Binding of digoxin to slow- and fast-twitch skeletal muscle fibres

We have found previously great interindividual variations in the binding of digoxin to skeletal muscle even after standardized rest. The present study was performed in order to find out if there is a difference in the binding of digoxin to slow- and fast-twitch fibres in man at rest and after moderate exercise. Seven healthy digitalized subjects (digoxin 0.50 mg/day) were investigated after 90 min of supine rest and after a 1 h moderate bicycle exercise. Muscle biopsy specimens were taken immediately before and 5 min after exercise and dissected under a microscope to single fibres. After histochemical typing of all fibres the digoxin content in slow- and fast-twitch fibres was measured separately. At rest, digoxin binding to slow-twitch fibres was 33% higher than to fast-twitch fibres (P less than 0.01). During exercise the digoxin binding increased by 28% in slow-twitch fibres but was unchanged in fast-twitch fibres. The difference in digoxin binding to the two fibre types may explain, at least partly, the interindividual variations in the binding of digoxin to skeletal muscle.     

Beta-blockade and binding of digoxin to skeletal muscle

The effect of beta-blockade and a 1-h bicycle exercise test on the digoxin concentration in skeletal muscle (thigh) and serum was studied in 10 healthy men, who had ingested 0.5 mg digoxin daily for 2 weeks. Each subject performed two exercise tests at 100-140 W during maintenance digoxin treatment and 24 h after the latest dose. They rested in the supine position for 2.5 h before the exercise. Sixty minutes before the start of the exercise 0.25 mg/kg b.w. propranolol or saline (control) were injected (single-blind). At the end of the exercise the mean heart rate was 30% lower with beta-blockade (P less than 0.001). During exercise the mean skeletal muscle digoxin concentration increased by 29% (P less than 0.01) in the control situation and by 12% (NS) with beta-blockade. The results indicate that propranolol partly inhibits the exercise-induced increase in skeletal muscle digoxin binding. This might be due to inhibition of a catecholamine-induced stimulation of Na+-K+ATPase during exercise.     

Effect of digoxin on physical performance in healthy man

The effect of digoxin on the maximal oxygen uptake, the heart rate reaction during submaximal and maximal bicycle exercise and the isokinetic skeletal muscle strength in the thigh was investigated in nine well-trained healthy young men. A daily dose of digoxin of 0.50 mg for 2 weeks, giving a steady state serum digoxin concentration of 1.0 +/- 0.2 nmol/l, did not significantly change maximal oxygen uptake or isokinetic muscle strength. However, the heart rate at rest and during exercise, both at submaximal and maximal levels, decreased significantly during digoxin administration.     

The effect of acute exercise on glycogen synthesis rate in obese subjects studied by 13C MRS

In obesity, insulin-stimulated glucose uptake in skeletal muscle is decreased. We investigated whether the stimulatory effect of acute exercise on glucose uptake and subsequent glycogen synthesis was normal. The study was performed on 18 healthy volunteers, 9 obese (BMI?=?32.6?±?1.2?kg/m², mean?±?SEM) and 9 lean (BMI?=?22.0?±?0.9?kg/m²), matched for age and gender. All participants underwent a euglycemic hyperinsulinemic clamp, showing reduced glucose uptake in the obese group (P?=?0.01), during which they performed a short intense local exercise (single-legged toe lifting). Dynamic glucose incorporation into glycogen in the gastrocnemius muscle before and after exercise was assessed by ¹³C magnetic resonance spectroscopy combined with infusion of [1-¹³C]glucose. Blood flow was measured to investigate its potential contribution to glucose uptake. Before exercise, glycogen synthesis rate tended to be lower in obese subjects compared with lean (78?±?14 vs. 132?±?24???mol/kg muscle/min; P?=?0.07). Exercise induced highly significant rises in glycogen synthesis rates in both groups, but the increase in obese subjects was reduced compared with lean (112?±?15 vs. 186?±?27???mol/kg muscle/min; P?=?0.03), although the relative increase was similar (184?±?35 vs. 202?±?51%; P?=?0.78). After exercise, blood flow increased equally in both groups, without a temporal relationship with the rate of glycogen synthesis. In conclusion, this study shows a stimulatory effect of a short bout of acute exercise on insulin-induced glycogen synthesis rate that is reduced in absolute values but similar in percentages in obese subjects. These results suggest a shared pathway between insulin- and exercise-induced glucose uptake and subsequent glycogen synthesis.     

