10) before and during 12 wk of supervised, strenuous bicycle exercise training of a frequency of 5 d x wk(-1). Muscle biopsies were obtained before and after training. RESULTS: After the training period, maximal oxygen consumption, maximal power output, and workload at lactate threshold increased markedly (P < 0.01) in both groups. Also, glycogen concentration, citrate synthase, and beta-hydroxyacyl-CoA dehydrogenase activity in the muscle were significantly higher in response to training (P < 0.01) in both groups. However, there were no differences between the two groups concerning any of the physiological and metabolic variables measured. CONCLUSIONS: Our results suggest that administration of vitamins C and E to individuals with no previous vitamin deficiencies has no effect on physical adaptations to strenuous endurance training.


Asunto(s)
Antioxidantes/farmacología , Ácido Ascórbico/farmacología , Suplementos Dietéticos , Terapia por Ejercicio , Resistencia Física/efectos de los fármacos , Vitamina E/farmacología , Adaptación Fisiológica/efectos de los fármacos , Adolescente , Adulto , Método Doble Ciego , Prueba de Esfuerzo , Humanos , Masculino , Músculo Esquelético/efectos de los fármacos , Consumo de Oxígeno , Resistencia Física/fisiología , Adulto Joven
18.
Diabetes ; 58(12): 2797-801, 2009 Dec.
Artículo en Inglés | MEDLINE | ID: mdl-19720803

RESUMEN

OBJECTIVE: Fibroblast growth factor-21 (FGF-21) is a potent metabolic regulator, which in animal models has been shown to improve glucose metabolism and insulin sensitivity. Recently, FGF-21 was shown to be expressed and secreted from murine muscle cells in response to insulin stimulation. RESEARCH DESIGN AND METHODS: We studied muscular FGF-21 expression and plasma FGF-21 after acute insulin stimulation in young healthy men during a hyperinsulinemic-euglycemic clamp. Furthermore, we investigated systemic levels and muscle FGF-21 expression in humans with or without insulin resistance and chronic elevated insulin. RESULTS: FGF-21 was barely detectable in young healthy men before insulin infusion. After 3 or 4 h of insulin infusion during a hyperinsulinemic-euglycemic clamp, muscular FGF-21 expression increased significantly. Plasma FGF-21 followed the same pattern. In individuals with chronic elevated insulin, muscular FGF-21 expression was associated with hyperinsulinemia in men but not in women. In plasma, hyperinsulinemia and fasting glucose were positively associated with plasma FGF-21 while plasma FGF-21 correlated negatively with HDL cholesterol. No associations between muscle and plasma FGF-21 were found in the individuals with chronic hyperinsulinemia. CONCLUSIONS: FGF-21 is expressed in human skeletal muscle in response to insulin stimulation, suggesting that FGF-21 is an insulin-regulated myokine. In support, we found an association between chronic hyperinsulinemia and levels of FGF-21.


Asunto(s)
Glucemia/metabolismo , Diabetes Mellitus Tipo 2/metabolismo , Factores de Crecimiento de Fibroblastos/metabolismo , Hiperinsulinismo/metabolismo , Resistencia a la Insulina , Insulina/metabolismo , Músculo Esquelético/metabolismo , Enfermedad Aguda , Biopsia , Diabetes Mellitus Tipo 2/sangre , Ensayo de Inmunoadsorción Enzimática , Ayuno , Femenino , Factores de Crecimiento de Fibroblastos/sangre , Humanos , Hiperinsulinismo/sangre , Insulina/administración & dosificación , Insulina/sangre , Modelos Lineales , Masculino , Reacción en Cadena de la Polimerasa , Adulto Joven
19.
Exp Physiol ; 94(11): 1124-31, 2009 Nov.
Artículo en Inglés | MEDLINE | ID: mdl-19592412