Exercise training prevents hyperinsulinemia, muscular glycogen loss and muscle atrophy induced by dexamethasone treatment

This study investigated whether exercise training could prevent the negative side effects of dexamethasone. Rats underwent a training period and were either submitted to a running protocol (60% physical capacity, 5 days/week for 8 weeks) or kept sedentary. After this training period, the animals underwent dexamethasone treatment (1 mg/kg per day, i.p., 10 days). Glycemia, insulinemia, muscular weight and muscular glycogen were measured from blood and skeletal muscle. Vascular endothelial growth factor (VEGF) protein was analyzed in skeletal muscles. Dexamethasone treatment evoked body weight loss (?24%), followed by muscular atrophy in the tibialis anterior (?25%) and the extensor digitorum longus (EDL, ?15%). Dexamethasone also increased serum insulin levels by 5.7-fold and glucose levels by 2.5-fold compared to control. The exercise protocol prevented atrophy of the EDL and insulin resistance. Also, dexamethasone-treated rats showed decreased muscular glycogen (?41%), which was further attenuated by the exercise protocol. The VEGF protein expression decreased in the skeletal muscles of dexamethasone-treated rats and was unaltered by the exercise protocol. These data suggest that exercise attenuates hyperglycemia and may also prevent insulin resistance, muscular glycogen loss and muscular atrophy, thus suggesting that exercise may have some benefits during glucocorticoid treatment.     

Mechanism of impaired capacity for prolonged muscular work following beta-adrenergic blockade in dogs

Summary Effect of glucose infusion on running ability was studied in dogs after beta-adrenergic blockade. Dogs pretreated with Inderal performed treadmill exercise of moderate intensity until exhaustion. The amount of work performed until exhaustion was 47.7% smaller than in control experiments without blockade. During exercise a significant decrease was found in plasma FFA, blood glucose and muscle glycogen concentration. In order to explain whether the impairment of working capacity is related to hypoglycaemia and a subsequent reduction of glucose supply to the central nervous system, intracarotid glucose infusion at a rate of 70 mg/min was given at the point of exhaustion. This infusion did not restore the working ability. The intravenous glucose infusion at a rate 45 mg/kg per min enabled the previously exhausted dogs to continue the run within 5–7 min. Subsequently they were able to run with glucose infusion at a rate 20 mg/kg per min for a long period of time until they became again exhausted.It was concluded that the impairment of working capacity is directly related to a deficiency of energy substrates available for working muscles. Although the drop in blood glucose level could be a factor forcing the dogs to stop running, the increase of glucose supply to the brain only did not restore the running ability.     

Muscle glycogen and glucose uptake during exercise in humans.

Six men were studied during 40 min of cycling exercise to examine the relationship between leg glucose uptake and muscle glycogen concentration. Exercise resulted in significant increases in leg glucose uptake, while muscle glycogen and arterial blood glucose concentrations declined. Arterial plasma insulin levels did not change significantly. There was a significant inverse relationship between muscle glycogen concentration and glucose uptake during exercise which suggests a possible regulatory influence of muscle glycogen on glucose uptake in the early stages of exercise in humans.     

Resistance training and insulin action in humans: effects of de-training

Aerobic endurance training increases insulin action in skeletal muscle, but the effect of resistance training has not been well described. Controversy exists about whether the effect of resistance training is merely due to an increase in muscle mass. We studied the effect of cessation of resistance training in young, healthy subjects by taking muscle biopsies and measuring insulin-mediated whole body and leg glucose uptake rates after 90 days of heavy resistance training (T) and again after 90 days of de-training (dT). Data on leg glucose uptake were expressed relative to accurate measures of leg muscle mass by MRI scanning. Muscle strength (239 ± 43 vs. 208 ± 33 N m), quadriceps area (8463 ± 453 vs. 7763 ± 329 mm²) and glycogen content (458 ± 22 vs. 400 ± 26 mmol (kg dry weight muscle)⁻¹) decreased, while myosin heavy chain isoform IIX increased 4-fold in dT vs. T, respectively (all P < 0.05). GLUT4 mRNA levels and enzyme activities and mRNA levels of glycolytic, lipolytic and glyconeogenic enzymes did not change with de-training. Likewise, capillary density did not change. Whole body glucose uptake decreased 11 % and leg glucose uptake decreased from 75 ± 11 (T) to 50 ± 6 (dT) nmol min⁻¹ (mm muscle)⁻² ( P < 0.05) at maximal insulin, the latter decrease being due to decreased arterio-femoral venous glucose extraction. The decrease was mainly due to reduced non-oxidative glucose disposal. We have thus shown that 90 days after the termination of heavy resistance training, insulin-mediated glucose uptake rates per unit of skeletal muscle have decreased significantly.     

Acute paraquat exposure determines dose‐dependent oxidative injury of multiple organs and metabolic dysfunction in rats: impact on exercise tolerance

This study investigated the pathological morphofunctional adaptations related to the imbalance of exercise tolerance triggered by paraquat (PQ) exposure in rats. The rats were randomized into four groups with eight animals each: (a) SAL (control): 0.5 ml of 0.9% NaCl solution; (b) PQ10: PQ 10 mg/kg; (c) PQ20: PQ 20 mg/kg; and (d) PQ30: PQ 30 mg/kg. Each group received a single injection of PQ. After 72 hours, the animals were subjected to an incremental aerobic running test until fatigue in order to determine exercise tolerance, blood glucose and lactate levels. After the next 24 h, lung, liver and skeletal muscle were collected for biometric, biochemical and morphological analyses. The animals exposed to PQ exhibited a significant anticipation of anaerobic metabolism during the incremental aerobic running test, a reduction in exercise tolerance and blood glucose levels as well as increased blood lactate levels during exercise compared to control animals. PQ exposure increased serum transaminase levels and reduced the glycogen contents in liver tissue and skeletal muscles. In the lung, the liver and the skeletal muscle, PQ exposure also increased the contents of malondialdehyde, protein carbonyl, 8‐hydroxy‐2′‐deoxyguanosine, superoxide dismutase and catalase, as well as a structural remodelling compared to the control group. All these changes were dose‐dependent. Reduced exercise tolerance after PQ exposure was potentially influenced by pathological remodelling of multiple organs, in which glycogen depletion in the liver and skeletal muscle and the imbalance of glucose metabolism coexist with the induction of lipid, protein and DNA oxidation, a destructive process not counteracted by the upregulation of endogenous antioxidant enzymes.     

Exercise training-induced improvements in insulin action

Individuals with insulin resistance are characterized by impaired insulin action on whole-body glucose uptake, in part due to impaired insulin-stimulated glucose uptake into skeletal muscle. A single bout of exercise increases skeletal muscle glucose uptake via an insulin-independent mechanism that bypasses the typical insulin signalling defects associated with these conditions. However, this 'insulin sensitizing' effect is short-lived and disappears after approximately 48 h. In contrast, repeated physical activity (i.e. exercise training) results in a persistent increase in insulin action in skeletal muscle from obese and insulin-resistant individuals. The molecular mechanism(s) for the enhanced glucose uptake with exercise training have been attributed to the increased expression and/or activity of key signalling proteins involved in the regulation of glucose uptake and metabolism in skeletal muscle. Evidence now suggests that the improvements in insulin sensitivity associated with exercise training are also related to changes in the expression and/or activity of proteins involved in insulin signal transduction in skeletal muscle such as the AMP-activated protein kinase (AMPK) and the protein kinase B (Akt) substrate AS160. In addition, increased lipid oxidation and/or turnover is likely to be another mechanism by which exercise improves insulin sensitivity: exercise training results in an increase in the oxidative capacity of skeletal muscle by up-regulating lipid oxidation and the expression of proteins involved in mitochondrial biogenesis. Determination of the underlying biological mechanisms that result from exercise training is essential in order to define the precise variations in physical activity that result in the most desired effects on targeted risk factors, and to aid in the development of such interventions.     