RESUMEN

Glucose ingestion during exercise attenuates the release of the myokine interleukin-6 (IL-6) from working skeletal muscle, which results in a diminished increase in plasma IL-6. Interleukin-6 receptor alpha (IL-6Ralpha) expression in skeletal muscle is induced by acute exercise, mediated in part by an increased IL-6 concentration in the bloodstream. We hypothesized that endurance training would increase the density of IL-6Ralpha in skeletal muscle and that glucose ingestion would attenuate the effect. Nine subjects performed 10 weeks of one-legged knee-extensor training. They trained one leg (Glc-leg) while ingesting a glucose solution (Glc) and ingested a placebo (Plc) while training the other leg (Plc-leg). Endurance training increased peak power by 14% and reduced the exercise-induced gene expression of IL-6 and IL-6Ralpha in skeletal muscle and IL-6 plasma concentration. The IL-6Ralpha density increased to a lesser extent in the Glc-leg, suggesting that glucose ingestion attenuates the effect of training on IL-6Ralpha by blunting the IL-6 response. We conclude that glucose ingestion during endurance training attenuates the increase in IL-6Ralpha density.


Asunto(s)
Glucosa/farmacología , Subunidad alfa del Receptor de Interleucina-6/biosíntesis , Resistencia Física/fisiología , Aptitud Física/fisiología , Adaptación Fisiológica/fisiología , Adulto , Ciclismo/fisiología , Western Blotting , Humanos , Interleucina-6/sangre , Subunidad alfa del Receptor de Interleucina-6/genética , Masculino , Músculo Esquelético/metabolismo , ARN Mensajero/biosíntesis , ARN Mensajero/genética , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa , Adulto Joven
20.
J Appl Physiol (1985) ; 106(6): 1771-9, 2009 Jun.
Artículo en Inglés | MEDLINE | ID: mdl-19228984

RESUMEN

Glucose ingestion during exercise attenuates activation of metabolic enzymes and expression of important transport proteins. In light of this, we hypothesized that glucose ingestion during training would result in 1) an attenuation of the increase in fatty acid uptake and oxidation during exercise, 2) lower citrate synthase (CS) and beta-hydroxyacyl-CoA dehydrogenase (beta-HAD) activity and glycogen content in skeletal muscle, and 3) attenuated endurance performance enhancement in the trained state. To investigate this we studied nine male subjects who performed 10 wk of one-legged knee extensor training. They trained one leg while ingesting a 6% glucose solution (Glc) and ingested a sweetened placebo while training the other leg (Plc). The subjects trained their respective legs 2 h at a time on alternate days 5 days a week. Endurance training increased peak power (P(max)) and time to fatigue at 70% of P(max) approximately 14% and approximately 30%, respectively. CS and beta-HAD activity increased and glycogen content was greater after training, but there were no differences between Glc and Plc. After training the rate of oxidation of palmitate (R(ox)) and the % of rate of disappearance that was oxidized (%R(dox)) changed. %R(dox) was on average 16.4% greater during exercise after training whereas, after exercise %R(dox) was 30.4% lower. R(ox) followed the same pattern. However, none of these parameters were different between Glc and Plc. We conclude that glucose ingestion during training does not alter training adaptation related to substrate metabolism, mitochondrial enzyme activity, glycogen content, or performance.


Asunto(s)
Adaptación Fisiológica/efectos de los fármacos , Metabolismo Energético/efectos de los fármacos , Glucosa/administración & dosificación , Resistencia Física/efectos de los fármacos , 3-Hidroxiacil-CoA Deshidrogenasas/metabolismo , Adaptación Fisiológica/fisiología , Adulto , Citrato (si)-Sintasa/metabolismo , Prueba de Esfuerzo , Fatiga , Glucógeno/metabolismo , Humanos , Masculino , Oxidación-Reducción , Palmitatos/metabolismo , Resistencia Física/fisiología , Músculo Cuádriceps/anatomía & histología , Músculo Cuádriceps/efectos de los fármacos , Músculo Cuádriceps/metabolismo
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