Effect of adrenaline on exchange of glucose in leg tissues and splanchnic area. A comparison with the metabolic response to surgical stress

Surgical trauma is accompanied by increased energy expenditure and raised arterial concentrations of adrenaline and glucose. In order to study the acute effects of an adrenaline infusion on glucose metabolism and oxygen uptake in the leg and splanchnic bed, adrenaline was administered at a rate giving plasma concentrations of adrenaline similar to those in connection with abdominal surgery. Seven healthy males participated in the study. Adrenaline 40 ng/(min X kg body weight) (0.22 nmol/(min X kg body weight] was infused producing a plasma concentration of 2.77 +/- 0.42 nmol/l (mean +/- SEM). Leg and splanchnic blood flows and the femoral and hepatic arterio-venous differences for oxygen, glucose, lactate and other metabolites were determined. Measurements were made before and between 30 and 40 min after the start of the adrenaline infusion. Following the infusion of adrenaline the leg blood flow increased by 140% and hepatic blood flow by 25%. The leg oxygen uptake increased by 30%, but no significant increase in splanchnic oxygen uptake was observed. The arterial glucose concentration rose by 35%. Splanchnic glucose output increased X 2.5, but no significant increase in leg glucose uptake was observed. Leg release of gluconeogenic substrates increased but only lactate and glycerol uptake increased in the splanchnic bed. Leg blood flow increased more than that usually seen after surgery, whereas leg oxygen uptake and splanchnic oxygen uptake was higher in the immediate postoperative period. Splanchnic glucose release increased more during the infusion than in connection with surgery. It is concluded that adrenaline at a plasma concentration similar to that during and immediately after surgery can induce changes in glucose metabolism which are of the same order or more pronounced than those seen in connection with abdominal surgery.     

Effect of hypoxia on glucose metabolism in human skeletal muscle during exercise

The effect of respiratory hypoxia on muscle glucose metabolism during short-term dynamic exercise has been investigated. Eight men cycled for 5 min at 120 +/- 6 W (mean +/- SE), which corresponded to 50% of maximal O2 uptake during normoxia (N), breathing air (N) on one occasion and 11% O2 (hypoxia-H) on the other. Biopsies were taken from the quadriceps femoris muscle before and after exercise. Oxygen uptake during exercise was not affected by H. The arterial blood glucose concentration during N exercise remained constant, but increased from 4.62 +/- 0.11 mmol l(-1) at rest to 5.22 +/- 0.19 mmol l-1 at the end of H exercise (P less than 0.05 vs N exercise). The intracellular glucose content at rest was low and did not change during N exercise, but was four times higher after exercise during H vs N (P less than 0.01). Glucose 6-P increased under both conditions but significantly more during H (P less than 0.01), while glucose 1,6-P2 was not significantly different between treatments either at rest or after exercise. It is concluded that: (1) glucose uptake by skeletal muscle during short-term exercise. It is concluded that: (1) glucose uptake by skeletal muscle during short-term exercise during H is not associated with a stoichiometric glucose utilization; (2) the inhibition of hexokinase during H (evidenced by increase in muscle glucose) is due primarily to the increase in glucose 6-P; and (3) glucose 1,6-P2 is of minor importance for the regulation of contraction-mediated flux through hexokinase in human skeletal muscle.     

Effect of exercise training on plasma high-density lipoprotein cholesterol level at constant weight

Previous investigations have demonstrated an increase of plasma high-density lipoprotein cholesterol (HDL-Chol) and a decrease in the ratio of low density lipoprotein (LDL)-Chol/HDL-Chol (Atherogenic Index; AI) as a result of exercise training. The question of whether elevation of HDL-Chol was a consequence of weight reduction or physical training itself was unsolved. The present study was designed to prevent the weight reduction that is associated with exercise training. Five healthy and mildly active male volunteers, aged 28-31 years, participated in a 4-week training programme. They ran on a treadmill at 140-160 m/min at 0% grade for 50 min, 5 times a week, equivalent to an energy expenditure of 9 kcal/kg body weight/day. Subjects maintained their body weights by increasing calorie intake to match increased energy expenditure. No changes were observed in mean body weight, skinfold thickness, basal metabolism, and maximal oxygen uptake after the training programme. The HDL-Chol level increased from 54 to 73 mg/dl (P less than 0.05), and the reduction of AI was 30.8% (P less than 0.05) in response to the exercise training. However, the exercise training did not induce changes in plasma total cholesterol and triglyceride (TG) levels. The results of this experiment suggested that moderate physical training itself can be a potent factor for the regulation of HDL-Chol level and improvement of the AI in the absence of alterations in body weight.     

抗阻练习模型大鼠骨骼肌中胰岛素生长因子1和肌肉生长抑制素的变化

背景：抗阻练习对人体骨骼肌系统和代谢的良性作用大部分都与其引起的肌肉肥大相关。但抗阻训练对骨骼肌中肌肉生长调节的正向调节因子和负向调节因子的影响尚不十分清楚。 目的：采用大鼠负重爬梯抗阻练习模型,探讨抗阻练习对大鼠骨骼肌局部胰岛素生长因子1和肌肉生长抑制素的影响。 方法：SD大鼠随机分成实验组和对照组。采用负重爬梯的抗阻练习模型,每周训练3次,负重从体质量的30%逐渐增加到200%。训练10周后取左侧腓肠肌,用免疫组织化学法和RT-PCR法分别测定肌肉中胰岛素生长因子1多肽含量和肌肉生长抑制素的表达。 结果与结论：10周抗阻练习后,实验组大鼠腓肠肌中胰岛素生长因子1多肽含量明显增加,肌肉生长抑制素 mRNA的表达显著下降。大鼠骨骼肌中的胰岛素生长因子1和肌肉生长抑制素都对抗阻练习非常敏感,在肌肉对抗阻练习的适应过程中分别起到正向和负向调节作用。     

Improved glucose tolerance after intensive life style intervention occurs without changes in muscle ceramide or triacylglycerol in morbidly obese subjects

Aim: This study investigated the effect of a 15‐week life style intervention (hypocaloric diet and regular exercise) on glucose tolerance, skeletal muscle lipids and muscle metabolic adaptations in 14 female and 9 male morbidly obese subjects (age: 32.5 ± 2.3 years, body mass index: 46.1 ± 1.9 kg m^?2). Method: Before and after the life style intervention, an oral glucose tolerance test was performed and a muscle biopsy was obtained in the fasted state. Maximal oxygen uptake was measured by an indirect test. Results: After the intervention, body weight was decreased (P < 0.05) by 11 ± 1%, maximal oxygen uptake increased (P < 0.05) by 18 ± 5% and glucose tolerance increased (P < 0.05) by 12 ± 3%. Muscle glycogen was significantly increased by 47 ± 14%, but muscle ceramide and triacylglycerol content remained completely unchanged. No sex difference was observed for any of these parameters, but during submaximal exercise a marked decrease (P < 0.05) of 15 ± 2% in respiratory exchange ratio was seen only in females indicating an enhanced fat oxidation. Conclusion: Despite a marked weight loss and an improved aerobic capacity muscle ceramide and triacylglycerol remained unchanged after intensive life style intervention, and muscle lipids hence do not seem to play a major role for the improved glucose tolerance in these morbidly obese subjects. Interestingly, only the females improved fat oxidation during submaximal exercise after the intervention implying the presence of a sex‐dependent response to intensive life style adaptation.     

Treadmill exercise training fails to reverse defects in glucose, insulin and muscle GLUT4 content in the db/db mouse model of diabetes

OBJECTIVE: Regular exercise is recommended for the treatment of type 2 diabetes because of the benefits on body weight and glycemic control. The present study was designed to compare the impact of voluntary wheel and forced treadmill running on the metabolic state in the db/db mouse model of type 2 diabetes. Our hypothesis is that voluntary exercise training reduces body weight, blood glucose and insulin levels and restores GLUT4 levels in skeletal muscle, whereas forced exercise training produces a greater effect. STUDY DESIGN: Male diabetic db/db mice were assigned to sedentary (DS), voluntary wheel running (DV), and forced treadmill running (DT) groups for 12 weeks. Nondiabetic heterozygote littermates served as control (CN). RESULTS: Over the 12-week period, DV and DT mice ran a total of 4.24+/-0.18km and 11.8km, respectively. At week 12, fasting plasma glucose was decreased in DV mice compared to DS mice and occurred in the absence weight loss. In DT mice, body weight and fasting plasma glucose were not improved with exercise when compared to DS mice and were actually higher compared to DV mice. After training, fasting plasma insulin was increased in DS mice compared to CN mice and training failed to normalize plasma insulin levels. Gastrocnemius GLUT4 content was reduced in DS mice compared to CN mice and training had no effect in preventing this depression from occurring. CONCLUSION: The results of this study indicate that while voluntary exercise improved only blood glucose, forced treadmill exercise training failed to restore body weight, blood glucose and insulin, and muscle GLUT4 content.     

Targeting the activin type IIB receptor to improve muscle mass and function in the mdx mouse model of Duchenne muscular dystrophy

The activin receptor type IIB (ActRIIB) is a transmembrane receptor for transforming growth factor-β superfamily members, including myostatin, that are involved in the negative regulation of skeletal muscle mass. We tested the translational hypothesis that blocking ligand binding to ActRIIB for 12 weeks would stimulate skeletal muscle growth and improve muscle function in the mdx mouse. ActRIIB was targeted using a novel inhibitor comprised of the extracellular portion of the ActRIIB fused to the Fc portion of murine IgG (sActRIIB), at concentrations of 1.0 and 10.0 mg/kg(-1) body weight. After 12 weeks of treatment, the 10.0 mg/kg(-1) dose caused a 27% increase in body weight with a concomitant 33% increase in lean muscle mass. Absolute force production of the extensor digitorum longus muscle ex vivo was higher in mice after treatment with either dose of sActRIIB, and the specific force was significantly higher after the lower dose (1.0 mg/kg(-1)), indicating functional improvement in the muscle. Circulating creatine kinase levels were significantly lower in mice treated with sActRIIB, compared with control mice. These data show that targeting the ActRIIB improves skeletal muscle mass and functional strength in the mdx mouse model of DMD, providing a therapeutic rationale for use of this molecule in treating skeletal myopathies.     

Effects of hyperinsulinemia on lactose secretion and glucose uptake by the goat mammary gland

Hove , K. Effects of hyperinsulinemia on lactose secretion and glucose uptake by the goat mammary gland. Acta physiol. scand. 1978. 104. 422–430. Lactose secretion by goat mammary glands was studied after intra-arterial infusions of insulin and/or glucose causing rises in plasma insulin concentrations in mammary venous blood of about 3–5 mg/ml. Such levels are sufficient to strongly stimulate insulin sensitive processes when present in the systemic circulation. Two goats with mammary glands in situ and two with one of the glands autotransplanted to the neck were used for the experiments. Increasing the insulin concentration in blood to the mammary gland induced a decrease in lactose yields during a 3 h infusion (p < 0.02). Simultaneously arterial plasma glucose decreased by 15–20 mg/100 ml to about 50 mg/100 ml. When the systemic hypoglycemic effect of the insulin infusion was offset by a simultaneous intra-venous infusion of glucose, no significant change in lactose secretion was observed during 8 hours of hyperinsulinemia. No change in mammary glucose uptake as measured by mammary blood flow x mammary arterio-venous glucose differences could be detected. (Average glucose uptake for 2 h before infusion: 30.9 mg/min; during 8 h of infusion: 31.2 mg/min.) It may be concluded that increased levels of insulin in the blood perfusing the mammary gland did not affect mammary glucose uptake or lactose synthesis as long as blood glucose was maintained at normal levels. The results therefore indicate that the glucose turnover in mammary glands, which in high yielding dairy ruminants represents the main organ of glucose utilization in the body, is in fact independant of changes in plasma insulin concentrations.